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Pharmacokinetics and Pharmacodynamics of Atazanavir‐containing Antiretroviral Regimens, with or without Ritonavir, in Patients who are HIV ‐positive and Treatment‐naïve
Author(s) -
Bertz Richard J.,
Persson Anna,
Chung Ellen,
Zhu Li,
Zhang Jenny,
McGrath Donnie,
Grasela Dennis
Publication year - 2013
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/phar.1205
Subject(s) - ritonavir , atazanavir , pharmacokinetics , medicine , population , pharmacology , pharmacodynamics , lopinavir , viral load , gastroenterology , human immunodeficiency virus (hiv) , antiretroviral therapy , virology , environmental health
Study Objective To investigate the pharmacokinetic and pharmacodynamic relationships of the human immunodeficiency virus (HIV) –protease inhibitor atazanavir ( ATV ) in the presence and absence of the pharmacokinetic booster ritonavir, utilizing ATV plasma trough concentrations (C trough ) and clinical biomarkers of antiviral efficacy and safety over 48 weeks. Design Randomized, open‐label, multicenter, study designed to compare the efficacy and safety of ATV 300 mg plus ritonavir 100 mg ( ATV 300/r) with that of ATV 400 mg ( ATV 400). Setting Thirty clinic sites across 10 countries in Africa, Europe, North America, and South America. Patients Patients who were HIV‐positive and treatment‐naïve. Interventions Randomized to once‐daily ATV 400 (105 patients) or ATV 300/r (95 patients) plus lamivudine and extended‐release stavudine. Measurements and Main Results The C trough approximately 24 hours after the prior unobserved dose was measured through week 48. Composite C trough (i.e., the geometric mean of all trough concentrations over the 48 weeks), population inhibitory quotient ([IQ], i.e., C trough divided population estimated protein binding adjusted effective concentration at 90% [EC 90 , 14 ng/ml]), composite population IQ (i.e., ATV composite trough divided by population estimated protein binding adjusted EC 90 ), HIV RNA, CD4 cell counts, and metabolic and safety parameters were also assessed. For ATV400 and ATV300/r, respectively, geometric mean composite C trough (CV%) were 127 (106) ng/ml and 670 (63) ng/ml, geometric mean composite population IQ were 9 and 48, and composite C trough values of HIV EC 90 or more were achieved in 98% and 100% of patients. High ATV C trough was associated with low HIV RNA at week 48; however, 88% of patients had HIV RNA less than 400 copies/ml in the lowest composite C trough quartile. There was no clear relationship between ATV C trough and changes in CD4 cell count. Increases in total bilirubin or jaundice were associated with higher C trough . Modest increases in triglycerides and cholesterol were associated with the addition of ritonavir. Conclusion ATV ‐containing regimens with or without ritonavir achieved ATV exposures that provide robust antiretroviral efficacy and acceptable tolerability in treatment‐naïve patients.