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  14th International Workshop on Clinical Pharmacology of HIV Therapy
April 22-24, 2013
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No Clinically Significant Interactions Between Boceprevir or Telaprevir and Dolutegravir
  14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
In healthy volunteers, boceprevir and telaprevir, the two licensed HCV protease inhibitors, had no clinically significant impact on the pharmacokinetics of dolutegravir [1], the investigational integrase inhibitor now in phase 3 trials [2]. GlaxoSmithKline investigators concluded that dolutegravir can be administered with either of the HCV agents without dose adjustment.
Both boceprevir and telaprevir are strong CYP3A inhibitors and P-glycoprotein substrates and thus affect the metabolism of many antiretrovirals. Dolutegravir is primarily metabolized via UGT1A1, though CYP3A4 also plays a minor role in its metabolism.
To assess possible interactions between dolutegravir and boceprevir or telaprevir, GlaxoSmithKline investigators conducted a randomized, two-cohort, two-period study involving 32 healthy volunteers. Sixteen people in cohort 1 took 50 mg of dolutegravir daily for 5 days. Then they continued the same dose of dolutegravir for 10 days with 800 mg of boceprevir three times daily. Cohort 2 took dolutegravir the same way, but with 750 mg of telaprevir three times daily in the 10-day period.
Most study participants (59%) where men and most (72%) were white. Age averaged 42.5 years. Two study discontinuations were attributed to treatment: (1) grade 3 elevated alanine aminotransferase during dolutegravir/boceprevir codosing, and (2) grade 1 creatinine elevation with dolutegravir alone and then with dolutegravir plus boceprevir. All other adverse events recorded (most frequently headache, anorectal discomfort, dysgeusia, and maculopapular rash) were mild.
Geometric least-squares mean ratios (and 90% confidence intervals) for dolutegravir plus an HCV protease inhibitor versus dolutegravir alone showed that boceprevir had almost no impact on dolutegravir pharmacokinetics, while telaprevir moderately elevated dolutegravir values:
DTG + BCV vs DTG alone:
DTG area under concentration-time curve: 1.07 (0.948 to 1.20)
DTG maximum concentration: 1.05 (0.960 to 1.15)
DTG minimum concentration: 1.08 (0.911 to 1.28)
DTG elimination half-life: 1.05 (0.959 to 1.14)
DTG + TPV vs DTG alone:
DTG area under concentration-time curve: 1.25 (1.20 to 1.31)
DTG maximum concentration: 1.19 (1.11 to 1.26)
DTG minimum concentration: 1.37 (1.29 to 1.45)
DTG elimination half-life: 1.18 (1.08 to 1.28)
Telaprevir concentrations with dolutegravir were similar to published values for telaprevir alone. The investigators could not make such a comparison for boceprevir because relevant data were not available.
The GlaxoSmithKline team concluded that "dolutegravir can be coadministered without dose modification with either of these new treatments for HCV."
1. Johnson M, Borland J, Chen S, et al. The effect of boceprevir and telaprevir on dolutegravir pharmacokinetics, in healthy adult subjects. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_07.
2. AIDSinfo Drug Database. Dolutegravir.