Clinical Implications of Altered Drug Transporter Abundance/Function and PBPK Modeling in Specific Populations: An ITC Perspective

Abstract

The role of membrane transporters on pharmacokinetics (PKs), drug-drug interactions (DDIs), pharmacodynamics (PDs), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in the diseased patient population or specific populations, such as pediatrics or pregnancy, is still emerging. This white paper highlights recent advances in studying the changes in transporter expression and activity in various diseases (i.e., renal and hepatic impairment and cancer) and some specific populations (i.e., pediatrics and pregnancy) with the focus on clinical implications. Proposed alterations in transporter abundance and/or activity in diseased and specific populations are based on (i) quantitative transporter proteomic data and relative abundance in specific populations vs. healthy adults, (ii) clinical PKs, and emerging transporter biomarker and/or pharmacogenomic data, and (iii) physiologically-based pharmacokinetic modeling and simulation. The potential for altered PK, PD, and toxicity in these populations needs to be considered for drugs and their active metabolites in which transporter-mediated uptake/efflux is a major contributor to their absorption, distribution, and elimination pathways and/or associated DDI risk. In addition to best practices, this white paper discusses current challenges and knowledge gaps to study and quantitatively predict the effects of modulation in transporter activity in these populations, together with the perspectives from the International Transporter Consortium (ITC) on future directions.

Protein Abundance of Drug Transporters in Human Hepatitis C Livers

“…Velpatasvir is a substrate of P-gp, BCRP, and OATP1B1/1B3 (some 23% of dose metabolized by CYP3A4, 2C8, and 2B6, with minimal renal elimination and some biliary excretion), and its AUC levels (when co-administered with sofosbuvir) increase stepwise in mild (by 9.2%) and moderate (29.9%) HCV-induced hepatic impairment. Co-administration of cyclosporine, a known inhibitor of uptake carrier and efflux transporters, including OATPs, P-gp, MRP2, and BCRP [ 25 ], resulted in AUC increase in the drug by ~two-fold (summarized in [ 26 ]). The studies in hepatic impairment (accessed by Child–Pugh score) in HCV-negative patients with liver cirrhosis, hepatitis B infection, alcoholic liver disease, or previous HCV infection demonstrated an AUC increase in glecaprevir (a substrate of P-gp, BCRP, and OATP1B1/1B3, with about 28% of dose metabolized mostly by CYP3A4, minimal renal and some biliary excretion) (when co-medicated with pibrentasvir) in mild (by 33%), moderate (by 100%), and severe (1010%) hepatic impairment.…”

“…The studies in hepatic impairment (accessed by Child–Pugh score) in HCV-negative patients with liver cirrhosis, hepatitis B infection, alcoholic liver disease, or previous HCV infection demonstrated an AUC increase in glecaprevir (a substrate of P-gp, BCRP, and OATP1B1/1B3, with about 28% of dose metabolized mostly by CYP3A4, minimal renal and some biliary excretion) (when co-medicated with pibrentasvir) in mild (by 33%), moderate (by 100%), and severe (1010%) hepatic impairment. Administration of a single 100 mg and single 400 mg cyclosporine dose increased the drug AUC by 37% and five-fold, respectively (summarized in [ 26 ]). In the same type of patients as in the case of glecaprevir, pharmacokinetics of pibrentasvir (a substrate of P-gp and BCRP; not metabolized, with some biliary elimination; 96.6% of radiolabeled drug recovered in feces with negligible metabolism observed and no measurable radioactivity in urine) was evaluated.…”

Physiologically‐Based Pharmacokinetic Modeling‐Guided Dose Management of Oral Anticoagulants when Initiating Nirmatrelvir/Ritonavir (Paxlovid) for COVID‐19 Treatment

“… 8 , 9 Notably, application of PBPK models in diseased and specific populations, in addition to DDIs, has demonstrated promising performance in the evaluation of clinically relevant yet untested scenarios. 23 PBPK‐guided dose recommendations, as an alternative to real‐world studies, have been approved in several drug labels in recent years, 23 , 24 and has been applied for nirmatrelvir/ritonavir‐related study. 25 In view of this urgent conundrum where clinical studies cannot be conducted in a timely manner, our study aimed to utilize a ritonavir PBPK model, which was validated against multiple DDI data and elimination pathways, to investigate the DDI potential of ritonavir with rivaroxaban and warfarin, and offer dosing and risk management strategy, during and after 5‐days of nirmatrelvir/ritonavir treatment.…”

“…However, direct clinical data between nirmatrelvir/ritonavir and oral anticoagulants are still limited 8,9 . Notably, application of PBPK models in diseased and specific populations, in addition to DDIs, has demonstrated promising performance in the evaluation of clinically relevant yet untested scenarios 23 . PBPK‐guided dose recommendations, as an alternative to real‐world studies, have been approved in several drug labels in recent years, 23,24 and has been applied for nirmatrelvir/ritonavir‐related study 25 .…”

Predicting changes in the pharmacokinetics of CYP3A‐metabolized drugs in hepatic impairment and insights into factors driving these changes

“…For example, the change in the expression of DMET in the liver depends on the etiology of the disease (e.g., alcoholic vs. hepatitis C cirrhosis). 7,[9][10][11][12][13] Alteration of hepatic function and other physiological parameters caused by HI leads to changes in drug pharmacokinetics (PK) that may require adjustment of drug dosage. For example, the area under the plasma concentration-time curve (AUC) of a drug, primarily metabolized by the cytochrome P450 (CYP) 3A enzymes, can be increased more than 10-fold in HI versus healthy volunteers (HV).…”