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PBPK modeling to characterize the interplay between metabolism and transport in the disposition of simeprevir in healthy volunteers and HCV infected patients
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Reported by Jules Levin
15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, Washington DC; May 19-21, 2014
Sivi Ouwerkerk-Mahadevan1 and Jan Snoeys1
1Janssen Research & Development, Beerse, Belgium
15th Intl Wrkshp Clinical Pharm HIV Therapy The 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy - written by Courtney V. Fletcher, Pharm.D. Dean and Professor College of Pharmacy University of Nebraska Medical Center Jennifer J. Kiser, Pharm.D. Assistant Professor School of Pharmacy University of Colorado at Denver - (06/11/14)
Kiser reports-
"1. Reduced Activity or Expression of Liver Uptake Transporter May Explain Higher Plasma Levels of HCV Drugs in Asians.
Several studies have found higher plasma exposures of HCV agents in Asian populations. This is sometimes attributed to weight differences, but Sivi Ouwerkerk-Mahadaven presented data from physiologic based pharmacokinetic modeling with simeprevir which suggests Japanese patients have a 15% lower liver volume, lower CYP3A4 abundance, and intrinsically lower OATP1B1 activity and in fact may have lower liver levels of simeprevir, but higher plasma levels. An analysis of ~1200 Asian and non-Asian subjects receiving asunaprevir (P_32) failed to identify differences in the genes encoding OATP1B1 or OATP2B1 as the cause for higher plasma levels of asunaprevir in Asians and instead postulate that there may be population differences in cell surface expression."
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