Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity.
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Mathias AA, German P, Murray BP, Wei L, Jain A, West S, Warren D, Hui J, Kearney BP
Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity.
Clin Pharmacol Ther. 2010 Mar;87(3):322-9. doi: 10.1038/clpt.2009.228. Epub 2009 Dec 30.
- PubMed ID
- 20043009 [ View in PubMed]
- Abstract
GS-9350 is a new chemical entity under development as a potent, mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) isoforms. Its intended use is to increase the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. Unlike ritonavir, which is in current clinical use for this purpose, GS-9350 is devoid of anti-HIV activity. The pharmacokinetics of GS-9350 and its efficacy in increasing systemic exposure of the probe CYP3A substrate midazolam were examined in a study involving single- and multiple-dose escalations of GS-9350 from 50 to 400 mg. Single-dose escalation from 50 to 400 mg resulted in a 164-fold increase in GS-9350 exposure, whereas multiple-dose escalation in the dosage range of 50-300 mg resulted in a 47-fold increase in exposure. GS-9350 potently inhibited midazolam apparent clearance (95% reduction), similar in effect to ritonavir 100 mg. GS-9350 was generally well tolerated at all doses, and there was no evidence of dose-limiting toxicity. Establishing proof-of-concept, GS-9350 is currently under phase II development as a potential alternative to ritonavir for use with antiretroviral agents (including the HIV integrase inhibitor elvitegravir) that are often prescribed along with a "booster" drug.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Cobicistat Cytochrome P450 3A4 Protein Humans YesInhibitorDetails Cobicistat Cytochrome P450 3A5 Protein Humans YesInhibitorDetails Cobicistat Cytochrome P450 3A7 Protein Humans YesInhibitorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Cobicistat Cytochrome P450 2D6 Protein Humans NoSubstrateInhibitorDetails Cobicistat Cytochrome P450 3A4 Protein Humans NoSubstrateDetails Cobicistat Cytochrome P450 3A5 Protein Humans NoSubstrateDetails Cobicistat Cytochrome P450 3A7 Protein Humans NoSubstrateDetails