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

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          Abstract

          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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          Author and article information

          Journal
          J Clin Pharmacol
          Journal of clinical pharmacology
          Wiley
          1552-4604
          0091-2700
          November 2018
          : 58
          : 11
          Affiliations
          [1 ] Clinical Pharmacology, Genentech Inc., South San Francisco, CA, USA.
          [2 ] Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA, USA.
          [3 ] Early Clinical Development, Genentech Inc., South San Francisco, CA, USA.
          [4 ] Clinical Safety, Genentech Inc., South San Francisco, CA, USA.
          Article
          10.1002/jcph.1261
          29786857
          4967c0f7-3344-45ea-a52c-02a09437335f
          History

          OATP,coproporphyrin I and III,drug-drug interaction,endogenous biomarker,statin

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