Transporter Substrate/Inhibition/Induction, DDI | An ISSX 2023 Short Course

Recorded On: 09/10/2023

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This short course, featured during the 25th North American ISSX Meeting in September 2023, focuses on challenges and advances of transporter mediated drug disposition and translation from preclinical to human. Drug transporters play an important role in drug disposition, and are often associated with organ toxicity. The short course discusses the transcriptional and post-transcriptional regulation of transporters and the outcomes of the regulation. The ICH M12 step 1 draft guideline is published and currently under public consultation. The short course also discusses the similarity and difference between ICH M12 and the current regulatory guidance, and its application. The conventional allometric method to predict of human dose and pharmacokinetics remains challenging for transporter substrate. The short course introduces the application of PBPK modeling approaches including model development and validation in preclinical species as an optimal tool to translate in vitro transport kinetics to in vivo situation. Assessing transporter drug-drug interactions can be crucial in drug development, and many endogenous metabolites are identified as useful markers for transporter DDIs. The latest advantages of using transporter DDI biomarkers are discussed.

Considerations of Endogenous Biomarkers to Assess Transporter DDIs in Early Drug Development: An IQ Update and Beyond
Bridget Morse, Eli Lilly and Co., Indianapolis, Indiana, USA

Clinical Studies on Pharmacogenomics and DDIs Involving Drug Transporters
Xinning Yang, US Food and Drug Administration, Silver Spring, Maryland, USA

Drug Induced Organ Toxicity: Transporter Roles and Derisking Approaches
Jason Sprowl, University at Buffalo, Buffalo, New York, USA

Approaches to Predict Human PK Profiles for Compounds Undergoing Transporter Mediated Clearance in Early Drug Development: From Dedrick Plot to PBPK Modeling
Xiaomin Liang, Gilead Sciences, Inc. Foster City, California, USA

Chairs: Yurong Lai, Gilead, San Francisco, California, USA and Jason Sprowl, University at Buffalo, Buffalo, New York, USA

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SC 4.1 Considerations of Endogenous Biomarkers to Assess Transporter DDIs in Early Drug Development: An IQ Update and Beyond | Bridget Morse

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Open to view video. The success of static and mechanistic models for prospectively predicting transporter-mediated drug-drug interactions (DDIs) has been variable. Uncertainty in the in vitro-to-in vivo translation of inhibition data using these models may lead to conducting unnecessary dedicated clinical DDI studies. For this reason, identification of reliable endogenous biomarkers for assessing in vivo transporter activity has been given high priority; however, critical evaluation of potential biomarkers is warranted to understand their use for informing the need for clinical DDI studies. Over the last several years, substantial clinical data has been generated regarding endogenous biomarkers for transporters expressed in both liver and kidney. DDIs via inhibition of hepatic organic anion transporting polypeptides (OATPs) 1B1/1B3 have the potential to substantially impact substrate drug exposure. Given the specific challenges in predicting OATP1Bmediated DDIs with existing methodologies (static and physiologic models), identification of reliable biomarkers for OATP1B would be particularly valuable. The OATP1B Biomarkers Working Group was formed under the IQ Consortium to assess coproporphyrin (CP)-I as a biomarker for informing OATP1B DDI risk using the robust clinical data available in literature. Through constructing a dataset and assessing the relationship between OATP1B substrate drug and CP-I exposure changes, the IQ working group identified changes in plasma CP-I exposure that may be used to prioritize, delay, or replace clinical OATP1B DDI studies. Subsequent recommendations for collection and interpretation of CP-I data will be discussed. This short course will also address the relative merits of other biomarkers for OATP1B activity, with certain bile acid conjugates showing greatest promise. In addition, biomarkers for renal transporters will be presented, including bile acid and cortisol metabolites for organic anion transporters (OATs) and creatinine and N1-methylnicotinamide for organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs). Specific biomarker applicability, including DDI risk assessment, will be discussed.

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SC 4.2 Clinical Studies on Pharmacogenomics and DDIs Involving Drug Transporters | Xinning Yang

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Open to view video. Drug-drug interaction (DDI) assessment is an integral part of drug development. These DDIs can involve the modulation of various transporters, which may affect drug concentrations in the systemic circulation and/or specific tissues, thereby impacting drug efficacy and/or safety. When in vitro experiment results and/or clinical data (including endogenous biomarkers) indicate that an investigational drug may affect transporters in vivo, clinical DDI studies are often conducted to characterize the impact to inform the labeling of drug products. Compared to CYP enzymes, substrates and inhibitors of transporters are generally less selective, which leads to some challenges when interpreting the results and extrapolating the finding obtained with one pair of substrate/perpetrator to another. This presentation will cover some considerations when designing a study, interpreting the result illustrated by case examples, and discussing lists for examples of in vivo transporter substrates/inhibitors in the regulatory guidances. Like CYP enzymes, transporter genes have polymorphisms affecting transporters' expression and activity. Pharmacogenetic studies/analyses may help determine the importance of certain transporters in the pharmacokinetics of drugs. The presentation will also discuss the utility and limitations of pharmacogenetic evaluation of transporters.

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SC 4.3 Drug Induced Organ Toxicity: Transporter Roles and Derisking Approaches | Jason Sprowl

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Open to view video. Drug transporters play an important role in modulating organ-specific exposure of drugs and many studies have underlined their role in contributing to organ toxicity. This session will highlight the characterization of several ABC transporters and solute carriers that are involved in drug toxicity, along with approaches to reduce the risk of such adverse events. Strategies including pharmacogenetic driven treatment options or consideration of harmful/beneficial drug-drug interactions will be discussed.

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SC 4.4 Approaches to Predict Human PK Profiles for Compounds Undergoing Transporter Mediated Clearance in Early Drug Development: From Dedrick Plot to PBPK Modeling | Xiaomin Liang

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Open to view video. Predicting human pharmacokinetics (PK) from in vitro and animal data is essential in the early drug development phase. During the lead optimization, developing a reliable method to accurately envisage human PK and assess the risk of drug-drug interactions (DDI) and PK variabilities in genetic polymorphism or targeted disease populations is crucial for a drug discovery program. Over the past decade, numerous methodologies were published in the prediction of two key PK parameters, clearance (CL) and volume of distribution at steady state (Vss). With the input of estimated bioavailability (F%) and absorption rate constant (ka), a one-compartmental kinetic model is commonly used to simulate the plasma concentration-time profile for an orally administrated molecule. However, the one-compartmental approach likely underpredicts terminal half-life (T1/2) and trough concentration (Ctrough) but overestimates the maximal concentration (Cmax) for compounds with bi- or multi-phasic PK profiles. To overcome this limitation, Dedrick and Wajima proposed empirical methods to transform plasma concentration-time curves from preclinical animals to human PK profiles by either correcting dose per body weight and species equivalent time scaling or superimposing plasma concentration-time profiles from across species by normalizing the time axis with the mean residence time (MRT) and the concentration axis with plasma concentration at steady state (Css). Although both methods offer potential advantages to manage the bi-phasic PK profiles, the reported predictivity of the human PK is poor. The active hepatic uptake contributes to both the systemic CL and Vss. Currently, the extended clearance concept (ECC) is proposed to define the rate-determining process and provide a diagnostic value of transporter-enzyme interplay. However, the method does not differentiate the changes in hepatic CL from the fast and steep distribution attributed to Vss because of transporter-mediated active organ (liver) distribution. To overcome the shortcomings of ECC, the physiologically-based pharmacokinetic (PBPK) modeling approach is increasingly used to predict human PK in the pharmaceutical industry. Unfortunately, directly scaling transporter-mediated CL from in vitro hepatocyte uptake data is challenging as significant and compound-dependent empirical scaling factors (SF) are needed to bridge the in vitro and in vivo (IVIVC) discrepancies. The short course presentation summarizes the conventional methods to predict human CL and Vss and instructs a strategic framework for developing a human PBPK model for substrates of organic anion-transporting polypeptide (OATP) transporters in drug discovery phase. By introducing an intermediate step in developing PBPK models in preclinical species, the SF for individual CL parameter is validated in the preclinical model. The calibrated SF can be integrated into the human model to predict plasma profiles. The human model is further applied to capture the PK variations, including DDI, subjects carrying OATP gene polymorphisms, and hepatic impairment patients.

Transporter Substrate/Inhibition/Induction, DDI | An ISSX 2023 Short Course

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