St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
University of Liverpool, Liverpool, UK.
J Antimicrob Chemother. 2017 Jul 1;72(7):2035-2041. doi: 10.1093/jac/dkx108.
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.
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.
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.
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.
我们研究了在停止药物摄入后 72 小时内，血浆、唾液和尿液中阿扎那韦/考比司他和达芦那韦/考比司他的药代动力学（PK）。
健康志愿者每日接受一次 300/150mg 的阿扎那韦/考比司他固定剂量组合治疗 10 天，然后进行 10 天的洗脱期，然后每日接受一次 800/150mg 的达芦那韦/考比司他固定剂量组合治疗 10 天。在第 10 天和第 72 小时后，对每个阶段进行全面的 PK 分析，并通过非房室方法确定到血浆、唾液和尿液中最后可测量浓度的参数。
16 名受试者完成了研究。阿扎那韦和达芦那韦的几何均数（GM）终末消除半衰期值至 72 小时分别为 6.77 和 6.35 小时。所有受试者在给药后 24 小时的阿扎那韦浓度均高于建议的最低有效浓度 150ng/mL，14/16 名受试者在给药后 30 小时的浓度高于该目标（GM 分别为 759 和 407ng/mL）。16 名受试者中有 13 名在给药后 24 小时的达芦那韦浓度高于目标浓度 550ng/mL，5 名受试者在给药后 30 小时的浓度高于目标浓度（GM 分别为 1033 和 382ng/mL）。考比司他的半衰期至 72 小时分别为阿扎那韦的 4.21 小时和达芦那韦的 3.62 小时。阿扎那韦和达芦那韦给药后 24 小时的 GM 值（C24）分别为唾液中的 141 和 43ng/mL，尿液中的 24857 和 11878ng/mL。唾液/尿液中的浓度衰减与两种药物的血浆浓度相匹配。
阿扎那韦和达芦那韦的浓度衰减模式不同，这可能部分解释了考比司他的半衰期（阿扎那韦的半衰期比达芦那韦长）。这是首次在唾液和尿液中测量药物 PK 宽容度，这是更易于检测药物依从性的标志物。
