Prediction of Renal Transporter Mediated Drug-Drug Interactions for Pemetrexed Using Physiologically Based Pharmacokinetic Modeling

Abstract

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC 50 ) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (V max ) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m 2 of pemetrexed supplemented with folic acid and vitamin B 12 , recovered the clinical data adequately. The observed/predicted increases in C max and the area under the plasma-concentration time curve (AUC 0-inf ) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC 0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

“…estimation of transporter K m and V max ) is preferable, to account for potential saturation issues (4,53). Uptake transporter kinetic parameters can be estimated from cellbased in vitro uptake assays using the conventional two-step method (8). The main disadvantages of the two-step method are that data are generated using parallel experiments under different conditions (e.g.…”

“…low between occasion variability), the relative expression, abundance and/or activity of multiple transporters in transfected cells may not necessarily represent the in vivo setting. Differences in transporter expression levels can be accounted for as REF scaling factors based on emerging proteomic abundance data (22); however, examples of this approach are limited for kidney and in some instances these scalars have been estimated using clinical data, as reported for pemetrexed (8). Furthermore, expression vs. activity relationships need to be addressed both in vitro and in vivo before transporterspecific REFs can be used with confidence.…”

“…For example, under appropriate in vitro conditions (e.g. expression system, pH gradient/ membrane potential), some renal drug transporters (including multidrug and toxin extrusion protein 1 (MATE1, SLC47A1) and 2-K (MATE2-K, SLC47A2) and OAT4 (SLC22A11) expressed on the apical membrane of proximal tubule cells in vivo can act as both uptake and efflux transporters (8,32), highlighting the importance of careful interpretation of such in vitro data when translating to in vivo.…”

“…Cell lines such as MDCK-II, Chinese hamster ovary (CHO), human embryonic kidney (HEK-293) and HeLa can be stably or transiently transfected to express renal drug transporters (8,32,33). Transfected cell lines are widely used and commercially available and allow measurement of kinetic parameters for individual transporter(s) and drug combinations, including investigation of inhibitory potency as either IC 50 or inhibition constants (K i ).…”

“…Expression of a specific protein is accounted for by the relative expression factor (REF), which represents the ratio of the abundance of a particular protein (e.g. organic anion transporter (OAT) 3 (OAT3, SLC22A8)) in the kidney in vivo compared with the expression in the cellular system used to generate the in vitro data (5,8). Similarly, the relative activity factor (RAF) may be applied, which accounts for differences in activity of a protein of interest between in vivo and in vitro by using a selective probe substrate.…”