A Physiologically-Based Pharmacokinetic Model of Trimethoprim for MATE1, OCT1, OCT2, and CYP2C8 Drug-Drug-Gene Interaction Predictions.

Denise Türk,Thorsten Lehr,Nina Hanke

doi:10.3390/pharmaceutics12111074

Denise Türk, Thorsten Lehr + Show 1 more

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https://doi.org/10.3390/pharmaceutics12111074

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Journal: Pharmaceutics	Publication Date: Nov 10, 2020
Citations: 11	License type: CC BY 4.0

Affiliation: Saarland University

Abstract

Trimethoprim is a frequently-prescribed antibiotic and therefore likely to be co-administered with other medications, but it is also a potent inhibitor of multidrug and toxin extrusion protein (MATE) and a weak inhibitor of cytochrome P450 (CYP) 2C8. The aim of this work was to develop a physiologically-based pharmacokinetic (PBPK) model of trimethoprim to investigate and predict its drug–drug interactions (DDIs). The model was developed in PK-Sim®, using a large number of clinical studies (66 plasma concentration–time profiles with 36 corresponding fractions excreted in urine) to describe the trimethoprim pharmacokinetics over the entire published dosing range (40 to 960 mg). The key features of the model include intestinal efflux via P-glycoprotein (P-gp), metabolism by CYP3A4, an unspecific hepatic clearance process, and a renal clearance consisting of glomerular filtration and tubular secretion. The DDI performance of this new model was demonstrated by prediction of DDIs and drug–drug–gene interactions (DDGIs) of trimethoprim with metformin, repaglinide, pioglitazone, and rifampicin, with all predicted DDI and DDGI AUClast and Cmax ratios within 1.5-fold of the clinically-observed values. The model will be freely available in the Open Systems Pharmacology model repository, to support DDI studies during drug development.

Highlights

Trimethoprim is an inhibitor of bacterial folic acid metabolism used to treat bacterial infections
According to literature [29,30] and our own analyses, trimethoprim pharmacokinetic profiles are not altered by simultaneous administration of sulfamethoxazole
The trimethoprim plasma concentrations measured during the first and eighth day of rifampicin co-administration and the observed increase in trimethoprim renal clearance on the eighth day of this drug–drug interactions (DDIs) [16] are well captured by the model after implementation of P-gp and CYP3A4

Summary

Introduction

Trimethoprim is an inhibitor of bacterial folic acid metabolism used to treat bacterial infections. It is either applied as monotherapy or in combination with sulfonamides, e.g., sulfamethoxazole (“cotrimoxazole”). Due to the frequent prescription of trimethoprim, investigation of its drug–drug interaction (DDI) potential is clinically relevant. The antibiotic is a potent inhibitor of multidrug and toxin-extrusion protein (MATE) 1 and MATE2-K [2], and recommended by the FDA as a clinical MATE inhibitor. Trimethoprim less potently inhibits organic cation transporter (OCT) 1 and OCT2 [3,4]. This combined inhibition potential can be observed during clinical studies of trimethoprim with metformin, where co-administration of trimethoprim increases the area under the concentration–time curve (AUC) of metformin by 30% [4]. Metformin is listed by the FDA as the only recommended MATE1, MATE2-K, and OCT2 substrate for clinical DDI studies [2]

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