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  12th International Workshop on Clinical Pharmacology of HIV Therapy
Miami, FL April 13-15, 2011
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No Dolutegravir (GSK572, integrase) Dose Adjustment Needed With Efavirenz or Tipranavir/Ritonavir
  12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
Separate pharmacokinetic studies in healthy adults without HIV indicated that the experimental integrase inhibitor dolutegravir (S/GSK1349572) needs no dose adjustment in antiretroviral-naive people when given with efavirenz or ritonavir-boosted tipranavir [1]. Although dolutegravir trough concentrations dropped about 75% with either efavirenz or tipranavir/ritonavir, the levels attained were equivalent to those found to be efficacious in an earlier dose-ranging study in people with HIV.
Dolutegravir, an unboosted, once-daily integrase inhibitor being developed by GlaxoSmithKline, (GSK) is in phase 3 clinical development for antiretroviral-naive and experienced people. Earlier research showed a 70% drop in dolutegravir area under the concentration-time curve (AUC) when given to healthy volunteers with etravirine, the newest nonnucleoside [2]. Giving a boosted protease inhibitor with dolutegravir and etravirine markedly curtailed the magnitude of this interaction.
GSK investigators planned two new trials in healthy volunteers to assess interactions between dolutegravir and efavirenz or tipranavir/ritonavir. In the first study 12 volunteers took a single 100-mg dose of dolutegravir. After more than 6 days taking no drug, they took 50 mg of dolutegravir once daily for 5 days, then dolutegravir plus 600 mg of efavirenz once daily for 14 days. In the second study 18 volunteers took 50 mg of dolutegravir once daily for 5 days, then 500/200 mg of tipranavir/ritonavir twice daily (without dolutegravir) for 7 days, then dolutegravir plus tipranavir/ritonavir for 5 days.
Volunteers tolerated dolutegravir plus efavirenz well, no serious adverse events occurred, and no one taking these drugs dropped out of the study. Photosensitivity was the only grade 2 adverse event. Four of 18 people (22%) taking the integrase inhibitor with tipranavir/ritonavir had to drop out because of liver enzyme elevations that occurred during administration of tipranavir/ritonavir without dolutegravir.
Dolutegravir concentrations in plasma were lower when taken with efavirenz than when taken alone--57% lower for AUC, 39% lower for maximum concentration (Cmax), and 75% lower for minimum concentration (Cmin). Coadministration of tipranavir/ritonavir also lowered dolutegravir plasma concentrations--59% for AUC, 46% for Cmax, and 76% for Cmin.
The GSK researchers proposed that efavirenz and tipranavir/ritonavir lower dolutegravir exposure through induction of UGT1A1 and CYP3A4. Nevertheless, dolutegravir concentrations remained well above the protein binding-adjusted 90% inhibitory concentration of dolutegravir for nonresistant virus and at levels that proved effective in a phase 1 trial in people with HIV. As a result, the investigators saw no need for dose adjustments if dolutegravir is taken with efavirenz or tipranavir/ritonavir by antiretroviral-naive people.
Dolutegravir is also being studied in people with raltegravir-resistant virus. In a phase 2 trial presented at the 2011 Conference on Retroviruses, twice-daily dolutegravir controlled replication of raltegravir-resistant virus, including virus bearing Q148 resistance mutations [3].
1. Song I, Borland J, Lou Y, et al. Effects of enzyme inducers, tipranavir and efavirenz, on the pharmacokinetics of the integrase inhibitor, dolutegravir (S/GSK1349572). 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_02.
2. Song I, Min S, Borland J, et al. The effect of etravirine alone and with boosted protease inhibitors on the pharmacokinetics of the integrase inhibitor, S/GSK1349572. 11th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2010. Sorrento, Italy. Abstract 26. http://www.natap.org/2010/PK/PK_11.htm.
3. Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 151LB. http://www.natap.org/2011/CROI/croi_33.htm.