.

Mechanistic Understanding ofSubject-by-Formulation

Interactions.................. ... .,.,,,.,.,, ,.,..........................:.:,.&.:..,-,:,.(.~.,.:::::::::$:,>....<.................................................,,..,.<’.-,........,... ..:.:.....................,,.,.<.:.:.,.,,.................................

Lawrence J. Lesko, Ph.D.

OffIce of Clinical Pharmacology andBiopharmaceutics

CDERIFDA

Advisory Committee for Pharmaceutkxd Seienee

September 23-24,1999

Roe@illq Maryland

Outline,‘:~.,:::2%.::::x~::7.:=:++=+:=;.,...,,......................................................

“ Mechanistic Definition

● General Paradigm

Q Case Study

● Analysis

“ Conclusions

1

35475 la

.

Mechanistic Definition of SxF

When the in vivodissolution of a formulationsand absorption of its druq display sensitivity tophysiological variabks in the GIT witfiin therange found in healthy and/or patientvolunteers, and/or

When the excipients in a formulation influencephysiological variables, or the physical-chemical properties of a formulation and/or itsdrug, in the GIT

General Paradigm

‘“’’A””’ - =.+””PROPERTIES

~ FORMULATION ~IN VITRO PHYSICAL

I

IN IWO PEYSICAL-CHEMICAL CHEMICAL

‘ROpERT@~ GASTROJN&NAL TRACTpROpn-

PHYSIOLOGK!ALI

PEARMACOKINETICPROPERTIES PROPERTIES

WHOLE BOJ)Y ~

2

Risk Factors: Drug Properties:ii”

● SXF Unlikely ● SXF Likely

- HS/HP (BCS I Class) - LS/LP (IV), LS/HP (H)— rapid intrinsic dissolution and HS/LP (III)

— site- and transit time- — slow intrinsic dissolution

independent absorption site- and transit time-— no physical or chemical dependent absorption

incompatibilities – physical or chemical— achiraI incompatibilities

- uncomplicated PK – complicated PK

– no regional – pharmacological effects

pharmacological effects on GIT

ir

Risk Factors: Excipient Properties.’..

● Unlikely” ● Likely—no effects on GIT pH – alters local GIT pH

– no effects on permeability – promotes permeability

no effects on transit time – pharmacological effect on

— no physical or chemical GIT motility

interactions – physical or chemical

no effects on presystemic interactions

CYP 3A4 metabolism – inhibits presystemic CYP— no effects on PGP and 3A4 metabolism

other transport processes — reduces PGP and otherefflux systems

3

Risk Factors: Formulation Properties.c~

● Unlikely ● Likely—

—

—

.

pharmaceutical —

equivalents

simple formulations —

● solutions

● solid, oral Ill

low excipientidrug ratio —

uncomplicated

manufacturing

rapid and pH- —

independent dissolution

not pharmaceuticalequivalent

complex formulations

● transdermal

● m

high excipient/drug ratio

complicatedmanufacturing

slow and pH-dependentdissolution

Risk Factors: GIT Properties of SubjectsG~

● Physiological Variables “ Physiological Range—

—

—

—

—

pH gradient

gastric emptying time

SITT

colonic residence time

intestinal permeabilitygradient

activity and capacity ofenterocyte CYP 3A4

activity and capacity of

– genetic or environmental

control

– gender

– age

– race

– disease states

– diet— co-administered drugs

intestinal transportprocesses

4

Case Method Approach

● Stepwise analysis of actual examples of SXF– determine risk factors of drug, excipients,

formulation and subjects—obtain insight into mechanism

● When multiple risk factors are present at thesame time, a SXF is most likely to occur

CASE STUDY:

CALCIUM-CHANNEL BLOCKER

(DRUG X)

5

. .

Clinical Study Summary.,,,.,.:.,.:,,.>,.,.,.,:.,.,.,:.:........,.:<j,,,,:::,:::,:,:.,.:.:.,.,.,.,.,.,.,.,.,.,.,........................................................,...,.... ................................................................

c Two-way crossover, non-replicated, single dose,fasting BE study

● Healthy, young males (n = 12) andfemales (n= 13)

Q Oral capsules

● Plasma levels of parent (P) and metabolize (M)

s Standard ANOVA analysis of [S(G) x F]

PKData for Parent: Product A.,.,.,,...........................>...........................................>y.y....>..>....<*#...$~.~.....*......................7......,,.,,/.........................................,,>,...,,,,,,...,,.,,,,.,.,.

250

2(W

150

s l(n)$

t=z o[1

o 10 20 30 40 so

Time in Hours

/FemalembJecta

5

PKData for Parent; Product B;~..:.:.:.,...::.:....:..,:.-.:-:...:.:-::.,.,................................:,:,:,:,:?:::,:::,:::W::,!?<>.Z:7.....

250

200

Ho

IWJ

!9

iiEo [1

o 10 24 30 40 50

Time in Hours

BE Data/.,7,,....~,.......-.-............<,@...........,.:,..,:.......,.....................,,,.,,:,::,.;+;:W>-.+:;:.:..<.,.:,::,>..:.>...:.:>,$,, :..,,,:.:::..:,.......... .................................................... ,..,,,.,, ....,.,...X.,.,.,,,,.,................................................... .{:7

6

6000

6000

4000

2000

1000

0

Stick Plot; All Subjects

,Stick Plot: All Subjects

.. ““”’”’~~,,,,:.,:,.:,,,,,,....,.,,,,,.,,,:::,,,:,,,.,:,,..:,..=....:.:.:.:.:.:.:.::::.:.:.:.7.t..*.<</<>;.,.~.x4z.,.............5--...................::.:.:z-:,.::-...-.-.:.:.>:.:.:...ti/,:.m>..z.>>..........

I1

PRODUCT A PRODUCT B

.

7

.

Step- Wise Analysis,.

. Risk Factors- “Class II” (LS/HP) drug

– pH- sensitive excipients

– complex formulation (ER)—overlapping CYP 3A4/PGP substrate

– significant saturable first pass effect

– F <50%

– female and male subjects

Drug Volubility.....................r.....................Y.....c.,,,.,.2,..,.:,....:,...;,.......................:.,.,.,.,.:.,.:.,.............................,<.,,....,.........,.,.:-:,,:.,.::.,.,,....-..:-’.-...:-:......-.............}.,.,...........>/+....>...........................

1-2

8 1.0

&0.8

~ 0.6

r%0.4

0.2

0.0 1

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

pH

8

Formulation Dissolution

Q*.. O..00.0-O

$

lii EiilIii Ed fatzi Ea

Time in Hours

Role of Excipients---"."."."".'.".".","."."-~~~z;::%z~:Jwz,....,.....,:.:,.,...........,............................................................................... ,..,..:..:.:..:,,.,:.,.;.;.,~:,::~:.:.::.:::3:.:.:-:-:.:.:.::-:.:z.:,..:,:.:.:.xt.,......’.

● Rate-limiting step in absorption is in vivodissolution

● Control release rate

● Different mechanisms for each Product

● Excipient effects in Product ApH-sensitive

9

Contributions of Subjects...................’....

● Gender differences between males andfemales?– focus on physiological variables

● under geneticand/or environmentalcontrol● subpopulationdifferencesin distribution● gastriclintestinaltransit times, membrane

permeability,IwminalpH, mucosal blood flow

● intestinal metabolism bv CYP 3A4

● enterocvte PGP transDort

1

Intestinal CIT 3A4...... :..... . ...,.............................“.........................,...... ..... .........................,, .,................... ..//.....,.(/.>.................-.-:-..-7+?.;~::.::“:::’”’“’““““’”-”7“““””””””’’”””’’-”””“.’..’.x,,.,,,,,:, ,.................................... .

● Large intersubject variability in substrate clearances

● Intrasubject < intersubject (30X) variability- influeawof geneticfactors> environmentalfactors

● Content and expression is site-dependent saturable

● Gender dtierences

● oral clearance < F

●FPE<F

●BA>F

● less CYP 3A4 or homeostaticmechanism?

10

Intestinal PGP.,,.,,,,.,.;.,.,.,,,.,.:,,.,.,.:.,.,.,.,.,.,.:.,,,.,:::,,::,<~f,!:::?,.................................,,,,,:,,,.....................,.,.,.,.:.,.,.,.,.,......................,.,:.:,x..

“ More limited data, particularly, genderdifferences– increasing gradient in content/activity fi-om

proximal segment to distal segment of gut—saturable

– dose-dependent effective permeability

–activityin M>F

Mechanistic Hypothesk‘““““““.”.””””.”.”:~:.xi???:?~~~*~:~ti?~K:*$%:3??$x.,,......................................... .......e......................,...,,/,,,.,..............................................................,.,.,. .,::...................................... . ..........

● SXF with Product B– slower dissolution at pH 4.5

- faster & more complete dissolution at pH 6.8

– larger &action of dose released in ileum● lower CYP 3A4 content & activity

- readily samable

“ gender differences in PGP efflux (F < M)

- greater absorption, higher Cmax & AUC● [concentration x residence time]

11

Supportive Evidence......................:.,.,;.,.,.,:::,::*:*,.....................................................,....,.......,.,.

“ [M/P]AUC ratio for Product B– 10/13 F had lower ratio

– 2/12 M had lower ratio

“ Similar SXF observed in multiple dose BE study– higher AUC & Cmax for Product B in F

● Literature– lower oral clearance of CYP 3A4 substrates in F

●

●

●

Conclusions.:;:“’““”“’“’“’””““''"'"'''''"'''':'~'''''~~~'~'''ff;'='~`'=*'~::-"~'~.:.’%::::.::5:-:*.............-......2.-.............0....?--,.--.-=........................’,............9...>....::.:.:.:...,.....+,>-

Need to collect more data to understand themechanistic basis of SXF

Additional experience with replicate BE studydesigns in subject subgroups will provide datasets relevant to SXF

Stepwise analysis of drug, excipient,formulation and subject factors will lead tobetter understanding of SXF

12

Acknowledgements. ........... “’”’’’”’”’”’=’=~~~~~:~%~~~~::.+.,+:.:,:!:+:.................. ...................................,-

Ajaz Hussain, Ph.D.

Mei-Ling Chen, Ph.D.

Rabi Patnaik, Ph.D.

13