Quantitative prediction of breast cancer resistant protein mediated drug‐drug interactions using physiologically‐based pharmacokinetic modeling

Costales, Chester; Lin, Jian; Kimoto, Emi; Yamazaki, Shinji; Gosset, J; Rodrigues, A. David; Lazzaro, Sarah; West, Mark; West, Michael; Varma, Manthena V.

doi:10.1002/psp4.12672

Cited by 29 publications

(36 citation statements)

References 48 publications

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“…Our previous studies, using a large set (n = 42) of OATP1B1 inhibitors, suggested that the clinical DDI risk is likely for inhibitors with R value > 1.5, although a quantitative relationship could not be seen between the R value and statin AUC ratios. 9,26 Later observation may suggest uncertainty in quantitative translation of in vitro Ki to in vivo Ki. In fact, inhibitor-specific in vitro-in vivo disconnect of about 2-fold to 37-fold was noted for OATP1B Ki based on extensive mechanistic PBPK analysis.…”

Section: Articlementioning

confidence: 99%

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Effect of a Ketohexokinase Inhibitor (PF‐06835919) on In Vivo OATP1B Activity: Integrative Risk Assessment Using Endogenous Biomarker and a Probe Drug

Tess

Kimoto

King‐Ahmad

et al. 2022

Clin Pharma and Therapeutics

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PF-06835919 is a first-in-class ketohexokinase inhibitor (KHKi), recently under development for the treatment of metabolic and fatty liver diseases, which inhibited organic anion transporting polypeptide (OATP)1B1 in vitro and presented drug-drug interaction (DDI) risk. This study aims to investigate the dose-dependent effect of KHKi on OATP1B in vivo activity. We performed an open-label study comparing pharmacokinetics of atorvastatin (OATP1B probe) dosed alone (20 mg single dose) and coadministered with two dose strengths of KHKi (50 and 280 mg once daily) in 12 healthy participants. Additionally, changes in exposure of coproporphyrin-I (CP-I), an endogenous biomarker for OATP1B, were assessed in the atorvastatin study (1.12-fold and 1.49-fold increase in area under the plasma concentration-time profile (AUC) with once-daily 50 and 280 mg, respectively), and a separate single oral dose study of KHKi alone (100-600 mg, n = 6 healthy participants; up to a 1.80-fold increase in AUC). Geometric mean ratios (90% confidence interval) of atorvastatin AUC following 50 and 280 mg KHKi were 1.14 (1.00-1.30) and 1.54 (1.37-1.74), respectively. Physiologically-based pharmacokinetic modeling of CP-I plasma exposure following a single dose of KHKi predicted in vivo OATP1B inhibition from about 13% to 70% over the 100 to 600 mg dose range, while using the in vitro inhibition potency (1.9 µM). Model-based analysis correctly predicted "no-effect" (AUC ratio < 1.25) at the low dose range and "weak" effect (AUC ratio < 2) on atorvastatin pharmacokinetics at the high dose range of KHKi. This study exemplified the utility of biomarker-informed modelbased approach in discerning even small effects on OATP1B activity in vivo, and to project DDI risk at the clinically relevant doses.

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Section: Articlementioning

confidence: 99%

“…and OATP1B inhibitors (e.g., rifampicin single dose). An extensively validated rosuvastatin PBPK model was directly adopted from Costales et al 26 The pitavastatin substrate model developed by Duan et al 27 and modified by Kimoto et al, 9 was used as is.…”

Section: Pbpk Modeling and Simulationsmentioning

confidence: 99%

Effect of a Ketohexokinase Inhibitor (PF‐06835919) on In Vivo OATP1B Activity: Integrative Risk Assessment Using Endogenous Biomarker and a Probe Drug

Tess

Kimoto

King‐Ahmad

et al. 2022

Clin Pharma and Therapeutics

Self Cite

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“…On the other hand, the specific uptake of rosuvastatin in our OATP1B1 expression system was not high enough to determine K i,OATP1B1 for CysA to support the substrate dependence in K i,OATP1B between rosuvastatin and CP‐I. We note that, even though CysA has been reported to inhibit BCRP in vitro, 23 in the current analysis, we did not consider inhibition of BCRP‐mediated transport of rosuvastatin by CysA in the PBPK model. This limitation may have resulted in underestimation of the k a and/or F a F g of rosuvastatin when co‐administered with CysA.…”

Section: Discussionmentioning

confidence: 76%

Physiologically‐based pharmacokinetic model‐based translation of OATP1B‐mediated drug–drug interactions from coproporphyrin I to probe drugs

Mochizuki

Aoki

Yoshikado

et al. 2022

Clinical Translational Sci

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The accurate prediction of OATP1B-mediated drug-drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically-based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming

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“…Although imperfect, the I gut /IC 50 value of ≥ 10 criterion appears to better predict a potential P-gp DDI than it does when applied to BCRP. 36,37 In fact, in the absence of OATP1B1 inhibition (which applies to abrocitinib), BCRP I gut / IC 50 values of 100-1000 did not necessarily result in an observed clinically meaningful DDI with rosuvastatin.…”

Section: Articlementioning

confidence: 99%

Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers

Vourvahis

Byon

Chang

et al. 2022

Clin Pharma and Therapeutics

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Abrocitinib is an oral Janus kinase 1 (JAK1) inhibitor currently approved in the United Kingdom for the treatment of moderate-to-severe atopic dermatitis (AD). As patients with AD may use medications to manage comorbidities, abrocitinib could be used concomitantly with hepatic and/or renal transporter substrates. Therefore, we assessed the potential effect of abrocitinib on probe drugs and endogenous biomarker substrates for the drug transporters of interest. In vitro studies indicated that, among the transporters tested, abrocitinib has the potential to inhibit the activities of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter 3 (OAT3), organic cation transporter 1 (OCT1), and multidrug and toxin extrusion protein 1 and 2K (MATE1/2K). Therefore, subsequent phase I, two-way crossover, open-label studies in healthy participants were performed to assess the impact of abrocitinib on the pharmacokinetics of the transporter probe substrates dabigatran etexilate (P-gp), rosuvastatin (BCRP and OAT3), and metformin (OCT2 and MATE1/2K), as well as endogenous biomarkers for MATE1/2K (N 1 -methylnicotinamide (NMN)) and OCT1 (isobutyryl-L -carnitine (IBC)). Co-administration with abrocitinib was shown to increase the plasma exposure of dabigatran by ~ 50%. In comparison, the plasma exposure and renal clearance of rosuvastatin and metformin were not altered with abrocitinib co-administration. Similarly, abrocitinib did not affect the exposure of NMN or IBC. An increase in dabigatran exposure suggests that abrocitinib inhibits P-gp activity. By contrast, a lack of impact on plasma exposure and/or renal clearance of rosuvastatin, metformin, NMN, or IBC suggests that BCRP, OAT3, OCT1, and MATE1/2K activity are unaffected by abrocitinib.

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Quantitative prediction of breast cancer resistant protein mediated drug‐drug interactions using physiologically‐based pharmacokinetic modeling

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 29 publications

References 48 publications

Effect of a Ketohexokinase Inhibitor (PF‐06835919) on In Vivo OATP1B Activity: Integrative Risk Assessment Using Endogenous Biomarker and a Probe Drug

Effect of a Ketohexokinase Inhibitor (PF‐06835919) on In Vivo OATP1B Activity: Integrative Risk Assessment Using Endogenous Biomarker and a Probe Drug

Physiologically‐based pharmacokinetic model‐based translation of OATP1B‐mediated drug–drug interactions from coproporphyrin I to probe drugs

Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers

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