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Lower cobicistat and atazanavir troughs in smokers with HIV
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20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands
Mark Mascolini
Smokers had significantly lower plasma trough concentrations of cobicistat and atazanavir than nonsmokers in a 68-person Italian study [1]. A University of Torino group also charted a trend to lower intracellular cobicistat troughs in smokers.
Although high proportions of people with HIV smoke, little research addresses the potential impact of nicotine and its metabolites on antiretroviral pharmacokinetics (PKs). Nicotine is an inducer of membrane transporters (P-gp and BRCP) and CYP enzymes involved in antiretroviral metabolism. To learn more about the potential impact of smoking on HIV protease inhibitor and cobicistat PKs, a University of Torino team compared smokers and nonsmokers with HIV.
The study involved 68 people taking cobicistat-boosted atazanavir or darunavir, including 32 smokers and 36 nonsmokers. The researchers collected plasma and cell samples at the midpoint and end of the dosing interval (12 and 24 hours after dosing).
Forty-nine of 68 participants (72%) were men, 40 (15 smokers) took darunavir/cobicistat and 28 (16 smokers) atazanavir/cobicistat. Overall median age stood at 51 years (interquartile range [IQR] 48 to 56) and body mass index at 25.4 kg/m2 (IQR 23 to 27.5).
Cobicistat plasma trough concentration proved significantly lower in smokers than nonsmokers (median 26.9 versus 65.2 ng/mL, P = 0.021), and there was a strong trend toward lower cobicistat intracellular concentrations in smokers (median 85.7 versus 156.2 ng/mL, P = 0.059). Cobicistat intracellular/plasma ratio did not differ significantly between smokers and nonsmokers.
Atazanavir plasma trough concentration also lay significantly lower in smokers than nonsmokers (median 519.6 versus 920.6 ng/mL, P = 0.037). This comparison also found weak trends toward lower intracellular atazanavir levels in smokers (median 798.8 versus 1229.1 ng/mL, P = 0.126) and toward a higher atazanavir intracellular/plasma ratio in smokers (1.537 versus 0.866, P = 0.093).
All plasma and intracellular levels of cobicistat, atazanavir, and darunavir correlated significantly (P < 0.001) in both smokers and nonsmokers. The researchers did not report darunavir concentrations and did not attempt to factor in the potential impact of other variables on cobicistat and atazanavir PKs.
Earlier research documented lower atazanavir exposure in smokers than nonsmokers [2].
This appears to be the first study to find lower cobicistat troughs in plasma and cells. The Torino team sees a need to consider the impact of smoking on induction of efflux pumps and drug-metabolizing enzymes in people taking antiretrovirals.
References
1. Ferrara M, Trentalange A, Alcantarini C, et al. Cobicistat (COBI)-boosted protease inhibitors plasma and intracellular pharmacokinetics in nicotine users. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 47.
2. Higgins N, Zingman BS, Slish J, et al. Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir. Am J Addict. 2007;16:488-494.
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