Pharmacokinetics and Pharmacodynamics of Tebipenem for Multi-Drug Resistant Enterobacteriaceae1L. McEntee*, 1N. Farrington, 1A. Johnson, 1S. Gore, 2A. Rubio, 2L. Utley, 2T. Parr, 3P. Ambrose, 1S. Das, 1W. Hope

1Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, UK2Spero Therapeutics, Cambridge, MA, USA

3Institute for Clinical Pharmacodynamics, Schenectady, USALaura McEntee, Saturday 9th June 2018

SAT-555 University of Liverpool, +44 (0) 151 794 5471, l.mcentee@liv.ac.uk

• Increasing prevalence of multi-drug resistant (MDR) bacteria is a serious

threat to global health with limited treatment options

• Tebipenem pivoxil (TBPM-PI, SPR994) is a new carbapenem that is

orally bioavailable

• SPR994 is active against a range of Enterobacteriaceae with a variety of

resistance mechanisms and is currently licensed for use in children in

Japan

• The pharmacokinetics and pharmacodynamics (PK-PD) of SPR994 is

poorly described

• Dose finding, dose fractionation, and pharmacokinetic studies were

performed to determine the PK-PD of SPR994 that best links drug

exposure with antimicrobial activity

• All experiments were performed under a UK Home Office License with

local ethical committee clearance at the University of Liverpool

Mouse Models• Neutropenic thigh mouse model against a well characterised wild-type

challenge strain of Escherichia coli ATCC 25922 was used

• Male CD-1 mice weighing 25-30 grams

• Endpoint of studies was average CFU/g of both thighs or drug

concentrations in plasma

Dose Finding Studies

• Treatment started 2 hours post inoculation. SPR994 was administered

via oral gavage every 8 hours (q8h), in a total of 3 studies

• Inhibitory Sigmoid Emax model was fitted

• Further pharmacodynamics were examined in a range of wild-type and

ESBL-producing Escherichia coli and Klebsiella pneumoniaeDose Fractionation Study

• EC20, EC40, EC60 and EC80 of SPR994 was administered orally every 6,

12, or 24 hours (q6h, q12h, or q24h) for dose fractionation studies

• Difference in groups were compared using ANOVA and non-linear

regression

Pharmacokinetics (PK)

• PK of SPR994 was estimated using 3.33, 8.33, 16.67, and 33.33mg/kg

administered q8h orally

• Drug concentrations in mouse plasma were measured using LC/MS/MS

• Results were mathematically modelled using Pmetrics

INTRODUCTION

METHODS

RESULTS

• Stasis, -1, and -2 log kill were demonstrated over 12 strains of E. coli and K. pneumoniae, with a dose of SPR994 6.67mg/kg

q8h required to achieve stasis in mice

• The pharmacodynamics of SPR994 were comparable across the various strains of E. coli and K. pneumoniae tested, and

were independent of the presence of ESBL

• The PK-PD driver in mice for SPR994 is AUC:MIC*1/Tau and these data will be used in part as an index to help identify

dosing regimens for patients

CONCLUSIONS1. Pharmacokinetics showed SPR994 is orally bioavailable and has linear PK

3. The dose fractionation study showed the fractionated schedules out

performing the once daily dose, with ANOVA supporting this conclusion.

SPR994 exhibits time dependent PD which cannot be described with fT>MIC

(D), but is quantified using Cmin:MIC (Fig. 6) & AUC:MIC*1/tau (Fig. 7)

4. Dose finding studies with 6 strains of E. coli supports the AUC:MIC*1/Tau PK-PD driver of SPR994

6. E. coli & K. pneumoniae dose finding studies demonstrate

minimal differences between species, wild-type, or ESBL-

producers

Fig. 10 AUC:MIC*1/Tau:MIC of E. coli & K. pneumoniae wild-type & non-wild-type

strains

5. Dose finding studies with 6 strains of K. pneumoniae supports the AUC:MIC*1/Tau PK-PD driver of SPR994

Fig. 9 AUC:MIC*1/Tau:MIC of K. pneumoniae strains

r2=0.96r2=0.901

r2=0.729

r2=0.329

Fig 2: dose vs effect Fig 3: Cmax:MIC vs effect

Fig 4: AUC:MIC vs effect Fig 5: fT>MIC vs effect

Fig 7: AUC:MIC*1/Tau vs effectFig 6: Cmin:MIC vs effect

2. Strains used, molecular information & MICs

Organism Strain Identifier Known Molecular Information SPR859 MIC

(ug/mL)

E. c

oli

ATCC25922 QC strain 0.015

ATCC35218 TEM-1 0.03

NCTC13462 CTX-M2 0.015

SPT719 CP_SHV_ESBL,CP_TEM_WT 0.03

SPT720 MCR-1 0.5

SPT731 CP_CTX-M_Group1,CP_TEM_WT,ST131 O25b clade 0.06

K. p

neum

onia

e

ATCC43816 QC strain 0.015

ATCC27736 QC strain 0.06

NCTC13465 CTX-M25 0.03

SPT722 CTX-M15, OXA-1, SHV-28, TEM-1 0.25

SPT723 CP_CTX-

M_Group1,CP_SHV_ESBL,CP_SHV_WT,CTX-M-

15,OXA-1/30,SHV-5

0.5

SPT725 CP_SHV_ESBL,CP_SHV_WT 0.25

RESULTS

Fig. 8 AUC:MIC*1/Tau:MIC of E. coli strains

A: ESBL B: wild-type C: ESBL D: ESBL E: mcr-1+ F: ESBL

G: wild-type H: wild-type I: ESBL

J: ESBL K: ESBL L: ESBL

Fig. 1 PK of SPR994

Red:3.33mg/kgq8hBlue:8.33mg/kgq8hMagenta:18.67mg/kgq8hGreen:33.33mg/kgq8h

r2=0.764