Intestinal P‐gp and Putative Hepatic OATP1B Induction: International Transporter Consortium Perspective on Drug Development Implications

Abstract

There is an increasing interest in transporter induction (i.e., decreased systemic drug exposure due to increased efflux‐limited absorption or transporter‐mediated clearance) as a mechanism of drug–drug interactions (DDIs), although evidence of clinical relevance is still evolving. Intestinal P‐glycoprotein (P‐gp) and hepatic organic anion transporting polypeptides 1B (OATP1B) can be important determinants of drug absorption and disposition, as well as targets for DDIs. Current data indicate that intestinal P‐gp protein levels can be induced up to threefold to fourfold in humans primarily with pregnane X receptor (PXR) activators, and that this induction can decrease the systemic exposure of drugs with P‐gp efflux‐limited absorption (e.g., ≤ 67% decrease in the exposure of total dabigatran following rifampin multiple oral dosing). Evaluation of the clinical relevance of P‐gp induction as a DDI mechanism must consider the induction potential of the perpetrator drug for P‐gp and attenuation of exposure of the victim drug in the context of its therapeutic window. Practical drug development recommendations are provided herein. Reports are contradictory on OATP1B induction by PXR activators in human hepatocytes and liver biopsies. Some clinical investigations demonstrated that rifampin pretreatment decreased exposure of OATP1B substrates, while other studies found no differences, and the potential involvement of other mechanisms in these observed DDIs cannot be definitively ruled out. Thus, further studies are needed to understand hepatic OATP1B induction and potential involvement of other mechanisms contributing to reduced exposure of OATP1B substrates. This review critically summarizes the state‐of‐the‐art on intestinal P‐gp and hepatic OATP1B induction, and highlights implications for drug development.

Improved Prediction of the Drug-Drug Interactions of Pemafibrate Caused by Cyclosporine A and Rifampicin via PBPK Modeling: Consideration of the Albumin-Mediated Hepatic Uptake of Pemafibrate and Inhibition Constants With Preincubation Against OATP1B

“…7a). The effect of the repeated exposure to RIF on OATP1B induction is still controversial, 39,40 but the current results support the importance of considering OATP1B induction by RIF in quantitatively predicting the DDI between PMF and RIF, and possibly for other OATP1B substrates.…”

Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices

“…Recently, Lutz et al published data establishing proof of concept that induction of ABCB1 in vivo can be extrapolated based on analysis of CYP3A induction magnitude by PXR ligands ( Lutz et al, 2018 ). However, as of yet, there is no widely accepted experimental model to study induction of metabolizing enzymes and transporters in the intestine that has high screening capacity and sufficiently similar characteristics to in vivo systems ( Zamek-Gliszczynski et al, 2021 ). In this study, we used hPCISs prepared from the jejunum, which is the major site of drug absorption after oral administration ( Murakami, 2017 ), and, moreover, it reveals a significant ABCB1 activity ( Li et al, 2017a ).…”

“…This was also highlighted in the recent white paper published in 2021, where authors stated: “A validated in vitro system to study intestinal P-gp induction currently is not available and quantitative approach to predict the exposure of inducer drugs in the gut is still limited. Therefore, for foreseeable future determining definitively whether a drug induces intestinal P-gp and subsequent dosing recommendation will be based on clinical studies in conjunction with PBPK modeling and/or clinical induction calibration approaches” ( Zamek-Gliszczynski et al, 2021 ). As a surrogate technique for predicting the pharmacokinetic effect of PXR-mediated ABCB1 induction in vivo , the FDA currently recommends using data from CYP3A induction studies as the ABCB1 levels correlate with magnitude of CYP3A induction ( Lutz et al, 2018 ; FDA, 2020 ).…”

Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors

“…Because P-gp expression is relatively enriched in the gastrointestinal tract [42], IV administration of vincristine may circumvent P-gp inhibition observed with orally administered drugs such as venetoclax and digoxin. Intestinal P-gp induction is known to decrease systemic exposure and may attenuate both the absorption fraction and absorption rate [43]; therefore, intestinal P-gp inhibition via orally administered drugs may be expected to increase systemic exposure. The developed PBPK model reasonably predicted the range of vincristine PK profiles and PK parameters compared with observed values.…”