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Clinical Pharmacokinetics of Darunavir

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Abstract

Darunavir (TMC114) is a newly developed HIV-1 protease inhibitor with potent antiviral activity against both wild-type and multidrug resistant HIV-1 strains. The drug is currently approved by the US FDA for antiretroviral treatment-experienced patients with limited therapeutic options. The approved dosage of darunavir is 600mg in combination with ritonavir 100mg twice daily. Darunavir is rapidly absorbed after oral administration, reaching peak plasma concentrations after 2.5–4 hours. Absorption is followed by a fast distribution/elimination phase and a subsequent slower elimination phase with a terminal elimination half-life of 15 hours in the presence of low-dose ritonavir. Darunavir is approximately 95% plasma protein bound, mainly to α1-acid glycoprotein. Systemic exposure is increased by 30% when darunavir is taken with a meal. Darunavir is extensively and almost exclusively metabolised by cytochrome P450 (CYP) 3A4. Coadministration with small doses of the strong CYP3A4 inhibitor ritonavir results in an increase in darunavir bioavailability from 37% to 82%. Darunavir and its metabolites are mainly excreted in faeces (79.5%) and, to a lesser extent, in urine (13.9%). With regard to the necessary coadministration with low-dose ritonavir as a potent CYP3A4 inhibitor, coadministration of other substrates of CYP3A4 with darunavir/ritonavir requires caution or is even contraindicated. Guidance is derived from drug-drug interaction trials and experience from comparable ritonavir-boosted protease inhibitor regimens.

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  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

No sources of funding were used to assist in the preparation of this review. Dr Keikawus Arastéh received honoraria for participation in advisory boards for Tibotec, Inc. and received fees as the head investigator for the German sites in the darunavir trials TMC114-C207, TMC114-C213, TMC114-C215 and TMC114-C214. Dr Michael Rittweger has no conflicts of interest that are directly relevant to the content of this review.

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    Michael Rittweger &  Keikawus Arastéh

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Rittweger, M., Arastéh, K. Clinical Pharmacokinetics of Darunavir. Clin Pharmacokinet 46, 739–756 (2007). https://doi.org/10.2165/00003088-200746090-00002

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