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Pharmacokinetics and Pharmacodynamics of Tebipenem for ... · PDF file 1Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, UK 2Spero Therapeutics, Cambridge,

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  • Pharmacokinetics and Pharmacodynamics of Tebipenem for Multi-Drug Resistant Enterobacteriaceae 1L. 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, UK 2Spero Therapeutics, Cambridge, MA, USA

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

    SAT-555 University of Liverpool, +44 (0) 151 794 5471, [email protected]

    • 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 pneumoniae Dose 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

    ol i

    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

    ne um

    on ia

    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: 3.33 mg/kg q8h Blue: 8.33 mg/kg q8h Magenta: 18.67 mg/kg q8h Green: 33.33 mg/kg q8h

    r2=0.764

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