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Once-Daily Etravirine Plus Darunavir/Ritonavir With No NRTIs: 48-Week PKs
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14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
A once-daily regimen combining the nonnucleoside etravirine and the protease inhibitors darunavir/ritonavir--and excluding nucleosides (NRTIs)--yielded concentrations similar to those seen in prior trials, according to results of a 48-week pharmacokinetic analysis in antiretroviral-experienced people or naive individuals with transmitted resistance [1]. Having a lower etravirine 24-hour area under the concentration-time curve (AUC24h) appeared to heighten chances of a 48-week viral load above 50 copies.
The approximate 41-hour half-life of etravirine supports once-daily dosing, though it is now licensed for antiretroviral-experienced people at a dose of 200 mg twice daily. Darunavir/ritonavir at a once-daily dose of 800/100 mg is licensed for antiretroviral-naive people and treatment-experienced individuals without darunavir resistance mutations.
Janssen researchers and collaborators conducted the INROADS trial (http://www.clinicaltrials.gov/ct2/show/NCT01199939) to assess the effectiveness, pharmacokinetics, and safety of once-daily etravirine (400 mg) with darunavir/ritonavir (800/100 mg) in antiretroviral-experienced people or treatment-naive individuals with transmitted resistance mutations. The presentation at the Pharmacology Workshop focused on a week-4 pharmacokinetic substudy and week-48 population pharmacokinetics.
The study involved 49 people with a median age of 45. Thirty-nine participants were men, 24 were African American, 16 were white, 8 were American Indian, and 1 was Hispanic. Median weight stood at 79.2 kg and median body mass index at 26 kg/m(2) (near the lower end of the overweight range).
In the week-48 population pharmacokinetic analysis, etravirine AUC24h and 12-hour concentration averaged 14,600 ng x h/mL and 424 ng/mL. These values were similar to etravirine concentrations in the SENSE trial, which dosed etravirine at 400 mg once daily plus nucleosides in antiretroviral-naive people. Darunavir AUC24h and trough concentrations averaged 109,000 ng x h/mL and 2810 ng/mL, similar to levels in the ARTEMIS trial, which used the same once-daily dose of darunavir/ritonavir with tenofovir/emtricitabine in naive people.
Overall, 40 of 49 people (82%) had a week-48 viral load below 50 copies. Neither darunavir AUC24h nor darunavir trough correlated with a viral load below 50 copies at week 48. There did seem to be a relation between etravirine AUC24h and virologic response. When the researchers divided participants into quartiles reflecting the range of AUCs, they found 48-week sub-50-copy response rates of 69% and 75% in the two lower AUC quartiles, versus 92% and 92% in the two upper AUC quartiles. Analysis of DUET trial data on etravirine yielded a similar association.
Full pharmacokinetic data were available for 7 people enrolled in the 4-week intensive PK substudy. The investigators compared etravirine and darunavir concentrations with those measured in a previous pharmacokinetic study of etravirine plus darunavir/ritonavir at the same once-daily doses (http://clinicaltrials.gov/show/NCT00534352). Compared with the prior study, in the new study etravirine minimum concentration (Cmin) was 34% lower, AUC24h was 12% lower, and maximum concentration (Cmax) was nearly the same. Darunavir Cmin, Cmax, and AUC24h were 66%, 69%, and 77% higher in the new study.
The researchers concluded that the concentrations achieved with once-daily etravirine and darunavir in antiretroviral-experienced people or naive individuals with transmitted resistance "were adequate for effective virologic control." But they cautioned that etravirine is not licensed at the once-daily dose.
Reference
1. Kakuda TN, Brochot A, McLeay S, et al. Pharmacokinetics and pharmacodynamics of once-daily etravirine and darunavir/ritonavir in early treatment-experienced subjects. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract PP_06.
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