Once-daily atazanavir/cobicistat and darunavir/cobicistat exposure over 72 h post-dose in plasma, urine and saliva: contribution to drug pharmacokinetic knowledge

Background: We investigated the pharmacokinetics (PK) of atazanavir/cobicistat and darunavir/cobicistat once daily over 72 h following drug intake cessation in plasma, saliva and urine. Methods: Healthy volunteers received a fixed-dose combination of 300/150 mg of atazanavir/cobicistat once daily for 10 days, followed by a 10 day washout period and then a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily for 10 days. Full PK profiles were assessed for each phase for 72 h following day 10 and parameters determined to the last measurable concentration in plasma, saliva and urine by non-compartmental methods. Results: Sixteen subjects completed the study. Geometric mean (GM) terminal elimination half-life values to 72 h of atazanavir and darunavir were 6.77 and 6.35 h, respectively. All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/mL 24 h post-dose and 14/16 subjects had concentrations higher than this target at 30 h post-dose (GM of 759 and 407 ng/mL, respectively). Thirteen out of 16 subjects had darunavir concentrations higher than the target of 550 ng/mL at 24 h post-dose and 5/16 subjects had concentrations higher than the target at 30 h post-dose (GM of 1033 and 382 ng/mL, respectively). Cobicistat half-life to 72 h was 4.21 h with atazanavir and 3.62 h with darunavir. GM values 24 h after the observed dose ( C 24 ) for atazanavir and darunavir were 141 and 43 ng/mL, respectively, in saliva and 24857 and 11878 ng/mL, respectively, in urine. Concentration decay in saliva/urine mirrored plasma concentrations for both drugs. Conclusions: Different concentration decay patterns were seen for atazanavir and darunavir, which may be partially explained by cobicistat half-life (longer with atazanavir than darunavir). For the first time, we also measured drug PK forgiveness in saliva and urine, which represent easier markers of adherence.