Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B‐Mediated Drug–Drug Interactions Using Population Pharmacokinetic Modeling and Simulation

Barnett, S.; Ogungbenro, Kayode; Ménochet, Karelle; Shen, Hong; Lai, Yurong; Humphreys, W. Griffith; Galetin, Aleksandra

doi:10.1002/cpt.983

Cited by 59 publications

(148 citation statements)

References 37 publications

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“…Subsequently, we evaluated the predictability of the DDIs between statins and RIF in the same clinical dataset, taking into account the difference between the in vitro K i of RIF for statins and CP‐I. Accounting for intersubstrate differences in K i is consistent with the recent report of Barnett et al ., who considered the IC 50 values of RIF for both CP‐I and rosuvastatin in vitro and conducted mixed model analysis of clinical interaction data. Such considerations enhance the value of a PBPK model used to translate CP‐I interaction data to other OATP1B substrates.…”

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confidence: 69%

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PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3

Yoshikado

Toshimoto²,

Maeda

et al. 2018

CPT Pharmacom & Syst Pharma

110

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The aim of the present study was to establish a physiologically based pharmacokinetic (PBPK) model for coproporphyrin I (CP‐I), a biomarker supporting the prediction of drug‐drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B), using clinical DDI data with an OATP1B inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (K i,u,OATP1Bs) and multidrug resistance‐associated protein two‐mediated biliary excretion were estimated as 0.23 and 0.87 μM, respectively, from previous reports. Sensitivity analysis demonstrated that the K i,u,OATP1Bs and biosynthesis rate of CP‐I affected the magnitude of the interaction. K i,u,OATP1Bs values optimized by nonlinear least‐squares fitting were ~0.5‐fold of the initial value. It was determined that the blood concentration‐time profiles of four statins were well‐predicted using corrected individual K i,u,OATP1B values (ratio of in vitro K i,u(statin)/in vitro K i,u(CP‐I)). In conclusion, PBPK modeling of CP‐I supports dynamic prediction of OATP1B‐mediated DDIs.

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confidence: 69%

“…Barnett et al . estimated in vivo K i,u for the RIF‐mediated inhibition of hepatic elimination clearance using empirical models for CP‐I and rosuvastatin.…”

Section: Discussionmentioning

confidence: 99%

PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3

Yoshikado

Toshimoto²,

Maeda

et al. 2018

CPT Pharmacom & Syst Pharma

110

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“…Accordingly, the change in renal clearance is unlikely the cause of the observed increase in plasma concentration, especially for coproporphyrin I. In addition, recent model‐based analysis suggested that renal clearance of coproporphyrin I accounts for ≈15% of total elimination . Therefore, even the complete suppression of renal elimination cannot explain the observed increase in plasma concentration.…”

Section: Discussionmentioning

confidence: 95%

Effect of OATP1B1/1B3 Inhibitor GDC‐0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects

Liu¹,

Cheeti²,

Yoshida³

et al. 2018

The Journal of Clinical Pharma

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Developed as an oral anticancer drug to treat estrogen receptor-positive breast cancer, GDC-0810 was shown to be a potent inhibitor of organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) from an in vitro assay. A clinical study was conducted to assess the drug-drug interaction potential between GDC-0810 and pravastatin, which is a relatively selective and sensitive OATP1B1/1B3 substrate. Fifteen healthy female subjects of non-childbearing potential were enrolled in the study. On day 1 in period 1, a single 10-mg dose of pravastatin was administered to all subjects. Following a 4-day washout period, 600 mg of GDC-0810 was administered once daily on days 5 through 8 in period 2 to achieve steady-state concentrations. On day 7, a single dose of 10-mg pravastatin was coadministered with the 600-mg GDC-0810 dose. Concentrations of pravastatin (periods 1 and 2) and GDC-0810 (period 2 only) were quantified in blood samples and subsequently used to calculate the pharmacokinetics (PK) parameters. The pravastatin mean maximal concentration and area under the curve values were approximately 20% and 41% higher, respectively, following pravastatin coadministration with GDC-0810 compared to pravastatin alone. Based on the magnitude of change in this drug-drug interaction study, dose adjustments for pravastatin (and other OATP1B1/1B3 substrates) were not considered necessary when administered with GDC-0810. Retrospectively, the endogenous biomarkers of OATP1B1/1B3, coproporphyrin I and III, were also measured and showed changes comparable to those of pravastatin, indicating their utility in detecting weak inhibition of OATP1B1/1B3 in the clinical setting.

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“…made an assumption that nonhepatic clearance is dominated by urinary elimination. However, an earlier model‐based analysis of CPI, which was based on C‐labeled coproporphyrin dosing, suggested some involvement of nonbiliary, nonrenal elimination pathways . Overall, we currently have incomplete understanding of the elimination profiles of CPI.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Barnett et al . reported model‐based analyses of CPI kinetic profiles in the presence of rifampin and demonstrated that similar in vivo K i values can be obtained from CPI and rosuvastatin kinetic profiles.…”

mentioning

confidence: 93%

Quantitative Prediction of OATP‐Mediated Drug‐Drug Interactions With Model‐Based Analysis of Endogenous Biomarker Kinetics

Yoshida¹,

Guo

Sane³

2018

CPT Pharmacom & Syst Pharma

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Quantitative prediction of the magnitude of transporter‐mediated clinical drug‐drug interactions (DDIs) solely from in vitro inhibition data remains challenging. The objective of the present work was to analyze the kinetic profile of an endogenous biomarker for organic anion‐transporting polypeptides 1B (OATP1B), coproporphyrin I (CPI), and to predict clinical DDIs with a probe OATP1B substrate (pravastatin) based on “in vivo” inhibition constants (Ki). The CPI kinetics in the presence and absence of strong and weak OATP1B inhibitors (rifampin and GDC‐0810) were described well with a one‐compartment model, and in vivo Ki were estimated. Clinical DDIs between pravastatin and these inhibitors were predicted using physiologically based pharmacokinetic (PBPK) models coupled with the estimated in vivo Ki and predicted magnitude matched well with the observed DDIs. In conclusion, model‐based analysis of the CPI profile has the potential to quantitatively predict liability of a new molecular entity (NME) as an OATP1B inhibitor early in drug development.

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Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B‐Mediated Drug–Drug Interactions Using Population Pharmacokinetic Modeling and Simulation

Cited by 59 publications

References 37 publications

PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3

PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3

Effect of OATP1B1/1B3 Inhibitor GDC‐0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects

Quantitative Prediction of OATP‐Mediated Drug‐Drug Interactions With Model‐Based Analysis of Endogenous Biomarker Kinetics

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