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Good 4-Week Dolutegravir Response in Experienced Adolescents--PKs Comparable to Adults
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XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
Four weeks of treatment with dolutegravir, an integrase inhibitor, plus an optimized background regimen, yielded a good virologic response rate in a pilot study of 10 adolescents, all of them with antiretroviral experience [1]. Most youngsters in this study started the adult dose, and dolutegravir concentrations were comparable to those seen in adults.
Dolutegravir (S/GSK1349572) is in development for antiretroviral-naive or experienced adults [2,3]. P1093 is an ongoing phase 1/2 open-label dose-finding and safety study in children 6 weeks to under 18 years old. This analysis focused on 12- to 18-year-old youngsters.
Study participants have never taken an integrase inhibitor when they begin weight-based doses of approximately 1 mg/kg once daily. They can be taking an unchanged failing regimen for at least 8 weeks, or they can be off treatment for at least 4 weeks. Study participants must have a viral load above 1000 copies and must have at least one fully active drug to add to dolutegravir.
Youngsters start dolutegravir as monotherapy if they are not taking antiretrovirals, or they start the integrase inhibitor while continuing a stable, failing antiretroviral regimen. Between 5 and 10 days after dosing begins, intensive pharmacokinetic evaluations are conducted over 24 hours.
Target dolutegravir exposures are a 24-hour area under the concentration-time curve (AUC) of 37 to 67 ug*h/mL and a 24-hour concentration 0.77 to 2.26 ug/mL. After the initial PK evaluation, participants add an optimized background regimen (and stop current antiretrovirals if they are already being treated). Safety, tolerability, and viral load assessments are conducted every 4 weeks.
This analysis involved 10 adolescents, 7 of them girls, 6 of them black, and 4 white. Median age was 13.5 (range 12 to 17), and weight averaged 57.3 kg (standard deviation 17.7). Median CD4 count and percent were 543 and 22%, and median viral load was 4.4 log10 copies/mL (about 25,000 copies). Median time on antiretroviral therapy was 12.8 years. All children had taken nucleosides, 9 had taken a protease inhibitor, and 4 had taken a nonnucleoside. Four youngsters had triple-class experience.
Nine youngsters weighing at least 40 kg took 50 mg of dolutegravir once daily (the one-tablet dose for antiretroviral-naive adults) and 1 youngster weighing between 30 and 40 kg took 35 mg daily (one 10-mg tablet and one 25-mg tablet).
Dolutegravir achieved the target 24-hour AUC (mean 46.0 ug*h/mL) and the target 24-hour concentration (mean 0.90 ug/mL) in these youngsters. Intersubject variability was moderate for both 24-hour AUC (coefficient of variation 43%) and 24-hour concentration (coefficient of variation 58%).
After 4 weeks of dosing, 7 of 10 participants had a viral load below 40 copies and 9 had a load below 400 copies. Median decline from baseline viral load was 2.8 log10 copies/mL (95% confidence interval -3.1 to -2.6).
Study participants tolerated dolutegravir well with no grade 3 or 4 clinical events, no drug-related adverse events, and no discontinuations. No one stopped dolutegravir because of adverse events. There were no grade 3 or 4 laboratory events and no trends in lab abnormalities.
The researchers proposed that these findings support selection of a 50-mg dolutegravir dose in children 12 to under 18 years old and weighing at least 40 kg. This study will continue as the investigators add 12 youngsters to the cohort.
References
1. Hazra R, Viani R, Acosta E, et al. Pharmacokinetics, safety and efficacy of dolutegravir (DTG; S/GSK1349572) in HIV-1-positive adolescents: preliminary analysis from IMPAACT P1093. XIX International AIDS Conference. July 22-27, 2012. Washington, DC. Abstract TUAB0203.
2. Aidsmeds.com. Dolutegravir (GSK-572). http://www.aidsmeds.com/archive/GSK-572_2422.shtml.
3. van Lunzen J, Maggiolo F, Arribas JR, et al. et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12:111-118.
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