Etravirine lowers levels of maraviroc given at 300 or 600 mg twice daily

Mark Mascolini, NATAP.org

Etravirine may greatly lower concentrations of maraviroc when the drugs are taken without a ritonavir-boosted protease inhibitor (PI), according to results of a retrospective, multicenter French analysis of antiretroviral-experienced people [1]. Maraviroc concentrations were low regardless of whether this CCR5 antagonist was dosed at 300 or 600 mg twice daily.

Etravirine, the most recently licensed nonnucleoside, induces the CYP3A4 enzyme, while maraviroc is a CYP3A4 substrate. As a result, giving the drugs together may result in lower-than-normal maraviroc concentrations. Thus, a maraviroc dose of 600 mg twice daily is recommended with etravirine. Combinations of antiretrovirals with different mechanisms and with activity against virus resistant to the first three antiretroviral classes are favoured constituents of salvage regimens, which often exclude PIs because of resistance or toxicities.

To assess the impact of etravirine on maraviroc in treatment-experienced people, French investigators conducted this retrospective multicenter study of 67 people taking etravirine and maraviroc with or without one or two nucleosides, with or without raltegravir, and without a PI. The researchers excluded people taking other drugs likely to interact with maraviroc, and they excluded people with undetectable maraviroc levels. They figured trough concentrations (Ctrough, collected 12 hours after dosing) and Cave (any post dose concentration), and they set the target Ctrough at 75 ng/mL.

The 49 men (73%) and 18 women studied had a median age of 50 (IQR 46 to 55) and a median weight of 62 kg (IQR 61 to 70). Thirty people (45%) were taking 300 mg of maraviroc twice daily, 37 (55%) were taking 600 mg twice daily, and 50 (50%) were also taking raltegravir. Everyone took 200 mg of etravirine twice daily. The investigators analysed 106 samples to calculate Cave and 82 to calculate Ctrough.

In people taking maraviroc at 300 mg twice daily, median Cave and Ctrough were 63 ng/mL (IQR 29 to 127) and 53 ng/mL (IQR 27 to 84); for people taking 600 mg twice daily, median Cave and Ctrough were 62 ng/mL (IQR 35 to 90) and 59 ng/mL (IQR 36 to 84).

For the whole study group, 62% of Cave values and 67% of Ctroughs stood below the target of 75 ng/mL. Among people taking 300 mg of maraviroc twice daily, 60% of Cave values and 71% of Ctroughs were under 75 ng/mL. Among people taking 600 mg twice daily, 64% of Cave values and 65% of Ctroughs were under 75 ng/mL. Even when the Ctrough cutoff was 50 ng/mL, 39% of Ctroughs were suboptimal, regardless of maraviroc dose. So in this population, doubling the maraviroc dose did not lower the risk of subtherapeutic troughs.

Median etravirine Ctrough was 696 ng/mL (IQR 474 to 1068), which is about 180-fold higher than the protein binding-adjusted 50% effective concentration for etravirine against wild-type (nonmutant) virus. Median etravirine Ctrough did not differ significantly between people taking 300 mg of maraviroc twice daily and people taking 600 mg twice daily (813 and 679 ng/mL).

Surprisingly, the French team concluded, maraviroc Ctroughs were very similar with both maraviroc doses and quite lower than concentrations seen when the regimen contained a ritonavir-boosted PI. Those findings suggest that increasing the maraviroc dose has a modest effect on CYP3A4 induction by etravirine.

Two small cases series of treatment-experienced people starting maraviroc, etravirine, and raltegravir suggest that the combination can promote a good virologic response through 48 weeks [2,3].

comment

The method of determining Cavg here is different from that used previously by Pfizer. There was considerable discussion about maraviroc target concentrations.

References:

Solas C et al. Pharmacokinetic interaction between maraviroc and etravirine: a multicentre study in HIV-patients receiving an antiretroviral regimen without PI. 12th International Workshop on Clinical Pharmacology of HIV Therapy, 13-15 April 2011, Miami. Oral abstract O_13.
Youngblood C et al. Use of maraviroc-, raltegravir-, and etravirine-containing regimens in treatment-experienced patients: a case-series study. J Int Assoc Physicians AIDS Care (Chic). 2011 Mar 23. Epub ahead of print.
Nozza S et al. Raltegravir, maraviroc, etravirine: an effective protease inhibitor and nucleoside reverse transcriptase inhibitor-sparing regimen for salvage therapy in HIV-infected patients with triple-class experience. Letter to editor. AIDS. 2010;24:924-928.