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Lower Maraviroc Dose Needed With Darunavir
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8th International Workshop on Pharmacology of HIV Therapy
April 16-18, 2007, Budapest
Mark Mascolini
Darunavir/ritonavir boosts levels of the CCR5 antagonist maraviroc up to 4-fold, according to results of a Pfizer study [1]. Pfizer's John Davis suggested maraviroc's dose will need to be halved when given with darunavir/ritonavir, but some attendees felt a bigger dose cut may be appropriate. Pfizer is already recommending slicing maraviroc's dose in half when using it in an expanded access program with all other protease inhibitors (PIs) except tipranavir/ritonavir. Maraviroc had no impact on levels of darunavir or ritonavir in this study.
Inhibitors or inducers of the liver enzyme CYP3A4 or the drug transporter P-glycoprotein may all affect maraviroc concentrations. Ritonavir is a particularly strong inhibitor of CYP3A4. Maraviroc, which will probably be licensed later this year, seems a likely element of salvage regimens including the new PI darunavir in people with CCR5-tropic virus.
To test potential interactions between maraviroc and darunavir/ritonavir, Pfizer researchers gave one or both drugs to 12 healthy volunteers in a placebo-controlled crossover trial. Volunteers took maraviroc at a dose of 150 mg (twice daily), followed in 1.5 hours by 600/100 mg of darunavir/ritonavir (twice daily). Everyone fasted at least 2 hours before taking maraviroc and at least 1 hour afterwards. They took maraviroc (is this a misprint & it should be darunavir) or placebo within 15 minutes of a meal. After 10 days of therapy volunteers took no drugs for 2 weeks. Then they followed the same regimen, except now taking placebo if they took darunavir in the first phase and vice versa.
Although the food and dosing sequence in this study suggests optimal cotreatment with maraviroc plus darunavir may be complicated, Pfizer's Davis assured workshop attendees that maraviroc and darunavir can be dosed together with food. He also suggested that giving maraviroc with food would not affect his results greatly, even though he noted food lowers maraviroc exposure 50%.
Darunavir and ritonavir concentrations with maraviroc matched those seen in earlier studies of this dose without maraviroc. But average 12-hour maraviroc area under the concentration-time curve (AUC12) and maximum concentration (Cmax) on day 10 were three to four times higher with darunavir/ritonavir than with placebo (Table). Average time to maraviroc maximum concentration did not vary substantially with or without darunavir/ritonavir (2.4 versus 2.23 hours).
![level-1.gif](../images/042407/level-1.gif)
Results indicate that, as with other PIs, darunavir/ritonavir raises concentrations of maraviroc by inhibiting its metabolism. Some workshop attendees suggested an even lower maraviroc dose may be warranted with darunavir/ritonavir. Davis said Pfizer will probably propose the 50% cut in talks with the Food and Drug Administration.
Reference
1. Abel S, Ridgway C, Hamlin J, et al. An open, randomized, 2-way crossover study to investigate the effects of darunavir/ritonavir on the pharmacokinetics of maraviroc in healthy subjects. 8th International Workshop on Pharmacology of HIV Therapy. April 16-18, 2007. Budapest. Abstract 55.
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