Mecillinam Comparative bioavailability study - LEO … Declaration of Helsinki ... 1.9 Data capture and transfer ... 2.8 Analytical method validation

This document has been downloaded from \vwv-:.leo-pharma. c-om .subject to the terms of use state on the website. It contains data and results regarding approved and non-approved uses, formulations or treatment regimens, and jt is provided for transparency and informational purposes only. The content does not reflect the complete results from ail studies related to a product. As a document of scientific nature it is not to be seen as a rec.ommendation or advice regardillg the use of any products and you mustt always consult the specific prescribing information approved for the product prior to any prescription or use.

FINAL STUDY REPORT Mecillinam

Comparative bioavailability study

VOLUME 1/4 Body Report Ref. -MET 9802 FR

The clinic a! study report has be en redacted using the follo"'ing principle.s: Wbere nece ssacy, infonna tion is anonymised to protect the privacy of study -subjects and named persons associated with the trial as well as t o retain commercial confidential information. Sununary data are included but data on individual study subjects, including data listings, are rernov e d. Dris rna y result in pagenumber:snot being consecutively numbered. Access to anonymised data onindividualstudysubjectmaybe obtaineduponapprovalofaresearchproposalby the Patient and Scientific Review Board. Appendices to the dinical study report are omitted Further details and principles for anonymisation is a vail able in the document LEO PHAR.I\'1A PRINCIPLES FOR ANONYMISATION OF CUNICAL TRIALDATA

A COMPARATIVE SINGLE DOSE BIOAVAILABILITY STUDY OF MECILLINAM IN

EIGHTEEN HEAL THY MALE VOLUNTEERS FOLLOWING ORAL

ADMINISTRATION OF A NEW 400 MG PIVMECILLINAM TABLET VERSUS ORAL

ADMINISTRATION OF TWO 200 MG PIVMECILLINAM TABLETS

Re. : -Re. : MET 9802 FR

Date of first draft issue: Date of final report issue

The study was undertaken for :

Laboratoires LEO, France

January 261h 1999 November 161h, 1999

6 rue Jean Pierre Timbaud, BP 311 Montigny le Bretonneux

78054 Saint Quentin en Yvelines Cedex, (F)

Author's report:

, MD

MECILLINAM

REPORT APPROVAL

- I MET 9802 FR STUDY REPORT

Page 3 of 49

We, the undersigned, certify that this study was performed accordingly to the agreed protocol, and that this report describes accurately the results obtained. This study was conducted, unless specified, according to the-and- Standard Operating Procedures, and in compliance with the Good Laboratory Practice regulations :

PhD Scientific Affairs --

PhD unoanalysis Department--

D , Pharmacokinetics - -

22. ;\A. g3 Date

.A 1-{,-t/1 )'tj Date

Date

22. l! . q~ Date

MECILLINAM - I MET 9802 FR

STATEMENT OF THE QUALITY ASSURANCE

STUDY REPORT Page 4 of 49

The Quality Assurance Unit at IIIII certifies that the study was undertaken in conformity with the study protocol, the French regulations (law dated December 20, 1988 (no 88-1138) modified by law no 90-86, dated January 23, 1990 and law n 94-630 dated July 25, 1994), the Good Clinical Practices of the European convention and the F.D.A. and in agreement with the de-claration of Helsinki amended in Hong-Kong (1989).

Within the framework of the Quality Assurance system in place at- the standard operating procedures relative to the organisation, realisation, data collection, documents management and clinical studies verification ensure the ethical, scientific and technical quality of the trials. Control actions were taken at each step of the process in order to guarantee that the data collected is precise, complete and accurate. All- personnel takes part in the quality control.

,A_~- iA. ~~-Date

Quality Assurance Unit--

The Quality Assurance Unit (Q.A.U.) of-confirms that the present report reflects accurately and completely the raw data of the study.

TYPE OF INSPECTION DATE OF INSPECTION DATE OF REPORTING

Study inspection 15/09/1998

Data audit 03/12 to 04/12/1998 04/12/1998

Report audit 03/02/1999 03/02/1999

Date of the study inspection report ... .. .. .......... ... .. .............................. ..... .. .. .. ..... ... 16/11 /1999

t 5/11J j --' Date


TABLE OF CONTENTS


GLOSSARY ................................................................ ................................... .. .................... 10

STUDY SYNOPSIS ............................................................................................................. 11

INTRODUCTION ................................................................................................................. 16

STUDY OBJECTIVES ......................................................................................................... 17

1 INVESTIGATIONAL PLAN ............................................................................................... 18

1.1 Study design ........................................................................................................... ..... 18 1.1.1 Overview ... ............ ..... .. .. .. .. .. .. .. ............................ .. .. .. .. ......... .. .. ................ .. .. .. ... 18 1.1.2 Protocol amendements .. .. .. .. .. .. ...... ...................... .. .. ............. ....... ...................... 18

1.2 Ethics ....................................................................................................................... ..... 18 1.2.1 Ethics committee ........... ... ........ .... .... .. ... .. .. .. ... .... ...... .. .. .. .. .. .. .. ............. .. ... ... .. ..... 18 1.2.2 Declaration of Helsinki ............................ .... .......... ....... ........ ....... .. ................ ..... 18 1.2.3 Subject information .. .. .. ........... .... ... ... .. .. .. .. .. ...... ... .. .................. ... ... ... .. .. .... .. .. .. ... 18

1.3 Study population .......................................................................................................... 19 1.3.1 Inclusion criteria .. ....... .. .................... ......... .. .. .... ... ...... .... ................... .. .. .. .. .. .. ..... 19 1.3.2 Exclusion criteria ................... .. .................... .. .. .. .. ....... .. .. .. .. ......................... .. ... .. 19 1.3.3 Discontinuation (withdrawals from study) ............ .. .... .. .. ... .. .. .. .. ......... .......... .. ..... 20 1.3.4 Sample size- number of subjects .. ..... .. .... .... .. .. .. .. ............................ .. .. .. .. .... ... .. 20

1.4 Treatments ...... ............................................................................................................. 20 1.4.1 Dosage regimen ................. .. ... ... ... .. .. .. .. .. .. ... ... .. ....... ....... ........ .. ........ .... .. .. .. .. ..... 20 1.4.2 Drug administration .......... .. .. .. ... ...... .. ...... .. ... ... .. ... .. .. .... .. .... ..... .. ..... ... .... .. .. .. .. ..... 20 1.4.3 Diet ....... .. .. ..... ... ................. .. ............. .. ............... .. .. ...... .. ................... ................. 21 1.4.4 Randomisation ... .. ........ ... ..... .. ....................... .. ....... .. .. .. ... .............. .... .......... ....... 21 1.4.5 Drug blinding ............ .. .. .. ................... .. .. ....... .. .. .... .. .... ... .. ........... ... .......... .. .. ..... .. 21 1.4.6 Concomitant therapy .. .. .. .. ....... .... ......................... .. .... .. ...... .. ... .. .... .... .......... ....... 22 1.4. 7 Treatment compliance .. .. .. ...... .......... .. .. .. ..... .. .. .... .. .. .. .. .. .. .. ..... .. ........ .. .... .. .. ....... 22

1.5 Safety criteria ............................................................................... ................. ............... 22

1.6 Clinical and laboratory tests ....................................................................................... 22

1.7 Pharmacokinetic procedure ........................................................................................ 23 1. 7.1 Pharmacokinetic sampling ... .. .. .. ... ........ .. .. .... .... .. .. ........... ................. .. ........... .... 23 1.7.2 Samples shipment ..... .. .. .. .. .. .. .. .. ........... .. .. .. ........ ............. .. ........ .. .. ... .... .. ........... 24 1.7.3 Analytical procedure ............... .. .......... .. .. .. .. .. .. .. .. ... .. .. .. .. ... ........... .. ... .. .. .. .. ......... 24 1.7.4 Pharmacokinetic analysis .................... .. ...... ................. .. .. ........ .. ..... .. .......... .. .. ... 25

1.8 Statistical analysis ............................................................... .... .. .. ................................. 26

1.9 Data capture and transfer .................... .......... ................... .......................................... 27

!

I

l

MECILLINAM - I MET 9802 FR STUDY REPORT

Page 6 of 49

1.1 0 Data presentation ...................................................................................................... 27

2. RESULTS ......... .......... ............................................................................................ ......... 28

2.1 Study subjects ............................................................................................................. 28

2.2 Study deviations .......................................................................................................... 28

2.3 Demographic data and baseline characteristics ........ .... .................... ....................... 28

2.4 Clinical evaluation at inclusion and follow up visit .................................................... 28 2.4.1 Clinical screening ......................... ... .............. ................... .. .. .. .. .. .. .. ...... .. .... ............. 28 2.4.2 Vital signs ..................... .. .. ................. .. .............. ........ .. .. ..................... .. .. .... ... .......... 29 2.4.3 Electrocardiograms ......................................... .. ......... ...... .. ...... .. ............ .. .. ....... ...... 29 2.4.4 Laboratory test .............. ... ... ..... .. .. .. ... .. .......................................................... .. ..... .. . 29

2.5 Clinical tolerability evaluation during the study ............................................ ............ 30

2.6 Study completion tolerability evaluation .................................................................... 30 2.6.1 Clinical examination ... .. ..... .. ....... .. .................... .. ............................................ .. ....... 30 2.6.2 Vital signs .. ..... .. .. .......... ........................................................................................... 30 2.6.3 Electrocardiograms .. .. .. .. ................. .. .. .................. .......... ............. .. ......................... 30 2.6.4 Laboratory test ... .... ...... ................... .. .............. .. .... ........ .. ... .. .......................... ..... .... 30

2.7 Samples accountability ............................................................................................... 31

2.8 Analytical method validation ....................................................................................... 31

2.9 Plasma concentrations in study samples .................................................................. 31

2.1 0 Pharmacokinetic parameters ....................................................... ............................. 32

DISCUSSION ...................................................................................... ................................. 33

CONCLUSION ..................................................................................................................... 33

ARCHIVING OF DATA ........................................................................................................ 34

REFERENCES ................................................................................... .... ...... ....................... 35


Page 7 of 49

TABLES ...... .. .. .. ... .. .. .. .. .. .. ........................ ..... .. .. .. .. .. ...... .. ... .... ... ...... ....... .......................... ... 37

Table 1 :Age, weight, height of subjects and administered treatment.. ................... ... ... 38

Table 2 : Plasma concentrations of mecillinam (1Jg.mr1) measured in samples collected after single oral administration of 400 mg pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet (treatment A, test tablet) ............ .. .......... 39

Table 3 : Plasma concentrations of mecillinam (1Jg.mr1) measured in samples collected after single oral administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg/tablet (treatment B, reference tablet) ................... .. .. 40

Table 4 : Urine concentrations of mecillinam (IJg/ml) measured in samples collected after single oral administration of 400 mg pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet (treatment A, test tablet) ........................................... ... 41

Table 5 : Urine concentrations of mecillinam (IJg/ml) measured in samples collected after single oral administration of 400 mg pivmecillinam as two tablets of Selexi~ dosed at 200 mg/tablet (treatment B, reference tablet) ..................................... 42

Table 6 : Urinary volume (ml) collected after single oral administration of 400 mg pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet (treatment A, test tablet) ...................... ... .. ...... .. .. .. .. .. .. ... .. .. ........ .................. ......... .......... .... 43

Table 7 : Urinary volume (ml) collected after single oral administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg/tablet (treatment B, reference tablet) ... ........................................ ... .. .. .. ... .. .................. ......... ... ....... .. 44

Table 8 :Amount of mecillinam (mg) excreted in urines after single oral administration of 400 mg pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet (treatment A, test tablet) .. .............. ............... .... .. ... .......................................... .. 45

Table 9 : Amount of mecillinam (mg) excreted in urines after single oral administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg/tablet (treatment B, reference tablet) ............... ......... ... ....... ............. .... ... .............. ...... 46

Table 10 : Pharmacokinetic parameters of mecillinam calculated after single oral administration of 400 mg pivmecillinam as one pivmecillinam tablet dosed at 400 mg per tablet (treatment A, test tablet) .................................................... .. ...... .. 47

Table 11 : Pharmacokinetic parameters of mecillinam calculated after single oral administration of 400 mg pivmecillinam as two Selexid tablets dosed at 200 mg per tablet (treatment B, reference tablet) .............. .. ... ... .... .. ........... .. ...... .. .. ........ 47


Page 8 of 49

FIGURES .. .. ... ..... .. .. .. .. ... ... ................. ... .. .... .... ......................... .... .. ........................... ...... ..... 48

Figure 1

Figure 2

Figure 3

: Mean (+ S.D.) plasma concentrations of mecillinam obtained after administration of the two treatments .................... .......................... ............. ....... 49

: Individual plasma concentrations of mecillinam after single oral administration of one tablet of pivmecillinam dosed at 400 mg pivmecillinam/tablet (treatment A, test tablet) .................. ............................................. .. ... ...................... ........... 49

: Individual plasma concentrations of mecillinam after single oral administration of two tablets of Selexid dosed at 200 mg pivmecillinam/tablet (treatment B, reference tablet) .. .. .. .. ....... ........ .. .............. ....... .. ............................... .. .. ........ ... .. 50

Figure 4: Mean (+S.D) cumulative amounts of mecillinam excreted in urine after administration of the two treatments ...... .......... .. .. .. .. .. ..................... .................. . 50

MECILLINAM

APPENDIX I

APPENDIX II

APPENDIX Ill

APPENDIX IV

APPENDIXV

- I MET 9802 FR

APPENDICES

PROTOCOL PROTOCOL REVISIONS ETHICS COMMITTEE APPROVAL

ANALYTICS


INDIVIDUAL PLASMA CONCENTRATION PROFILES

STATISTICAL RESULTS

CLINICAL RESULTS

MECILLINAM

Cmax

lmax

Ke

t112

AU Co-t

AU Co . .,

c

F rel

- I MET 9802 FR

GLOSSARY

Maximum plasma concentration

Time to reach the maximum plasma concentration

Terminal rate constant

Terminal half-l ife


1Jg.mr1

h

h-1

h

Area under the concentration-time curve from time zero (predose) to time of the last quantifiable concentration IJg.mr1 .h

: Area under the concentration-time curve from time zero (predose) to infinite time 1Jg.mr1 .h

Plasma concentration 1Jg.mr1

Relative bioavailability

MECILLINAM

STUDY SYNOPSIS

NAME OF COMPANY LEO Pharmaceutical Products

NAME OF FINISHED PRODUCT:

NAME OF ACTIVE INGREDIENT:

- I MET 9802 FR STUDY REPORT Page 11 of 49 INDIVIDUAL STUDY TABLE REFERRING TO PART OF THE DOSSIER:

VOLUME:

MECILLINAM PAGE:

Title of the study: A comparative single dose bioavailability study of mecillinam in eighteen healthy male volunteers following oral administration of a new 400 mg pivmecillinam tablet versus oral administration of two 200 mg pivmecillinam tablets

Protocol-No.: -I MET 9802 FR Date of final report:

Investigators:

Clinical study centre:

Analytical study centre :

Time of clinical part: Time of analytical part: Time of pharmacokinetic part:

Principa! lnvesti~, M.D. Study Director:~ Pharmacokinetic Project Lead~, Ph.D. Director. Scientific Affairs :. ~

1 0/08/98 to 16/09/98 28/08/98 to 28/1 0/98 09/11 /98 to 11/11/98

Clinical phase: I

Objective: The aim of this study was to compare the bioavilability and tolerability of a new 400 mg pivmecillinam tablet with an equivalent dose of the marketed Selexid, pivmecillinam 200 mg after single oral administration in eighteen healthy male volunteers.

Study design: single centre study, randomised open two-way cross-over design.

Subjects (total and for each treatment): Planned for completion 18

Test product: LEO 400 mg tablet

Reference product : Selexid

Enrolled and randomized 21 not eliglible 3 completed as per protocol 18

unit dose: mode/route: regimen:

batch no:

unit dose: mode/route: regimen:

batch no:

400 mg oral one tablet dosed at 400 mg pivmecillinam per tablet 9815001

400 mg oral two tablets dosed at 200 mg pivmecillinam per tablet 9821205

MECILLINAM




- I MET 9802 FR STUDY REPORT Page 12 of 49 INDIVIDUAL STUDY TABLE REFERRING TO PART OF THE DOSSIER:

VOLUME:

MECILLINAM PAGE:

Duration of treatment: Two study periods separated by a one-week interval where no pivmecillinam was taken .

Blood sampling points: Before drug administration (TOh), and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0 and 10.0 hours after each administration. Urinary samples : TO (prior to administration) and during the following intervals [0-2] h, [2-4] h, [4-6] h, (6-12] hand [12-24] hours after each administration.

Analytical Method:

Criteria for evaluation:

Pharmacokinetics: Primary parameters:

HPLC with UV detection (A. = 220 nmj Calibration range : 0.1 to 20.0 ug.mr for plasma

10.0 to 5000 ug.mr1 for urine Quantification limit : 0.1 ug.mr1 in plasma

10.0 ug.mr1 in urine Intra-Assay-variability :

- plasma : 3.40% - urine : 4.33 %

- area under the plasma concentration/time profiles (AUC) for mecillinam extrapolated to infinity, - peak plasma concentration (Cmax).

Secondary parameters:

-time at which peak plasma concentrations are observed (tmax) . - t 112

-Fret

- u (o-t>

Safetv: -adverse event recording. Tolerability - clinical examination, -blood pressure, pulse rate, - biological laboratory data.

Statistical methods: Pharmacokinetics: Anova on log-transformed data for Cmax and AUCs, Wilcoxon signed rank test for tmax and t112, 90 % confidence intervals (bioequivalence range : 0.70 - 1.43 for Cmax and 0.80-1.25 for AUCs)

Tolerability :

Descriptive statistics

MECILLINAM - I MET 9802 FR STUDY REPORT Page 13 of 49 NAME OF COMPANY LEO Pharmaceutical Products



INDIVIDUAL STUDY TABLE REFERRING TO PART OF THE DOSSIER:

VOLUME:

MECILLINAM PAGE:

RESULTS

The mean ( S.D.) pharmacokinetic parameters of mecillinam and the statistical results are summarized in the following table:

MECILLINAM Cmax tmax AU Co-t AU Co- Ae N=18 (1Jg.mr

1) (h) (1Jg.mr1.h) (IJg.mr\h) (mg)

Treatment A (Test) Mean 2.96 1.14 6.27 6.48 73.07 S.D. 0.84 0.33 1.64 1.63 22.30

Treatment B (Ref.) Mean 3.03 1.22 6.50 6.73 69.27 S.D. 0.87 0.26 1.71 1.70 17.71

Statistics NS NS NS NS (ll NS

90% confidence 0.90-1 .06 0.89-1.04 0.89-1 .04 0.91-1 .20 Interval

(ll : Analysis of variance (PROC ANOVA on SAS system) on log-transformed data : Wilcoxon signed rank test (PROC UNIVARIATE on SAS system) on natural data

t112 (h)

1.08 0.24

1.06 0.14

NS

After administration of 400 mg of pivmecillinam, plasma concentrations of mecillinam increased rapidly up to a time varying from 0.50 to 1.50 hours, regardless the administered treatment. The maximal plasma concentrations of mecillinam were found between 1. 911Jg.mr1 and 4. 711J9 .mr 1

for treatment A and 1.69 1Jg.mr1 and 5.34 1Jg.ml"1 for treatment B. Then, plasma concentrations declined mono-exponentially with a mean terminal half-life of 1.08 hours for treatment A and 1.06 hours for treatment B. In this study, a 1 0-hour sampling time schedule was planned which appeared to be consistent with the mean value of half-life of mecillinam (about 1 hour) since the mean percentages of extrapolated AUC were 3.54 % and 3.61 % for treatment A and B, respectively.


Page 14 of 49





VOLUME:

MECILLINAM PAGE:

The mean plasma concentrations of mecillinam obtained after administration of the two treatments are presented in the following figure :

4.0

3.5

e 3.o c, .: 2.5 c 0

2.0 i ... c 1.5 Cll (,) c 0 1.0 (,)

0.5

0.0 0

Mean (+S.D.) plasma concentration of pivmecillinam after administration of the two treatments

2 3

-+- 400 mg pi\rnecillinam tablet

-D-- Selexid (two 200 mg tablets)

4

time (h)

5 6 7

DISCUSSION

8

No clinically significant abnormalities were found in clinical examination, laboratory tests, ECGs and vital signs.

Only one adverse event (nausea) was reported for one subject (nS. It was of mild intensity and lasted two hours. The relationship of this adverse event to investigational product was not excluded.

The mean maximal plasma concentration of mecillinam obtained after administration of the test formulation was 2.31 % lower than after administration of two tablets of Selexid. The 90% confidence interval (0.90-1.06) was in the limits of the bioequivalence range (0.80-1.25). There was no significant difference for the mean time to reach the maximal plasma concentration (tmax) between the two formulations.

Both AUCs were found slighlty lower for the test formulation (3.54 % and 3.71 %for AUC0.1 and AUC0_ , respectively). These variat ions were not significant. The 90% confidence intervals (0.89-1.04 for both AUC01 and AUCo-) were in the bioequivalence range (0.80-1.25). The relative bioavailability (Fre1) of the 400 mg test tablet versus the two 200 mg Selexid tablets based on AUCo.~ was 0.98 0.17.

MECILLINAM





Page 15 of 49


VOLUME:

MECILLINAM PAGE:

The terminal half-life as well as the MRT (not presented in the previous table) were not significantly different between the two treatments.

The mean amount of mecillinam found in the urines collected during the 24 hours following administration of each treatment (Ae) were similar (73.07 22.30 mg after administration of the test treatment and 69.27 17.71 mg after administration of the reference treatment). These amounts corresponded to about 25 to 27 % of the administered dose. The 90% confidence interval (0.91-1.20) was in the limits of the bioequivalence range (0.80-1 .25)

CONCLUSION

The clinical tolerability of pivmecillinam 400 mg test tablets and 200 mg reference Selexid tablets was good during the course of the study.

Only one mild adverse event was reported for one subject during the entire course of the study.

From the results of this study, it can be concluded that the new 400 mg tablet of pivmecillinam and two tablets of Selexid, dosed at 200 mg pivmecillinam per tablet, were bioequivalent in both terms of rate and extent of absorption.

MECILLINAM

INTRODUCTION


Page 16 of 49

Mecillinam is a f3-lactam antibiotic with a narrow spectrum of activity against most gram-negative bacteria, in particular enterobacteriaceae. The toxicity of mecillinam is low as is the case for most of the other penicillins. The drug is therefore considered as a safe alternative to other against gram-negative bacteria. Since many years mecillinam has been marketed in many countries including France as Selexid Leo tablet.

Mecillinam is effective for the treatment of infections of the urinary tract. The oral form of the drug, the prodrug pivmecillinam, is widely used for both upper and lower urinary tract infections. Pivmecillinam is the pivaloyloxymethylester of mecillinam and lacks antibacterial activity. Unlike mecillinam, it is readily absorbed from the gastro-intestinal tract and hydrolysed simultaneously to mecillinam in the blood and intestinal wall 1 .

After administration of a single oral dose of 200 mg of pivmecillinam, mecillinam exhibits a maximal plasma concentration (Cmax) ranging from 1 to 3 IJg/ml and occuring at a time of 1.0 to 1.5 hour after administration. The Cmax is dose-related and increased from a mean value of 1.8 IJg/ml after a 200 mg single dose administration to a mean value of 7 IJg/ml after a 800 mg single dose oral administration. The terminal half-life of mecillinam is short (about 1 hour) and it is essentially eliminated through the urinary tract as unchanged mecillinam as well as metabolites of the parent drug. Four metabolites of mecillinam have been identified and all of them possess a pharmacological activity 2 .

LEO has developed a new tablet containing 400 mg of pivmecillinam to be equivalent to two tablets of Selexid Leo tablets, 200 mg pivmecillinam. The present report describes the methods and procedures which have been followed in order to evaluate the bioavailability of this new tablet of mecillinam compared to the reference tablet of Selexid Leo tablets, 200 mg pivmecillinam.

i i i I I I

'l

i

I . I ! f

!

I

I ~


STUDY OBJECTIVES

Study aims of the study were as follows :


Evaluation of the tolerability of mecillinam after a single oral administration of one tablet containing 400 mg pivmecillinam and after two tablets each containing 200 mg pivmecillinam,

Evaluation of the bioavailability (based on plasma and urine levels) of mecillinam after single oral administration of . one tablet containing 400 mg pivmecillinam and after two tablets each containing 200 mg pivmecillinam.

Pharmacokinetics of mecillinam were assessed from plasma level versus time profiles and from urine level versus time profiles obtained for each volunteer after treatment. The pharmacokinetic parameters determined were the following :

AUC0-1,

AUC0-oo,

%extrapolated (i.e. ratio [(AUC0-t - AUC0-oo)/ AUC0-oo]),

MRT,

F rel.

MECILLINAM

1 INVESTIGATIONAL PLAN

1.1 Study design

1. 1.1 Overview


Page 18 of 49

The objective was to evaluate the bioavailability and tolerability of the new 400 mg mecillinam tablet and to compare these results with those obtained from a similar dose administered as two Selexid tablets dosed at 200 mgl tablet (reference formulation).

This was an open label study with two periods. At the beginning of each period, subjects received the test or reference products. Subjects were randomly allocated to one of the two selected sequences.

The two treatment administrations were separated by a 7 -day wash-out.

The administered treatments were as follows :

* Treatment A :

* Treatment B :

one pivmecillinam tablet of the test product dosed at 400 mg pivmecillinam I tablet.

two Selexid' tablets dosed at 200 mg pivmecillinam I tablet.

1.1 .2 Protocol amendements

Not applicable.

1.2 Ethics

1.2 .1 Ethics committee

Prior to the start of the study, the protocol was submitted for ethical review and the approval was obtained. The clinical study was conducted by . A copy of the protocol and the ethics committee approval are provided

1.2.2 Declaration of Helsinki

The study was conducted according to the principles of the Declaration of Helsinki and its amendments.

1.2.3 Subject information

Written informed consents were obtained before the subjects entered the study, ie before screening bloods, screening assessments or any other study related activity. A copy of the information sheet explaining the nature, purpose and risks of the study was provided to the subjects. The Subject Information Sheet was reviewed and approved by the Ethics Committee.

MECILLINAM

1.3 Study population

1.3.1 Inclusion criteria


Page 19 of 49

All subjects included in the study belong to the volunteers' panel.

- Eighteen (18) healthy male volunteers, aged between 18 and 40 years, were selected,

- Their weight was within 20 % of the ideal body weight of the scale proposed by the Metropolitan Insurance Company 3 4 ,

They were certified as "normal" by a comprehensive clinical assessment (detailed medical history, complete physical examination, and ECG) and laboratory investigations (haematological and blood chemistry tests, urinalysis), the results of which must be within the normal range and/or clinically acceptable for healthy subjects,

- They smoked less than 10 cigarettes/day (or equivalent),

- They had normal eating habits,

- They were able and willing to give a written informed consent,

- They were registered with French Securite Sociale in agreement with the French law (Huriet Law: no 88.1138- 20.12.88) on biomedical experimentation 5 6.

1.3.2 Exclusion criteria

Exclusion criteria were defined as follows :

- History of major medical/psychiatric illness or surgery which, in the judgment of the investigator, putted the subject "at risk" or was likely to modify handling of the study drug,

- Suffering from any acute or chronic systemic disease or disorder,

- History of hypersensitivity to at least one drug (abnormal drug reaction or idiosyncrasy or asthma),

- Regular use of sedatives, hypnotics, tranquillizers or any other addictive substances,

- Signs, symptoms, and laboratory test values outside the clinically acceptable 'normal range' for healthy subjects,

- History or evidence of acute or chronic alcohol abuse (>45 g of alcohol per day),

Excessive consumption of tea, coffee, chocolate, and/or other beverages containing caffeine (> 5 cups/day or approximately 500 mg of caffeine per day),

Positive HIV or HCV test, and/or a positive HBs test,

Received blood or plasma derivatives in the year preceding the initiation of the study,

Blood donation in the three months preceding the initiation of the study or intention to make blood donation during the study, or within the three months following the

MECILLINAM

study completion,


Page 20 of 49

- Drug treatment (including OTC medication) during the month preceding the study, except paracetamol which was allowed until one week before the administration,

- Drug treatment that could lead to induction of inhibition of hepatic microsomia! enzymes within 3 months of the study start,

- Subject who were within the exclusion period in the Healthy Volunteers National Register of the French Ministry of Health,

- Subject who, in the judgment of the investigator, was likely to be non-compliant or uncooperative during the study,

- Subject who had forfeited his freedom by administrative or legal award or who was under guardianship,

- Subject who was unwilling or unable to give his written informed consent,

- Subject who could not be contacted in case of emergency,

- Subject who had planned a strenuous physical activity during the study.

1.3.3 Discontinuation (withdrawals from study)

Subjects were planned to be withdrawn from the study when:

- their consent was withdrawn

- a severe adverse reaction has occured

- a hypersensitivity or allergic reaction clearly linked to the study drug has occured.

- a systemic illness unrelated to the study drug has occured during the study which has necessitated a concomitant therapy.

1.3.4 Sample size- number of subjects

Eighteen (18) healthy male volunteers were required to complete the study. Subjects who did not complete the study were not included in the pharmacokinetic analysis. The subjects had to satisfy all inclusion and exclusion criteria listed above.

1.4 Treatments

1.4.1 Dosage regimen

Two treatment arms of one single dose oral administration :

* Treatment A :

* Treatment B :

one pivmecillinam tablet of the test product dosed at 400 mg pivmecillinam I tablet.

two Selexid tablets dosed at 200 mg pivmecillinam I tablet.

1.4.2 Drug administration

Tablets were administered following a 10-hour overnight fast. However, the subjects were allowed to drink water during the fasted period.

MECILLINAM - I MET 9802 FR STUDY REPORT Page 21 of 49 Subjects took the medication with 200 ml room temperature mineral water. Subjects were dosed in erect position. A mouth check were performed to verify that the subjects had swallowed the dose.

Batch/serial number of the formulations, description of the formulations, content and analytical documentation are provided with the certificate of analysis (see Appendix 1).

1.4.3 Diet

During the 24 hours preceding the administration period and during the entire study duration, subjects abstained from smoking and drinking alcohol, coffee, tea or beverages containing cola. Smoking was strictly prohibited in the unit.

Prior to each administration, subjects fasted overnight for at least ten hours.

Breakfast was administered 2 hours after each drug administration. Breakfast consisted of two croissants and mineral water. The first meal was well-balanced in carbohydrates, lipids and proteins. It was served 4 hours after each administration. Dinner was served 12 hours after each administration.

Subjects had to eat their meal in thirty minutes.

Subjects were only allowed to drink mineral water. Water supply consisted of 1500 ml for each 24-hour period, as one bottle of mineral water, in order to allow the best normalization of water intake. Water intake was standardised from 1 hour before dosing up to the 4 hour blood sampling as follows : tablets were given with 200 ml of water ; another 200 ml of water were provided after the 2 hour blood sampling.

Each bottle was labeled with the subject's code, and had to be consumed during the 24-hour period. Control of empty bottles was made at the end of each period.

1.4.4 Randomisation

The study consisted of two periods. During each period, subjects received the test or reference products. Subjects were randomly allocated to one of the two possible sequences.

Randomization was done by

Numbers were assigned to subjects in their order of entry in the study, i.e. acceptation of the study conditions by subjects followed by the signature of the informed consent. In case of drop-out before any administration, the replacing subject was allocated the same number. The drop-out subjects received a four figures number: the three last figures consisting of the subject's previous number, the first figure corresponding to the drop-out number (for example subject 10 was allocated number 11 0).

1.4.5 Drug blinding

The study was open for the clinical part, and blind for the analytical part. The codes for treatments were broken by the investigator after all the analytical data were sent to the Sponsor.

MECILLINAM

1.4.6 Concomitant therapy


Page 22 of 49

Paracetamol (up to 2g daily) was the only therapy allowed during the study.

1.4.7 Treatment compliance

Subjects attended IIIII on the evening preceding dose administration of each period. Subjects remained within the lnstitut for 24 hours after drug administration.

Treatment compliance was also ensured by strictly monitoring the drug administration, e.g. dosing of the volunteers was performed in the presence of the co-investigator.

1.5 Safety criteria

Subjects were instructed by the investigator to report immediately the occurrence of any adverse event. An adverse event is defined as an indesirable experience occuring to a subject during the clinical study which could be associated with the use of the tested drug (whether or not considered drug related).

The study events were graded as follows:

mild if no interference with normal activity, acceptable and if it disappeared without residual effect moderate if significant interference with the study and/or the normal daily activities severe if considered as inacceptable by the physician or required treatment or required discontinuation .

Also were recorded serious adverse events which included any experience suggesting a significant hazard.

1.6 Clinical and laboratory tests

In the two weeks prior to the trial start, the subjects had a pre-study examination which included :

a detailed medical history, a medical examination, including blood pressure (supine and standing), pulse rate (supine and standing) after the subject had rested comfortably for five minutes using an automatic sphygmomanometer, respiratory rate, body weight, body height, a 12-lead electrocardiogram using a Hewlett-Packard Pagicardiette II cardiograph, a detailed neurological examination, including cranial and motor nerve functions, reflexes, motor coordination and sensory nerve functions.

Blood samples for the following routine haematological and biochemical testing were taken:

MECILLINAM - MET9802FR STUDY REPORT

Page 23 of 49

Haemoglobin, Red Blood Cell count, MCV, PCV, MCH, White Blood Cell count, Differential white blood cell count, Platelet count, Search for HBs antigen, HCV antibodies and HIV 1 & 2 antibodies. Creatinine, Glucose, Alkaline phosphatase, Alanine aminotransferase (ALAT/SGPT), Aspartate aminotransferase (ASAT/SGOT).

Urinalysis was performed by a standard stick test for glucose, ketones, density, blood, pH, proteins, nitrites, leucocytes. If an abnormal result was observed at screening, a quantitative determination was carried out. The results of urinalysis were included in the CRF.

An urine screen for drug abuse was done for benzodiazepines, opiates, amphetamines, barbiturates, cocaine, THC, prior to each administration.

All quantitative laboratory analysis have been submitted to the official quality control program of the French Ministry of Health (Decree of June 18th, 1979 setting the specifications mentioned on the article 6 of the decree no 78-1148 of December 7th, 1978 relative to the quality control of the clinical chemistry data allowed by the article L. 716- 14 of the Public Health Code, Official Bulletin no 79/27, text no 16887).

Results of the medical examination and ECG recordings are included in the subject's case report form, and were considered as baseline values.

Follow up laboratory tests (haematology, clinical chemistry and urinalysis) were performed about 10 days after the last administration.

1. 7 Pharmacokinetic procedure

1. 7.1 Pharmacokinetic sampling

For all subjetcs, on each period, blood samples have been collected for measurement of mecillinam plasma levels before drug (TOh). Then blood samples have been collected 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0 and 10.0 hours after each administration.

Each blood sample was drawn by direct veinipuncture. Each sample volume was of 10 ml and was collected into two separate polypropylene crista! tubes containing heparine. Samples were centrifuged at 4 oc at 1 000 g for 10 minutes immediately after collection. Plasma was rapidly transferred to two polypropylene tubes stoppered (airtight) and stored at minus 70 degrees Celsius (- 70C} until plasma level determinations of mecillinam were carried out. The total blood volume taken per subject for pharmacokinetic purposes was 260 ml (corresponding to 2 x 13 samples) over a 2-week period.

Urine were collected before any administration, then during the following intervals : [0-2] h, [2-4] h, [6-12] h and [12-24] hours after each administration. Urinary volume and pH were measured for each sample ; two 5 ml aliquotes were stored deep-frozen in polypropylene tubes (-80C} until mecillinam urinary levels determinations were performed.

MECILLINAM

1.7.2 Samples shipment


Page 24 of 49

Study samples have been transferred periodically to - facilities using the - company car using a container filled with enough dry ice. During their shipment, the duration of which was approximately four (4) hours, the study samples were kept at - 70C. Upon arrival at - the study samples have been immediately stored in a freezer at -70C until analysis. The sample reception was performed according to-standard operating procedure.

At the completion of the study, the study samples will be kept deep frozen until the approval of the final report by the sponsor. Then, upon agreement with the sponsor, the study samples will be either transferred to the sponsor facilities, or kept deep frozen for a longer period of time (to be defined) in-freezers, or destroyed at -facilities.

1. 7. 3 Analytical procedure

1.7.3.1 Method of analysis

In outline, the method of analysis involved purification of plasma samples by protein precipitation, and dilution of urine samples, before HPLC analysis, with UV detection.

The calibration range was from 0.100 to 20.0 1Jg.mr1 for plasma analysis (8 calibration standards) and from 10.0 to 5000 1Jg.mr1 for urine analysis (9 calibration standards).

Calibration standards were prepared immediately before use. Details of the method are provided in Appendix II.

1.7.3.2 Method validation

A complete method validation study was carried out prior to the analysis of samples from the clinical study. lntrabatch and interbatch variability and accuracy of the method were determined at the lowest and highest concentrations used in calibration and at two intermediate concentrations. Investigation of other aspects of method performance and checks on the stability were included in validation experiments. Details of validation investigation are reported in Appendix II. Moreover, the second HPLC system used for the assay of study samples was validated by the assay of three series of calibration standards and six samples at the limit of quantification (intrabatch assay).

1.7.3.3 Analysis of the study samples

Before processing the study samples, quality control (QC) samples were prepared at concentrations of 0.400, 5.00 and 18.0 1Jg.mr1 in plasma and 40.0, 500 and 4200 1Jg.mr1 in urine by an analyst independent of the study analyst.

The study samples were assayed as batches. Each batch comprised at least the samples of the 2 treatment periods of one subject. Each batch also comprised calibration standards and 6 QC samples (duplicate samples, at three levels of


Page 25 of 49

concentration). The calibration range was from 0.100 to 20 1Jg.ml"1 in plasma and from 10.0 to 5000 1Jg.ml"1 in urine.

1. 7.4 Pharmacokinetic analysis

The pharmacokinetic analysis was carried out by - Research Centre. The pharmacokinetic parameters were calculated, according to standard methods 7 8 , using the PHARM package (release 1.3) running on a personal computer.

The symbols used for pharmacokinetic parameters were those proposed by M. Rowland and G. Tucker 9 .

The following pharmacokinetic parameters were derived for each subject after each treatment administered :

The maximum plasma concentration (Cmax) and the time taken to reach Cmax (tmax) were obtained directly from the concentration-time data.

* ke and t112:

The terminal rate constant (ke) was estimated by log-linear regression analysis on data points visually assessed to be on the terminal log-linear phase. The time range used for each calculation of ke was from the earliest time point possible, commensurate with a high degree of fit and ended with the last time point at which the concentration could be quantifiable. The numerical test of fit was the correlation coefficient (r) , the value of which had to be equal to or exceed 0.95. In any case, at least three data points were used for fitting the terminal phase.

Also was considered the percentage of extrapolation of AUCo- which should normally not exceed 10%. When the fitting was not acceptable, values of correlation coefficient and/or percentage of extrapolation as close as possible of the target values were retained.

The terminal plasma half-life (t112) was calculated according to the following equation :

* AUCo.t and AUCo- :

0.693

ke

The area under the concentration-time curve from time zero (predose) to time of last quantifiable concentration (AUCo.J was calculated using linear trapezoidal method. The AUC from time zero to infinite time (AUCo-) was calculated as follows :

where C1 is the last quantifiable concentration.

MECILLINAM -I MET 9802 FR * MRT :

The mean residence time was calculated as follows :

AUMCo- J MRT= - - --

AUCo -

MECILLINAM - I MET 9802 FR STUDY REPORT Page 27 of 49 Analysis of Cmax ,AUCs and Uca-t) was carried out by analysis of variance using PROC ANOVA (or PROC GLM) on the logarithmically transformed data. A test of carryover was performed at the 5% level by means of a test of a sequence effect using the between subject error term. The 90% standard confidence interval limits for relative treatment differences were calculated by geometric means based on logarithmic transformation of the intraindividual ratios of Cmax and AUC and have to fall into the bioequivalence range of 0.80-1.25 for AUC and into the wider acceptance range of 0.70-1.43 for Cmax 10.

The analysis of tmax was based on the non-parametric Wilcoxon signed rank test and was carried out using PROC UNIVARIATE.

1.9 Data capture and transfer

The output of the detector is digitized by means of an analog to digital converter connected on a PC. The signal is identified and processed with the Turbochrom 4 software. The concentrations, associated to these measurements, are computed through weighted linear regression. The signals and the concentrations are stored on the HP NetServer disks before archiving. - software allows some calculations to be done from the results (mean, s.d., ... )and to print them on a laserprinter.

Study reports are built up using the word processing software Word (release 5.0) running on a PC. A - software converts the concentrations to the PHARM format and transfers them on the PC (MS/DOS) where PHARM (release 1.3) is resident. These data are then processed throughout the PHARM package for pharmacokinetic data generation.

1.1 0 Data presentation

Tables presented in the report are computer generated. The group mean and individual data are generated from the values held in the data base, and rounded appropriately for inclusion in the report. Subsequently, the calculation of means from individual data presented in the report will occasionnally yield a minor variation in the value.

MECILLINAM

2.RESULTS

2.1 Study subjects

-I MET 9802 FR STUDY REPORT Page 28 of 49

Twenty-one healthy male volunteers were enrolled and performed the screening tests ..

Three subjects were not eligible :

-Subject -Subject -Subject

because he was in his exclusion period uc,.ause of a bilirubin level above normal range (78.6 mmol/1) because of abnormal serology results

Eighteen volunteers completed the study as described in the protocol.

2.2 Study deviations

Blood sampling for mecillinam plasma levels was performed before dosing (HO) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, and 10 hours after each administration. No major relevant time deviations were observed during the study.

Two subjects (no1 and 5) presented minor time deviation for blood sampling (2 minutes delay).

Urine collection was performed before administration, then during the following intervals: [0-2] h, [2-4] h, [4-6] h, [6-12] h, and [12-24] hours after each administration. No major deviations occurred except for subject no1 and 4 who did not have any sample taken during the interval [2-4] hour period 2 (formulation A).

2.3 Demographic data and baseline characteristics

Demographic data and baseline characteristics of the volunteers, who took part in the study, are summarized in Table 1 and in Appendix V.

The mean values( S.D.) of these observed characteristics were :

-Age 26.6 7.3 years (range: 19- 38 years)

- Body weight 73.0 13.9 kg (range: 55.4- 97.8 kg)

-Height 176.3 7.5 (range: 162.0- 190.0 em)

2.4 Clinical evaluation at inclusion and follow up visit

2.4.1 Clinical screening

Each subject underwent a clinical examination at the time of his inclusion into - panel. A clinical history was taken and a complete examination performed at that time. On inclusion into the study, this examination was repeated and confirmed the previous examination.

MECILLINAM -I MET 9802 FR STUDY REPORT Page 29 of 49 The details of this examination are presented in the statistical analysis (appendix V.1, individual data).

No clinically relevant abnormality was observed during this examination.

2.4.2 Vital signs

Individual values of blood pressure and pulse rate were measured supine using an automatic device, after the subject had rested comfortably for five minutes, and standing in the following minute.

All values are presented in appendix V.1 of the statistical analysis.

Four subjects (no I no I no and no .) presented a standing pulse rate above normal range (respectively at 109 bpm, 107 bpm, 101 bpm and 107 bpm), but without any clinical relevance.

No other abnormalities were reported for any subject.

2.4.3 Electrocardiograms

Electrocardiograms were performed using the internationally recognized 12-leads with a Hewlett-Packard Pagicardiette II Cardiograph.

Recordings were included in each subject's case report form and ECG parameters are listed in appendix V.1 of the statistical analysis (individual data).

Three subjects no I nf and no. reported a first degree atrio-ventricular block. Subject no had aPR interval at 225 ms controlled at 191 ms. Subject no had aPR interval at 210 ms. Subject no had a PR interval at 209 ms.

None of these abnormalities was considered as clinically significant.

2.4.4 Laboratory test

The methods used to obtain the biological laboratory data and their normal ranges are described in the protocol.

All measured parameters are submitted to the official quality control programme of the French Ministry of Health (Decree of June 18th, 1979 setting the specifications mentioned in the article 6 of the decree nE 78-1148 dated December 7th, 1978 relative to the quality control of the clinical chemistry data allowed by the article L. 716 - 14 of the Public Health Code, Official Bulletin no 79/27, text no 16887).

The laboratory parameters and urinalysis measured at the time of inclusion of the subjects into the study are presented in the statistical analysis.

Some subjects presented minor biological abnormalities highlighted in individual data listing, without clinical significance, which did not prevent inclusion of these subjects in the study. These values are presented in individual data in appendix V.1 and in the


Page 30 of 49

descriptive statistics in appendix V.2. These subjects were asymptomatic and clinical examinations were normal. None of these abnormalities could be directly related to the study medication. They were all considered as not clinically relevant.

2.5 Clinical tolerability evaluation during the study

The clinical tolerability was good.

One adverse event was reported by subject no who suffered from mild nausea appeared on Day 1 of period 2, 16 minutes after administration of the new pivmecillinam formulation and lasting during two hours. The relationship with the study drug was not excluded.

2.6 Study completion tolerability evaluation

A clinical and biological evaluation was performed between six and ten days after the last administration of the second period.

2.6.1 Clinical examination

Clinical examination was performed six to ten days after the second and last administration. No abnormalities were found.

2.6.2 Vital signs

Four subjects (no I I I and presented not clinically significant out-of-normal range standing pulse rate values (respectively at 108 bpm, 102 bpm, 114 bpm and 102 bpm).


2.6.3 Electrocardiograms

Subjects (nl and nS presented a PR interval of 218 ms and 201 ms respectively (normal range : 120-200 ms). They reported a first degree atrio-ventricular block (already present at screening). These values were considered as not clinically significant.


2.6.4 Laboratory test

Three subjects (no I. and.) reported first high total bilirubin values of 23.9, 46.1 and 32.5 mmoi/L (normal range: 0-22.2) respectively, but controlled at 20.5 mmoi/L for the 2 last values. Subject no. presented high ASAT and ALA T values 111 and 53 IU/L (normal range: 5-50 IU/L) at the end of study evaluation, but controlled at 35 and 28 IU/L. His creatinine kinase was assessed and reached 350 IU/L (normal range: 10-70 IU/L).

Subject no. presented low red blood cells, haemoglobin, and haemotocrit values, and hight M.C.H values (33.3 pg instead of 32) at the end of study evaluation.

MECILLINAM - I MET 9802 FR None of these abnormalities were considered as clinically significant.

2. 7 Samples accountability


Samples from 18 subjects were received at - from August 19th, 1998 to September 31d, 1998.

The number of samples agreed with documentation provided with the samples.

Complete sample sets were received from all subjects except for subjects I and I Treatment A, where urine samples [2-4h] were lacking. Sample identification was based on information written on the tube labels.

2.8 Analytical method validation

The analytical specifications of the method are presented in Appendix II. The analytical procedure was validated in terms of specificity, linearity, recovery, intrabatch and interbatch precision and accuracy, dilution precision and accuracy, stability of the extracts, stability of plasma and urine samples after 3 freeze/thaw cycles, stability of plasma and urine samples at room temperature and at -?ooc prior to the analysis of the study samples. The carry-over of the assay was also validated.

The analytical procedure had a linear response within the calibration range of 0.100 to 20.0 1Jg.ml"1 for plasma and 10.0 to 5000 1Jg.ml"1 for urine. Investigation of intrabatch and interbatch accuracy showed that coefficients of variation were less than approximately 13% in plasma and 9% in urine at all concentrations studied and corresponding mean measured concentrations were less than 13% in plasma and 11% in urine different from theoretical concentrations. Results of method validation experiments are reported in detail in Appendix II.

Before analysing the study samples, it was verified that the linearity (3 calibration lines), precision and accuracy at the limit of quantification (6 replicates) were comparable to those previously established during the validation for plasma analysis.

Within each set of quality control (QC) samples (n=6) analysed with each batch of study samples, at least four QC samples were within 20% of their respective nominal value. Therefore, the accuracy and precision of the analysis of the study samples were judged acceptable. Additionally, the individual QC data were reviewed and showed that the mean recovery was 94.05% of the nominal value with a coefficient of variation of 3.40% in plasma and was 92.35% of the nominal value with a coefficient of variation of 4.33 % in urine.

2.9 Plasma concentrations in study samples

Analyses of study samples were performed from August 28th, 1998, to October 281h, 1998.

The individual plasma concentrations of mecillinam measured prior dosing until 10 hours after single oral administration of 400 mg pivmecillinam, as one 400 mg test tablet or two Selexid tablets, are presented in Tables 2 and 3.


Page 32 of 49

The individual urine concentrations of mecillinam measured prior dosing until 24 hours after administration of each treatment are presented in Tables 4 and 5. The corresponding amounts of mecillinam excreted in urine during the 24 hours following administration of each treatment are presented in Tables 6 and 7. The total amounts of mecillinam excreted in urine during the 24 hours following administration of each treatment are presented in Tables 8 and 9.

In Tables 2, 3, 8 and 9, mean values and standard deviations (S.D.) are also shown.

The comparative linear plot of the mean ( S.D.) mecillinam plasma concentration-time profiles obtained after single oral administration of 400 mg pivmecillinam as one of the two studied treatments are presented in Figure 1. Plasma concentration profiles for individual subjects are presented in Figures 2 and 3 and in Appendix Il l. The comparative linear plot of the mean ( S.D.) cumulative mecillinam urine concentration-time profiles obtained after administration of both treatments are presented in Figure 4.

2.1 0 Pharmacokinetic parameters

The individual pharmacokinetic parameters are presented in Tables 9 and 10. The mean ( S.D.) pharmacokinetic parameters and the statistical results are summarized in the following table:

MECILLINAM Cmax tmax AUCo.t AU Co-N=18 (1Jg.ml"1) (h) (1Jg.mr1.h) (1Jg.mr1.h)

Treatment A (Test) Mean 2.96 1.14 6.27 6.48 S.D. 0.84 0.33 1.64 1.63

Treatment B (Ref.) Mean 3.03 1.22 6.50 6.73 S.D. 0.87 0.26 1.71 1.70

Statistics NS NS NS NS (l l

90% confidence 0.90-1 .06 0.89-1.04 0.89-1.04 interval

: Analysis of variance (PROC ANOVA on SAS system) on log-transformed data

: W ilcoxon signed rank test (PROC UNIVARIATE on SAS system) on natural data

Ae t112 (mg) (h)

73.07 1.08 22.30 0.24

69.27 1.06 17.71 0.14

NS

MECILLINAM

DISCUSSION


Page 33 of 49

No clinically significant abnormalities were found in clinical examination, laboratory tests, ECGs and vital signs.

Only one adverse event (nausea) was reported for one subject (n.). It was of mild intensity and lasted two hours .. The relationship of this adverse event to investigational product was not excluded.

The mean maximal plasma concentration of mecillinam obtained after administration of the test formulation was 2.31 % lower than after administration of two tablets of Selexid. The 90% confidence interval (0.90-1.06) was in the limits of the bioequivalence range (0.80-1 .25). There was no significant difference for the mean time to reach the maximal plasma concentration (tmax) between the two formulations.

Both AUCs were found slighlty lower for the test formulation (3.54% and 3.71 % for AUC01 and AUCo-, respectively). These variations were not significant. The 90% confidence intervals (0.89-1.04 for both AUCa-1 and AUC0 ... ) were in the bioequivalence range (0.80-1.25). The relative bioavailability (Fret) of the 400 mg test tablet versus the two 200 mg Selexid tablets based on AUCo- was 0.98 0.17.

The terminal half-life as well as the MRT (not presented in the previous table) were not significantly different between the two treatments.

The mean amount of mecillinam found in the urines collected during the 24 hours following administration of each treatment (Ae) were similar (73.07 22.30 mg after administration of the test treatment and 69.27 17.71 mg after administration of the reference treatment). These amounts corresponded to about 25 to 27 % of the administered mecillinam dose. The 90% confidence interval (0.91-1 .20) was in the limits of the bioequivalence range (0.80-1.25)

CONCLUSION

The clinical tolerability of pivmecillinam 400 mg test tablets and 200 mg reference Selexid tablets was good during the course of the study.

Only one mild adverse event was reported for one subject during the entire course of the study.

From the results of this study, it can be concluded that the new 400 mg tablet of pivmecillinam and two tablets of Selexid, dosed at 200 mg pivmecillinam per tablet, were bioequivalent in both terms of rate and extent of absorption.

MECILLINAM

ARCHIVING OF DATA


Page 34 of49

Practical and technical information concerning the assay are available in laboratory books no- All the data are recorded as raw and processed data fi les on DA T cartridges using standard Windows Nr' software. They are stored in room no .

All the data and all the relevant documents pertaining to the study are stored in room no. and are available during 15 years following the report and can be consulted at any moment by the sponsor of the study.

Study samples will be stored deep-frozen no longer than one month after the generation of the final report. At this time, it will be discussed with the sponsor whether the study samples will be stored for a longer period, destroyed by -or returned back to the study sponsor.


REFERENCES

1. GODTFREDSEN W.O. An introduction to mecillinam. J. Anticrobial Chemother, 3, 1-4, 1977.

2. GAMBERTOGLIO J.G. and a/. Pharmacokinetics of mecillinam in healthy subjects. Antimicrobial Agents Chemother., 18, 952-956, 1980.

3. KNAPP R.S. A methodological critic of the "ideal weight" concept. J.A.M.A., 1982, 250, 506-511.

4. RUSSEL R.M. and a/. Reference weight. Practical considerations. Am. J. Med. , 1984, 76, 767-769.

5. BONNES PRATIQUES CLINIQUES.


A vis au promoteurs et aux investigateurs pour les essais cliniques des medicaments. Ministere des Affaires Sociales et de I'Emploi. Ministere charge de Ia Sante et de Ia Famille,1987.

6. PROTECTION DES PERSONNES DANS LA RECHERCHE BIOMEDICALE. Tome I- Textes legislatifs, reglementaires et internationaux. Tome II - Guide des textes legislatifs et reglementaires.

Republique Franr;aise. Ministere des Affaires Sociales et de l'lntegration.Loi no 88- 1138 du 20 decembre 1988 (J.O. du 22 decembre 1988) modifiee par Ia loi no 90- 86 du 23 janvier 1990 (J.O. du 25 janvier 1990). Septembre 1990.

7. GIBALDI M, PERRIER D Pharmacokinetics (2nd edition revised and expanded). Drugs and Pharmaceutical Sciences, Ed. Dekker, New York, Volume 15, 1982.

8. ROWLAND M., TOZER T. Clinical Pharmacokinetics - Concepts and Applications (2nd edition). Ed. Lea & Febiger, Philadelphia London, 1989.

9. ROWLAND M., TUCKER G. Symbols in pharmacokinetics. J Pharm Biopharm 8 (15): 497-507, 1980.

10. STEINJANS V.W., HAUSCHKE D. International harmonization of regulatory bioequivalence requirements. Clin. Research and Reg Affairs 10 (4) : 203-220, 1993.


TABLES

STUDY REPORT Page 36 of49

MECILLINAM - I MET 9802 FR STUDY REPORT Page 37 of 49

Table 1 : Age, weight, height of subjects and administered treatment

Subject Code Age Weight Height Randomization (:formulation)

Period 1 Period 2

I - - B A I - - A B I - - A B I .. - B A I - - A B I - - A B I - - B A I - - A B I - - B A - - A B - - A B - - A B - - B A - - B A - - B A - - B A - - A B - - B A Formulation A: one tablet containing 4 00 mg pivmecillinam per tablet Formulation B : TWo tablets of Sel exid containing 200 mg p i vmecillinam per tablet

Time (h) I I

0 . 01 0.51 1.01 1.51 2 . 01 2.51 3.01 4.01 5 . 0 1 6.01 7.01 8.01

10 . 01

I

Table 2: Plasma concentrations of mecillinam (~g.mr1) measured in samples collected after oral administration of 400 mg pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet

(Treatment A, test tablet)

Study :ref: Compound identif: MECILLINAI4

BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ 2.34 2.09 1.28 0.710 1.37 0.820 0.816 1 . 90 1.87 1.88 0 . 621 2.38 2.33 3 . 71 1.59 3.38 1.47 1.54 2.46 2.45 3 . 85 3.23 2 . 98 1 . 98 2.34 3.71 3.21 1.13 3.35 2.24 1.91 2.72 2. 09 3 . 27 4.20 2.49 3 . 04 2.21 3 . 96 2.10 0.755 2.34 1.80 1.30 1.80 1.35 2 . 27 2.64 1 .57 2 . 62 1 .92 2.54 1 . 25 0.500 1.43 1.20 0 . 809 1.11 0.896 1 . 49 1.61 1 .01 1.68 1. 75 1.53

0.841 0.399 0 . 997 0.788 0 . 596 o. 792 0 . 640 0.991 1.07 0.679 1 . 16 1.26 1.01 0.366 0 .244 0 . 641 0 . 375 0.339 0 .400 0 . 356 0 .411 0 . 548 0 . 377 0.510 0.565 0 . 527 0 . 189 0.176 0.349 0.181 0.155 0.199 0.174 0 . 183 0.305 0.200 0.256 0.268 0 . 260 0.103 0.125 0 .189 0 . 105 BLQ BLQ BLQ BLQ 0.194 0 . 101 0.140 0.123 0.123

BLQ 0.102 BLQ BLQ BLQ BLQ BLQ BLQ 0.116 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ

I study ref: Compound identif : IECILLINliM I Time(h) Mean s.o.

I 0.0 1 BLQ BLQ BLQ BLQ 0 0 0 .5 1 2.14 1.39 0 . 965 0.682 1 . 52 0.631 1.01 4. 7l 2 . 16 2.59 1.95 2 .71 0.906 1.51 3.78 1 . 57 2.86 1.91 2.67 0 . 848 2 .01 2 . 31 0 . 978 1.91 1.47 1.85 0.552 2.51 1 .49 0 . 661 1.33 1.01 1.22 0 .355 3 . 01 0 . 935 0 . 463 0.847 0 .712 0 . 830 0.232 4.01 0 . 443 0 . 231 0.410 0.352 0.415 0.108 5.01 0 . 213 0 . 126 0.238 0 . 182 0.215 0.0554 6 .0 1 0. 114 BLQ 0.111 BLQ 0.0863 0 .0675 7.0 1 BLQ BLQ BLQ BLQ 0.0121 0 . 0353 8.01 BLQ BLQ BLQ BLQ 0 0

10.01 BLQ BLQ BLQ BLQ 0 0 I

BLQ Below the limit of quantification (0 . 100 ug.ml-1 )

BLQ 1 . 73 2 . 64 2.20 1 . 63 1.16

0 . 74 4 0.367 0.220 0.125

BLQ BLQ BLQ

~ m ()

r r z )>

~

I ~ m -l

I I Time(h) I

I 0 . 0 1 0.5 1 1.01 1.51 2.01 2.51 3.01 4.01 5.01 6 . 0 1 7 . 0 1 8.01

10 .0 1 I

Table 3 : Plasma concentrations of mecillinam (1Jg.mr1) measured in samples collected after oral administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg/tablet

(Treatment B, reference tablet)

s t udy r ef: Compound identif: MECILLINAM

BLQ BLQ BLQ BLQ BLO BLO BLQ BLQ BLQ BLQ BLQ BLQ BLO 2. 4 9 2.11 0.607 1.08 0 . 934 1 . 33 0 . 929 2 . 66 1 .28 0.824 0 . 630 1 . 96 1.05 3 . 73 2 . 89 2 . 41 2. 4 3 2 . 08 2 . 16 2 . 60 3.68 2 . 95 2 . 10 2.73 3 . 64 2 . 62 3 . 1 6 2 . 61 2 . 59 2.03 2 .28 2 . 35 2.72 3.00 3.26 3 . 01 3 . 89 3.43 3. 70 3 . 03 1.56 2 . 29 1.40 1.42 1 . 73 1 . 95 1 . 70 2.61 2 . 09 2.89 2.38 3 . 20 2 . 10 1.09 1.57 1.02 0.926 1 . 06 1 . 29 01. 00 1. 81 1 . 25 2 . 01 1 . 50 2.14 1 . 33 0 . 742 1.16 0 . 680 0 . 732 0 . 716 0 . 847 0.668 1 . 24 0 . 820 1 . 38 0 . 894 1.38

0.665 0 . 412 0.689 0 . 318 0.375 0.345 0.409 0 . 291 0.632 0 . 423 0.628 0 .465 0 . 668 0 . 321 0.216 0. 4 34 0 .157 0.197 0 . 168 0 . 220 0.145 0.354 0 . 213 0 . 314 0.203 0 . 297 0 . 168 0. 142 0.216 BLQ BLQ BLQ 0 . 130 BLQ 0 . 184 0 . 101 0.168 0 . 124 0 . 161

BLO BLO 0.107 BLQ BLQ BLO BLO BLQ BLQ BLQ BLQ BLQ BLQ BLO BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ

I Study r ef: Compound i dentif: MECILLINAM I Time(h) I Mean S.D.

I 0.0 1 BLO BLQ BLO BLQ 0 0 0.5 1 2.29 1 . 71 1.12 1.22 1 .41 0.635 1 . 01 5.34 2 . 08 2. 42 1.69 2 .79 0 . 859 1 . 51 3 . 86 1. 73 1.57 1. 33 2 . 72 0 . 764 2.01 2. 45 1 . 09 1 . 10 1 .02 1 . 98 0. 679 2.51 1.64 0 . 764 0 . 821 0. 764 1.32 0. 4 63 3 . o I 1 . 13 0 .544 0 . 536 0.636 0.892 0 . 296 4 . 01 0 . 489 0 . 274 0.302 0 . 426 0. 45 3 0. 142 5 . 01 0 . 244 0 . 149 0.165 0 . 240 0.237 0.0788 6 . 01 0 . 137 BLQ BLQ 0 . 127 0.0995 0.0767 7 . 01 BLQ BLQ BLQ BLQ 0 . 00596 0 . 0253 8.01 BLQ BLQ BLQ BLQ 0 0

10 . 01 BLQ BLQ BLQ BLQ 0 0 I

BLQ : Below the limit of quantification (0.1 00 ug.ml-1)

BLQ 1.20 2.74 2.42 1 . 69

0 . 987 0.61 6 0 . 344 0 . 236 0 . 132

BLQ BLQ BLQ

s:: m 0 r r z )>

s::

I s:: ~

Table 4 : Urine concentrations of mecillinam (1Jg.ml"1) measured in samples collected after single oral administration of 400 pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet (treatment A, test tablet)

:- I Study ref . Compound identi . MECILLINAM I I I

Subjects I I Time I I Interval I I

I I I I

DOl I I OOh-OOh I BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLO BLQ BLQ BLQ BLQI 00h-02h I 707 179 161 528 BLQ 168 277 438 152 560 674 695 I 02h-04h I NS 105 993 NS 569 667 94.6 346 307 414 54.8 11301 04h-06h I 101 BLQ 220 299 140 112 18.3 30 . 1 67 . 5 56.7 BLQ 124 I 06h-12h I BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLO BLQ BLQ BLQ BLOI 12h-24h I BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ I

I I

Study ref . :- Compou.nd identif. MECILLINAM Subjects Time I I I .ntervall I

I I I I

DOl I I OOh-OOh I BLO BLQ BLQ BLQ BLQ BLQI 00h-02h I 810 497 173 369 348 315 I 02h-04h I 431 476 102 315 252 137 I 04h-06h I 79 .7 38.0 44.3 38.9 41.7 17.21 06h-12h I BLQ BLQ BLO BLQ BLQ BLQI 12h-24h I BLQ BLQ BLO BLQ BLQ BLQI

I I

NS : No sample BLQ : Balow tho l~t of ~Gntification (10. 0 ug .ml-1)

s:: m ()

r r z )> s::

I s:: m -1

Table 5 : Urine concentrations of mecillinam (1Jg.ml"1) measured in samples collected after single oral administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg/tablet (treatment B, reference tablet)

Study re.f . :- Compound identif. MECILLINAM I

Subjects I Time I I Interval I I

I I I I

DOl I I OOb-OOb I BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQI 00b-02b I 1070 354 396 144 217 37? 395 34. 4 734 172 233 909 I 02b-04h I 772 112 297 552 224 355 320 231 514 144 224 658 I 04b-06h I 91.3 23 . 3 74 . 9 118 54.3 20 . 3 68.4 102 113 33.3 39 . 7 14.2 1 06h-12b I BLQ BLQ BLQ BLQ BLO BLQ BLQ BLQ BLQ BLQ BLQ BLQI 12h-24h I BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQI

I I

Study re.f. :- Compound identif. MECILLINAM Subjects I Time I I Interval I I

I I I I

DOl I I OOh- OOh I BLO BLQ BLO BLQ BLO BLQI 00b-02h I 447 217 800 412 368 133 I 02h-04h I 1010 245 4 1 9 34 6 209 60.71 04h- 06h I 64 . 6 30.6 2 4. 3 85.2 60 . 0 12 . 71 06h-12h I BLQ BLQ BLO BLQ BLQ BLOI 12h-24h I BLQ BLQ BLO BLQ BLO BLOI

I I

BLQ : Belo~ the limit of quantification (10.0 ug.ml-1)

~ m 0 r r z )>

~

I ...... ~ m ~

Table 6: Urinary volumes {ml) collected after single oral administration of 400 mg pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet (treatment A, test tablet)

Subjects I Time I Intrval.l

I I

DOl I OOh-OOh I 80 68 00h-02h I 55 88 02h-04h I 0 280 04h- 06h I 160 420 06h-12h I 500 1500 12h-24h I 1220 1000

I

Study re,f, :-80 32 450 40 38 55 38 100 75 95 150

380 340 1000 440 400 480

Study ref . : -

Subjects! Time I Interval I

I I

DOl I OOh-OOh I 200 00h-02h I 90 02h-04h I 60 04h-06h I 100 06h-12h I 900 12h-24h I 500

I

250 110

45 180 750 550

Compound iclentil. MECILLINAM

280 420 260 250 310 160 68 120 220 85 180 85 38 50

95 250 92 80 97 240 60 50 270 51 140 120 140 100

600 1600 400 720 1340 1300 1040 710 1200 460 470 520 500 550

Compound iclentif. MECILLINAM

180 200 85 20 260 72 150 30 160 65 160 300 125 200 190 280 770 1500 1160 1550 860 580 610 780

s: m 0 r r z )>

s:

I ..... s: m -;

Table 7 :Urinary volumes (ml) collected after single oral administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg/tablet (treatment B, reference tablet)

Subjects I Time I Interval I

I I

DOl I OOh-OOb I 68 45 00b-02h I 28 150 02b-04b I 30 14 0 04b-06b I 38 150 06b-12h I 1100 600 12h-24b I 230 600

I

Study ref. :-25 so 380 68 68 180

120 so 85 100 80 75 54 0 300 1800 660 380 600

Study ref. : -

Subjects : Time I Interval I

I I

DOl I OOh-OOh I 220 00h-02h I so 02h- 04h I 65 04h-06b I 150 06h-12h I 780 12h- 24h I 500

I

280 250 145 210 750 490

Coupound identi. MEC:ILLINAM

100 480 so 120 120 65 48 so 75 380 45 250 200 65 75 110 210 so 180 75 45

250 150 295 53 120 260 250 1270 1100 1750 700 1300 1000 700

700 390 1500 700 420 205 380

Compound identi. MECILLINAM

150 120 320 150 48 120 85 100 so 55 80 270

180 55 100 250 600 1100 1200 1300 5 40 600 700 800

s:: m 0 r r z )> s::

I

(J) .... -uC Q) c

(Q -< CD AJ ~m V>-u 2.0 ~:::0

Table 8: Amount of mecillinam (mg) excreted in urines after single oral administration of 400 mg pivmecillinam as one tablet of pivmecillinam dosed at 400 mg/tablet (treatment A, test tablet)

=- I Study ref . Compound identif. MECILL.INAM I I I Subjects I I Time I I Interval I

I I

DOl I OOb-OOh o.oo 0 . 00 o.oo 0.00 0.00 0.00 o.oo 0 . 00 0.00 0.00 0.00 0.00 1 00b-02h 38.89 15 . 74 6.43 20.07 0.00 20.11 61.00 37 . 20 27.45 47.58 25.61 34.731 02h-04h NS 29.44 37 . 72 NS 56 . 86 63. 36 23.66 31 . 86 24 . 58 40 . 14 13.14 67.751 04b-06h 16 . 20 o.oo 16.52 28.44 21.00 5.61 4.95 1.54 9.46 6 . 80 0 . 00 12.361 06h-12h 0.00 0.00 0.00 0.00 0.00 0 . 00 0.00 0.00 0.00 0.00 0.00 0.00 1 12h-24h 0 . 00 0 . 00 0.00 0 . 00 0.00 0.00 0.00 0.00 0.00 0 . 00 0.00 0.00 1 Total I

00h-24h 55 . 10 45.18 60 . 67 48 .51 77.86 89.08 89.61 70.59 61.48 94.53 38.75 114 . 84 1 I

Study rc . - Compound iclcntif. MECILLINl\M Subjects I MEAN S.D. S.E.M. Time I I Interval I

I I

DOl I OOh-OOh 0.00 0.00 0.00 0.00 0.00 0 . 001 0 . 00 0.00 0 . 00 00h-02h 72 . 93 54 .66 44 . 86 26.57 52.15 9 . 461 33 . 08 19 . 90 4.69 02h-04h 25 . 84 21.43 16.40 20 . 50 40.25 41 . 191 30 . 78 19.04 4 . 49 04h-06h 7 . 97 6. 83 5 .54 7 . 78 7 . 92 4.821 9.10 7.40 1.74 06h-12h 0.00 0.00 0.00 0.00 0.00 0.001 0.00 0.00 0 . 00 12h-24h 0.00 0.00 0.00 0 . 00 0.00 0.001 0.00 0 . 00 0 . 00

Total I 00h-24h 106 . 74 82.92 66.80 54.86 100.32 55 . 471 72.96 22 . 48 5 . 30

I

NS : No s;uuple

s: m 0 r r z )>

s::

I s: m -1 0 N , :::0

CJ) -1

-u C Q) 0

Table 9 :Amount of mecillinam (mg) excreted in urines after single oral administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg/tablet (treatment B, reference tablet)

Study r ef. - Conrpouncl iclenti.f. MECILLINAM Subjects! Tillie I Interval.

DOl OOh- OOh 0 . 00 0 . 00 0 . 00 0.00 o.oo 0 . 00 0 . 00 0.00 0.00 0.00 0.00 0.00 00h-02h 30.08 53 . 14 26 .90 9. 81 39.14 18 . 85 29.64 13 . 06 33.03 43 . 03 46 . 68 59 .10 02h-04h 23.16 15.65 35 . 70 27.61 1 9.07 26.59 35 . 24 48.42 25 . 68 25.96 16 . 79 29.62 04h-06h 3.47 3.49 7 .49 9. 43 4.07 5.06 10 . 26 29 . 97 5 . 97 4 .00 10.31 3.551 06h-1.2h o.oo o.oo 0 . 00 0.00 0.00 0 . 00 0 . 00 0.00 o.oo 0 . 00 0.00 0.001 l2h-24h 0.00 0 . 00 0.00 0 . 00 0.00 0.00 0.00 0.00 0 . 00 0.00 0 . 00 0 . 001 Total I

00h-24h 56 . 70 72.29 70 . 09 4 6 . 85 62.28 50.50 75 . 14 91. 4 6 64. 68 72 . 99 73 . 78 92.271 I

study ref . =- Conrpouncl iclenti f. MECILLINAH Subjects! S.D. S . E .M. Ti me I Interval

DOl OOh-OOh 0.00 0 . 00 0 . 00 0.00 0.00 0 . 00 0 . 00 0.00 0.00 00h-02h 22 . 33 54.23 38.41 49. 4 1 31 . 25 13 . 30 33.97 15.03 3.54 02h-04h 65 . 88 35.56 20.96 19 . 05 16.69 16. 4 0 28 .00 12 . 85 3 . 03 04h-06h 9.69 6.43 4 .37 4 . 68 6. 00 3 . 18 1.30 6 . 17 1.46 06h-12h 0.00 0.00 0 . 00 0.00 0.00 0.00 0.00 0 . 00 0.00 12h-24h 0 . 00 0.00 0 . 00 0 . 00 0.00 0 . 00 0.00 0.00 0.00 Total

00h-24h 97.90 96 . 22 63 . 74 73.15 53 . 94 32 . 871 69.27 17 . 71 4 . 17 I

s: m 0 r r z )>

s:

I s: m -1 .rn Ul""' Q.o ~:::0


Page 46 of 49

Table 10 : Pharmacokinetic parameters of mecillinam calculated after single oral administration of 400 mg pivmecillinam as one pivemecillinam tablet dosed at 400 mg per tablet (treatment A, test tablet)

Puiod c... t,.., l:(a t,.,, Ae AUC0 . , Au c extrap. ' '"' ()1g.m1"1 ) (h) (h"') (h) (mg) ()lg . h .ml"1 ) ()lg.h.ml-1 ) e 2 3 . 71 1 . 00 0 . 72 0 . 91 55 . 09 7.54 7 . 69 1 . 86 0.80 1 2.09 0.50 0 . 36 1 . 93 45 . 18 3 .93 4.21 6.72 0.63 1 3.38 1.00 0 . 57 1 . 23 60 . 67 7. 72 8 . 06 4.16 1.12 2 2 .24 1.50 0.70 0 . 99 48 . 51 4 . 91 5.06 2.96 0.99 1 1. 91 1.50 0 . 65 1 . 06 77. 86 4 . 33 4.57 5 . 19 0.88 1 2 . 72 1 .50 0.69 1.01 89.08 5 . 55 5 . 84 4.97 1.06 2 2 . 45 1 . 00 0.67 1. 04 89.61 4 . 73 4.99 5.22 0.79 1 3 . 85 1 . 00 0.85 0 . 82 70.60 7.64 7 . 86 2 . 75 1.11 2 4 .20 1 .50 0.51 1.36 61.49 8 . 68 8.91 2 . 54 1.08 1 2 . 98 1 . 00 0.63 1.09 94 .52 6 . 11 6 . 27 2 . 55 1.03 1 3 . 04 1 .50 0.71 0.98 40.73 6.68 6 . 88 2 . 88 0 . 82 1 2.38 0 .50 0. 77 0.90 114.84 7.14 7 . 30 2.17 0.91 2 3.96 1 .50 0. 7l 0.98 106.74 8 . 64 8 . 82 1.95 1.02 2 2 . 64 1.00 0.59 1.19 82 . 92 5 . 88 6 . 10 3 . 51 1.04 2 4 . 71 1 . 00 0. 73 0.95 66 . 80 8.63 8 . 78 1.78 0.91 2 2 . 16 1.00 0 . 68 1 . 02 54 . 85 4 . 02 4. 21 4.40 0.90 1 2 . 86 1.50 0 . 69 1 . 01 100 .32 6.17 6.33 2 . 54 1 . 39 2 1.95 1.00 0.69 1 . 01 55 . 47 4 .48 4.75 5.58 1.06

2 . 96 l.H 0.66 1 . 08 73 . 07 6.27 6.48 3.54 0 . 98 0 .84 0 .33 0.11 0 . 24 22 . 30 1 . 64 1. 63 1.49 0.17

28 29 16 22 31 26 25 4 2 17 2 . 79 1 . 00 0.69 1.01 68.70 6 . 14 6 . 30 2 . 92 1.01 4 . 71 1 .50 0.85 1.93 114.84 8 . 68 8 . 91 6 . 72 1 . 39 1.91 0 .50 0.36 0 . 82 40.73 3 . 93 4 . 21 1 . 78 0.63

Table 11 :Pharmacokinetic of mecillinam calculated after single oral parameters administration of 400 mg pivmecillinam as two tablets of Selexid dosed at 200 mg pivmecillinam per tablet (treatment B, reference tablet)

Puiod c... t.... Ke t l /2 Ae AU Co-t AU Co &xtrap. (pg .ml-') (h) (h"' > (h) (mg) (pg.h.ml- 1 ) ()lg.h.ml-1) %

1 3 . 13 1.00 0.72 0.97 56 . 71 9 . 32 9.55 2 . 46 2 2 . 89 1.00 0.59 1.18 72 . 28 6 . 39 6 .63 3.65 2 2 . 59 1.50 0 .59 1.17 70 . 09 7 . 00 7.18 2.53 1 2 . 43 1.00 0.75 0.93 4 6 . 85 4.89 5.10 4 .12 2 2 . 28 1 . 50 0.62 1.12 62.28 4. 85 5.17 6 .15 2 2 . 35 1 . 50 0 . 7 4 0.94 50 . 50 5 .29 5.52 4 .14 1 2 . 72 1.50 0.66 1 . 06 75 .14 6.08 6.28 3.16 2 3 . 68 1 . 00 0.78 0 . 89 91 .45 6 . 88 7.07 2.65 1 3 . 26 1.50 0.63 1.10 64. 68 7.96 8.25 3.53 2 3 . 01 1 . 50 0.71 0.98 72 . 99 5.93 6 . 08 2 . 34 2 3 . 89 1.50 0.70 0 . 99 73 . 78 8.13 8 .37 2 . 87 2 3 . 64 1.00 0.68 1. 03 92.27 7.86 8 . 05 2 .29 1 3.70 1 . 50 0 . 73 0 . 96 91 . 90 8 .44 8 . 66 2.55 1 2. 14 1 . 00 0 .50 1.38 96.22 5 . 63 5.89 4 .47 1 5.34 1 . 00 0 . 72 0.96 63.74 9 . 44 9 . 63 1.98 1 2.08 1.00 0 . 67 1.04 73.15 4.45 4.67 4.80 2 2.42 1 . 00 0 . 63 1 . 10 53.94 4 . 30 4 . 56 5.74 1 1. 69 1 . 00 0 . 51 1.36 32.88 4 .22 4.47 5.57

3. 03 1 . 22 0 . 66 1.06 69.27 6 .50 6 . 73 3.61 0 . 87 0 .26 0 . 08 0 . 14 17 . 71 1 . 71 1.70 1.30

29 21 12 13 26 26 25 36 2.81 1.00 0 . 67 1.04 71.19 6 . 24 6.46 3.34 5 . 34 1 .5 0 0 . 78 1.38 97 . 90 9 . 44 9 . 63 6.15 1.69 1 0.50 0.89 32.88 4 . 22 4.47 1 .98


FIGURES



Page 48 of 49

Figure 1 : Mean (+S.D) plasma concentrations of mecillinam obtained after administration of the two treatments

4.0

3.5

- 30 e . t;, .:; 2.5 t: 0 ; Ill

2.0 ... .... t:

1.5 Q) (J c 0 (J 1.0

0.5

0.0 0 2 3

-+- 400 mg pivmecillinam tablet

-o- Selex id (two 200 mg tablets)

4

t ime (h)

5 6 7 8

Figure 2 : Individual plasma concentrations of mecillinam after single oral administration of one tablet of pivmecillinam dosed at 400 mg pivmecillinam I tablet (treatment A, test treatment)

6

5

-] 4 Cl .:; c 0 ~ 3 ... -c Q) (J

c 2 0 u

0 2 3 4

t ime (h)

5 6 7 8


Page 49 of 49

Figure 3 : Individual plasma concentrations of mecillinam after single oral administration of two tablets of Selexid dosed at 200 mg pivmecillinam I tablet (treatment 8, reference treatment)

6

5

-: 4 1: .= c 0 ~ 3 .. -c Ql u 8 2 u

0 2 3 4

time (h)

5 6 7 8

Figure 4 : Mean (+S.D) cumulative amounts of mecillinam excreted in urine after administration of the two treatments

t;; .. ... c :I 0 E ('l

Ql > ~ :I E :I u

100

80

60

40 -+-Treatment A (test formulation)

-o- Treatment B (Selexid) 20

Oo-----------~------------~----------~~----------~

0 3 6

time (h)

9 12

Name ----

Clinical Study Report MET 9802 FR 1999-11-22

Type

eDoc LEO RD 00124637 Version Number: 2.0

A ~pprova s Reason for signature

Approved Sponsor's Medical Expert

Date for signature

12-Mar-2009 04:22:04 PM

Documents

Mecillinam Comparative bioavailability study - LEO … Declaration of Helsinki ... 1.9 Data capture and transfer ... 2.8 Analytical method validation