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Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interaction Potential of Vemurafenib Using R-Value and Physiologically-Based Pharmacokinetic Models.

ABSTRACT: Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important determinants of transporter-mediated drug-drug interactions (DDIs). Current studies assessed the OATP1B1 and OATP1B3-mediated DDI potential of vemurafenib, a kinase inhibitor drug with high protein binding and low aqueous solubility, using R-value and physiologically-based pharmacokinetic (PBPK) models. The total half-maximal inhibitory concentration (IC_50,total) values of vemurafenib against OATP1B1 and OATP1B3 were determined in 100% human plasma in transporter-overexpressing human embryonic kidney 293 stable cell lines. The unbound fraction of vemurafenib in human plasma before (f_u,plasma) and after addition into the uptake assay plate (f_u,plasma,inc) were determined by rapid equilibrium dialysis. There was no statistically significant difference between f_u,plasma and f_u,plasma,inc. Vemurafenib IC_50,total values against OATP1B1 and OATP1B3 are 175 ± 82 and 231 ± 26 μM, respectively. The R-values [R = 1 + f_u,plasma × I_in,max/(f_u,plasma,inc × IC_50,total)] were then simplified as R = 1+I_in,max/IC_50,total, and were 1.76 and 1.57 for OATP1B1 and OATP1B3, respectively. The simulated pravastatin AUC ratio was 1.28 when a single dose of pravastatin (40 mg) was co-administered with vemurafenib (960 mg, twice daily) at steady-state, compared to pravastatin alone. Both R-value and PBPK models predict that vemurafenib has the potential to cause OATP1B1- and OATP1B3-mediated DDIs.

SUBMITTER: Kayesh R

PROVIDER: S-EPMC7750294 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Differential Preincubation Effects of Nicardipine on OATP1B1- and OATP1B3-Mediated Transport in the Presence and Absence of Protein: Implications in Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions.

Project description:Impaired transport activity of hepatic OATP1B1 and OATP1B3 due to drug-drug interactions (DDIs) often leads to increased systemic exposure to substrate drugs (e.g., lipid-lowering statins). Since dyslipidemia and hypertension frequently coexist, statins are often concurrently used with antihypertensives, including calcium channel blockers (CCBs). OATP1B1/1B3-related DDIs in humans have been reported for several CCBs. To date, the OATP1B1/1B3-mediated DDI potential of CCB nicardipine has not been assessed. The current study was designed to assess the OATP1B1- and OATP1B3-mediated DDI potential of nicardipine using the R-value model, following the US-FDA guidance. IC50 values of nicardipine against OATP1B1 and OATP1B3 were determined in transporter-overexpressing human embryonic kidney 293 cells using [3H]-estradiol 17β-D-glucuronide and [3H]-cholecystokinin-8 as substrates, respectively, with or without nicardipine-preincubation in protein-free Hanks' Balanced Salt Solution (HBSS) or in fetal bovine serum (FBS)-containing culture medium. Preincubation with nicardipine for 30 min in protein-free HBSS buffer produced lower IC50 and higher R-values for both OATP1B1 and OATP1B3 compared to in FBS-containing medium, yielding IC50 values of 0.98 and 1.63 µM and R-values of 1.4 and 1.3 for OATP1B1 and OATP1B3, respectively. The R-values were higher than the US-FDA cut-off value of 1.1, supporting that nicardipine has the potential to cause OATP1B1/3-mediated DDIs. Current studies provide insight into the consideration of optimal preincubation conditions when assessing the OATP1B1/3-mediated DDIs in vitro.

| S-EPMC10052025 | biostudies-literature

Potential drug-drug interaction of olverembatinib (HQP1351) using physiologically based pharmacokinetic models.

Project description:Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) (including T315I-mutant disease), exhibits drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6. A physiologically-based pharmacokinetic (PBPK) model was constructed based on physicochemical and in vitro parameters, as well as clinical data to predict 1) potential DDIs between olverembatinib and CYP3A4 and CYP2C9 inhibitors or inducers 2), effects of olverembatinib on the exposure of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 substrates, and 3) pharmacokinetics in patients with liver function injury. The PBPK model successfully described observed plasma concentrations of olverembatinib from healthy subjects and patients with CML after a single administration, and predicted olverembatinib exposure increases when co-administered with itraconazole (strong CYP3A4 inhibitor) and decreases with rifampicin (strong CYP3A4 inducer), which were validated by observed data. The predicted results suggest that 1) strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib exposure by approximately 2.39-, 1.80- to 2.39-, and 1.08-fold, respectively; strong, and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29-, and 0.35- to 0.56-fold, respectively 2); olverembatinib, as a "perpetrator," would have no or limited impact on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activity 3); systemic exposure of olverembatinib in liver function injury with Child-Pugh A, B, C may increase by 1.22-, 1.79-, and 2.13-fold, respectively. These simulations inform DDI risk for olverembatinib as either a "victim" or "perpetrator".

| S-EPMC9792776 | biostudies-literature

Evaluation for Potential Drug-Drug Interaction of MT921 Using In Vitro Studies and Physiologically-Based Pharmacokinetic Models.

Project description:MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug-drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.

| S-EPMC8308925 | biostudies-literature

Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors.

Project description:Failure to recognize important features of a drug's pharmacokinetic characteristics is a key cause of inappropriate dose and schedule selection, and can lead to reduced efficacy and increased rate of adverse drug reactions requiring medical intervention. As oral chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) are particularly prone to cause drug-drug interactions as many drugs in this class are known or suspected to potently inhibit the hepatic uptake transporters OATP1B1 and OATP1B3. In this article, we provide a comprehensive overview of the published literature and publicly-available regulatory documents in this rapidly emerging field. Our findings indicate that, while many TKIs can potentially inhibit the function of OATP1B1 and/or OATP1B3 and cause clinically-relevant drug-drug interactions, there are many inconsistencies between regulatory documents and the published literature. Potential explanations for these discrepant observations are provided in order to assist prescribing clinicians in designing safe and effective polypharmacy regimens, and to provide researchers with insights into refining experimental strategies to further predict and define the translational significance of TKI-mediated drug-drug interactions.

| S-EPMC7559291 | biostudies-literature

Physiologically Based Pharmacokinetic Models for Prediction of Complex CYP2C8 and OATP1B1 (SLCO1B1) Drug-Drug-Gene Interactions: A Modeling Network of Gemfibrozil, Repaglinide, Pioglitazone, Rifampicin, Clarithromycin and Itraconazole.

Project description:BackgroundDrug-drug interactions (DDIs) and drug-gene interactions (DGIs) pose a serious health risk that can be avoided by dose adaptation. These interactions are investigated in strictly controlled setups, quantifying the effect of one perpetrator drug or polymorphism at a time, but in real life patients frequently take more than two medications and are very heterogenous regarding their genetic background.ObjectivesThe first objective of this study was to provide whole-body physiologically based pharmacokinetic (PBPK) models of important cytochrome P450 (CYP) 2C8 perpetrator and victim drugs, built and evaluated for DDI and DGI studies. The second objective was to apply these models to describe complex interactions with more than two interacting partners.MethodsPBPK models of the CYP2C8 and organic-anion-transporting polypeptide (OATP) 1B1 perpetrator drug gemfibrozil (parent-metabolite model) and the CYP2C8 victim drugs repaglinide (also an OATP1B1 substrate) and pioglitazone were developed using a total of 103 clinical studies. For evaluation, these models were applied to predict 34 different DDI studies, establishing a CYP2C8 and OATP1B1 PBPK DDI modeling network.ResultsThe newly developed models show a good performance, accurately describing plasma concentration-time profiles, area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) values, DDI studies as well as DGI studies. All 34 of the modeled DDI AUC ratios (AUC during DDI/AUC control) and DDI Cmax ratios (Cmax during DDI/Cmax control) are within twofold of the observed values.ConclusionsWhole-body PBPK models of gemfibrozil, repaglinide, and pioglitazone have been built and qualified for DDI and DGI prediction. PBPK modeling is applicable to investigate complex interactions between multiple drugs and genetic polymorphisms.

| S-EPMC6885506 | biostudies-literature

Physiologically-based pharmacokinetic model of sparsentan to evaluate drug-drug interaction potential.

Project description:Sparsentan is a dual endothelin/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. In vitro data indicate that sparsentan is likely to inhibit or induce various CYP enzymes at therapeutic concentrations. Sparsentan as a victim and perpetrator of CYP3A4 mediated drug-drug interactions (DDIs) has been assessed clinically. A mechanistic, bottom-up, physiologically-based pharmacokinetic (PK) model for sparsentan was developed based on in vitro data of drug solubility, formulation dissolution and particle size, drug permeability, inhibition and induction of metabolic enzymes, and P-glycoprotein (P-gp) driven efflux. The model was verified using clinical PK data from healthy adult volunteers administered single and multiple doses in the fasted and fed states for a wide range of sparsentan doses. The model was also verified by simulation of clinically observed DDIs. The verified model was then used to test various DDI simulations of sparsentan as a perpetrator and victim of CYP3A4 using an expanded set of inducers and inhibitors with varying potency. Additional perpetrator and victim DDI simulations were performed using probes for CYP2C9 and CYP2C19. Simulations were conducted to predict the effect of complete inhibition of P-gp inhibition on sparsentan absorption and clearance. The predictive simulations indicated that exposure of sparsentan could increase greater than two-fold if co-administered with a strong CYP3A4 inhibitor, such as itraconazole. Other potential DDI interactions as victim or perpetrator were all within two-fold of control. The effect of complete P-gp inhibition on sparsentan PK was negligible.

| S-EPMC10864932 | biostudies-literature

Physiologically-Based Pharmacokinetic Models for CYP1A2 Drug-Drug Interaction Prediction: A Modeling Network of Fluvoxamine, Theophylline, Caffeine, Rifampicin, and Midazolam.

Project description:This study provides whole-body physiologically-based pharmacokinetic models of the strong index cytochrome P450 (CYP)1A2 inhibitor and moderate CYP3A4 inhibitor fluvoxamine and of the sensitive CYP1A2 substrate theophylline. Both models were built and thoroughly evaluated for their application in drug-drug interaction (DDI) prediction in a network of perpetrator and victim drugs, combining them with previously developed models of caffeine (sensitive index CYP1A2 substrate), rifampicin (moderate CYP1A2 inducer), and midazolam (sensitive index CYP3A4 substrate). Simulation of all reported clinical DDI studies for combinations of these five drugs shows that the presented models reliably predict the observed drug concentrations, resulting in seven of eight of the predicted DDI area under the plasma curve (AUC) ratios (AUC during DDI/AUC control) and seven of seven of the predicted DDI peak plasma concentration (Cmax ) ratios (Cmax during DDI/Cmax control) within twofold of the observed values. Therefore, the models are considered qualified for DDI prediction. All models are comprehensively documented and publicly available, as tools to support the drug development and clinical research community.

| S-EPMC6539736 | biostudies-literature

Evaluation of drug-drug interaction potential for pemigatinib using physiologically based pharmacokinetic modeling.

Project description:Pemigatinib is a potent inhibitor of fibroblast growth factor receptor being developed for oncology indications. It is primarily metabolized by cytochrome P450 (CYP) 3A4, and the ratio of estimated concentration over concentration required for 50% inhibition ratio for pemigatinib as an inhibitor of P-glycoprotein (P-gp), organic cation transporter-2 (OCT2), and multidrug and toxin extrusion protein-1 (MATE1) exceeds the cutoff values established in regulatory guidance. A Simcyp minimal physiologically based pharmacokinetic (PBPK) with advanced dissolution, absorption, and metabolism absorption model for pemigatinib was developed and validated using observed clinical pharmacokinetic (PK) data and itraconazole/rifampin drug-drug interaction (DDI) data. The model accurately predicted itraconazole DDI (approximate 90% area under the plasma drug concentration-time curve [AUC] and approximate 20% maximum plasma drug concentration [Cmax ] increase). The model underpredicted rifampin induction by 100% (approximate 6.7-fold decrease in AUC and approximate 2.6-fold decrease in Cmax in the DDI study), presumably reflecting non-CYP3A4 mechanisms being impacted. The verified PBPK model was then used to predict the effect of other CYP3A4 inhibitors/inducers on pemigatinib PK and pemigatinib as an inhibitor of P-gp or OCT2/MATE1 substrates. The worst-case scenario DDI simulation for pemigatinib as an inhibitor of P-gp or OCT2/MATE1 substrates showed only a modest DDI effect. The recommendation based on this simulation and clinical data is to reduce pemigatinib dose for coadministration with strong and moderate CYP3A4 inhibitors. No dose adjustment is required for weak CYP3A4 inhibitors. The coadministration of strong and moderate CYP3A4 inducers with pemigatinib should be avoided. PBPK modeling suggested no dose adjustment with P-gp or OCT2/MATE1 substrates.

| S-EPMC9286713 | biostudies-literature

Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir.

Project description:Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl-β-D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5-1.9-fold for Cmax and 1.9-2.8-fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant.

| S-EPMC5599937 | biostudies-literature

Complete OATP1B1 and OATP1B3 deficiency underlies human Rotor syndrome.

Project description:Rotor syndrome is an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, near-absent hepatic uptake of anionic diagnostics, and coproporphyrinuria. The mechanistic basis of other hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome has remained enigmatic. The existing paradigm of hepatic bilirubin excretion postulates a unidirectional elimination pathway: Uptake of conjugated bilirubin from blood by hepatocytes, glucuronidation of bilirubin, and excretion of conjugated bilirubin into bile by ABCC2, a canalicular bilirubin-glucuronide and xenobiotic export pump. An analogous view holds for drugs conjugated in the liver. Here we demonstrate by molecular-genetic analysis of 8 Rotor-syndrome families that Rotor syndrome is a two-gene disorder, with impaired hepatic re-uptake of bilirubin-glucuronide caused by complete deficiencies in the hepatic organic anion transporting polypeptides OATP1B1 and OATP1B3.

2012-01-16 | GSE33733 | GEO

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