Marta Neve 1, Hwa-ping Feng 2, Shekman Wong 3, Eva Hanze 4, Oskar Alskar 4, Italo Poggesi 1
1 Clinical Pharmacology Modeling and Simulations, GSK (Verona, Italy), 2 Clinical Pharmacology Modeling and Simulations, GSK (Upper Marion, USA), 3 Spero Therapeutics (Cambridge, USA), 4 qPharmetra (Uppsala, Sweden)
Introduction:
Tebipenem pivoxil (TBP-PI) is an orally bioavailable carbapenem prodrug that is rapidly converted in vivo to the active moiety, TBP [1]. Tebipenem pivoxil hydrobromide (TBP PI-HBr) is under development to treat adults with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP). A previously published population pharmacokinetic (popPK) model [2] was developed using plasma concentrations derived from the available whole blood concentration measurements. This derivation was based on a fixed conversion factor, under the assumption that TBP does not distribute into red blood cells. This assumption was later found to be incorrect, leading to an overestimation of plasma concentrations. To address this issue, plasma concentrations were measured in the most recent TBP-PI studies and a new popPK model was developed to simultaneously describe the available whole blood and plasma concentrations. The popPK model was used to support TBP dosing in different subpopulations, for example in subjects with different degrees of renal impairment.
Objectives:
• To characterise the pharmacokinetic (PK) profile of TBP following oral administration of TBP-PI-HBr in participants from Phase 1 and Phase 3 studies.
• To evaluate the impact of covariates on the TBP PK profile.
• To perform simulations aimed at determining dose adjustment in relevant subpopulations.
Methods:
Data from five Phase 1 studies and two Phase 3 studies were included in the popPK analysis. Doses ranged from 300 mg to 1200 mg and encompassed both single and repeated doses. A non-linear mixed effects approach was used in NONlinear Mixed Effects Modeling (NONMEM), utilising the first-order conditional estimation method with interaction. Model selection was guided by the objective function value, evaluation of numerical checks (such as parameter estimates and their precision), graphical goodness-of-fit, visual predictive checks, model stability, and scientific and physiological plausibility. For simulations, virtual populations were created from the National Health and Nutrition Examination Survey (NHANES) database [3] and were used in conjunction with the model to simulate TBP exposure in relevant subpopulations.
Results:
A total of 3295 plasma, 5307 whole blood, and 462 urine concentrations from 149 Phase 1 participants and 1252 Phase 3 participants, were included in the model development. The overall TBP PK profile was best described by a two-compartment disposition model with linear renal clearance (CLR) and non-renal clearance (CLNR); absorption was described using a transit compartment model. The blood-to-plasma relationship was characterised using a linear function, with haematocrit identified as a significant predictor of the blood-to-plasma coefficient. Administration of TBP with food resulted in slower absorption, an effect that was more pronounced in Phase 3 participants. Doses above 600 mg appeared to be absorbed slower than doses of 600 mg or less. CLR was estimated to be 16.5 L/h (95% CI:15.9 – 17.1) and CLNR was estimated to be 1.02 L/h (95% CI:0.622 – 1.41). Central volume of distribution (V1) and peripheral volume of distribution (V2) were estimated to be 18.2 L (95% CI:17.7 – 18.7) and 1.62 L (95% CI:1.53 – 1.72), respectively. Parameters were estimated with good precision (relative standard error <20%). Intersubject variability (expressed as % coefficient of variation) for CLR, V1, V2 and transit rate constant in fasted and fed condition were estimated at 35.4%, 20.1%, 21.6%, 35.7% and 32.8%, respectively. Weight and estimated glomerular filtration rate (eGFR) were included as covariates prior to evaluating additional factors: allometric scaling with fixed exponents was applied to volumes and intercompartment clearance, while eGFR was included to describe the impact of renal function on CLR. Other factors did not show any meaningful influence on PK based on the covariate analysis. Simulations indicated that the dose in adults with normal renal function or mild renal impairment (600 mg q6h), could be matched in terms of the overall daily systemic exposure using 300 mg q6h and 300 mg q12h in subjects with moderate and severe renal impairment, respectively.
Conclusions:
The newly developed model superseded the previously published one [2] and successfully described the PK of TBP. The disposition characteristics of TBP were similar to those of other carbapenems. The model was suitable for simulations that supported dose adjustments in subjects with moderate and severe renal impairment, ensuring matching of the daily systemic exposure.
References:
[1] Kato K, Shirasaka Y, Kuraoka E, Kikuchi A, Iguchi M, Suzuki H, Shibasaki S, Kurosawa T, Tamai I. Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport. Molecular pharmaceutics. 2010 Oct 4;7(5):1747-56.
[2] Ganesan H, Gupta VK, Safir MC, Bhavnani SM, Talley AK, Melnick D, Rubino CM. Population pharmacokinetic analyses for tebipenem after oral administration of pro-drug tebipenem pivoxil hydrobromide. Antimicrobial Agents and Chemotherapy. 2023 Jun 15;67(6):e01451-22.
[3] https://wwwn.cdc.gov/nchs/nhanes/
Reference: PAGE 34 (2026) Abstr 12223 [www.page-meeting.org/?abstract=12223]
Poster: Drug/Disease Modelling - Infection