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Variable Boceprevir Impact on Levels of Atazanavir and Raltegravir
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14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
Atazanavir area under the concentration-time curve (AUC) fell after HIV/HCV-coinfected people started the anti-HCV protease inhibitor boceprevir plus pegylated interferon and ribavirin, according to results of a small multicenter French study [1]. Raltegravir AUC rose nonsignificantly with boceprevir, while raltegravir maximum concentration fell.
Both boceprevir and telaprevir, another HCV protease inhibitor, are substrates and strong inhibitors CYP3A4 and so may affect concentrations of drugs metabolized by that enzyme [2,3]. Telaprevir is also a P-glycoprotein substrate [4]. French researchers conducted an open-label trial in people with HCV genotype 1 who had an HIV load below 50 copies/mL while taking standard doses of the HIV protease inhibitors atazanavir/ritonavir or the HIV integrase inhibitor raltegravir. After 4 weeks of pegylated interferon (1.5 ug/kg/wk) and ribavirin (1000 or 1200 mg/day), study participants added boceprevir at a dose of 800 mg three times daily. The investigators measured AUCs, maximum concentrations (Cmax), and trough concentrations (Ctrough) before HCV therapy began and after 4 weeks of boceprevir (study week 8).
The 14 study participants had a median age of 48, 10 were men, 9 were injection drug users, and only 1 was overweight. Ten had HCV genotype 1a, and median HCV RNA stood at 6.7 log10 IU/mL.
Twelve people completed the study, 7 taking atazanavir/ritonavir and 5 taking raltegravir. Atazanavir concentrations were lower with than without boceprevir, although only atazanavir AUC was significantly lower:
Ratio of median values week 8/day 0:
Atazanavir AUC0-8h: 0.43, P < 0.01
Atazanavir Cmax: 0.76, not significant
Atazanavir Cmin: 0.55, not significant
Raltegravir concentrations varied with boceprevir, with nonsignificant trends toward higher raltegravir AUC and Cmin and lower raltegravir Cmax:
Ratio of median values week 8/day 0:
Raltegravir AUC0-8h: 2.63, not significant
Raltegravir Cmax: 0.61, not significant
Raltegravir Cmin: 5.03, not significant
Average atazanavir trough fell from 763.8 to 507.7 ng/mL after 4 weeks of boceprevir, while average raltegravir trough slid from 337.7 to 153.9 ng/mL. A previous open-label crossover trial in 24 healthy volunteers found no clinically significant interactions between boceprevir and raltegravir [5].
The French study determined that atazanavir/ritonavir does not significantly alter boceprevir AUC, while raising boceprevir trough 87% and lowering boceprevir Cmax 26%. Raltegravir had no impact on boceprevir AUC, while raising boceprevir trough 50% and lowering Cmax 42%.
The investigators proposed that "pending more data, careful monitoring of HIV replication in patients [taking] atazanavir/ritonavir or raltegravir-based regimens receiving boceprevir would be appropriate."
Another study presented at the HIV Pharmacology Workshop involving healthy volunteers determined that neither boceprevir nor telaprevir had a clinically significant impact on levels of dolutegravir, an investigational HIV integrase inhibitor [6].
References
1. Garraffo R, Lavrut T, Poisot-Martin I et al. Pharmacokinetic interactions between boceprevir and atazanavir/r or raltegravir in HIV/HCV coinfected patients. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_15.
2. Seden K, Back D. Directly acting antivirals for hepatitis C and antiretrovirals: potential for drug-drug interactions. Curr Opin HIV AIDS. 2011;6:514-526.
3. Hulskotte E, Feng HP, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 771LB. http://www.natap.org/2012/CROI/croi_20.htm
4. Wilby KJ, Greanya ED, Ford JA, Yoshida EM, Partovi N. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol. 2012;11:179-185.
5. de Kanter CT, Blonk MI, Colbers AP, Schouwenberg BJ, Burger DM. Lack of a clinically significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir. Clin Infect Dis. 2013;56:300-306.
6. 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_16.
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