Pharmacokinetics and inhibitory quotient of atazanavir/ritonavir versus lopinavir/ritonavir in HIV-infected, treatment-naive patients who participated in the CASTLE Study

Objectives: To characterize the pharmacokinetics and inhibitory quotient (IQ) of atazanavir/ritonavir- and lopinavir/ritonavir-based regimens in HIV-infected, treatment-naive patients. Methods: The CASTLE Study was a 96 week randomized study comparing 300 mg of atazanavir once daily with 400 mg of lopinavir twice daily, each with low-dose ritonavir (100 mg) plus tenofovir disoproxil fumarate/emtricitabine in HIV-infected, treatment-naive patients. A subset of patients participated in an intensive pharmacokinetic evaluation of the atazanavir regimen (n=18) and the lopinavir regimen (n=21) at week 4. (ClinicalTrials.gov NCT00272779) Results: Atazanavir geometric mean (CV%) C-max, C-min and AUC over the dosing interval were 2897 (46) ng/mL, 526 (57) ng/mL and 28605 (46) ng.h/mL, respectively, and for lopinavir they were 10655 (51) ng/mL, 5944 (68) ng/mL and 90946 (59) ng.h/mL, respectively. The baseline protein binding-adjusted 90% effective concentration (PBA-EC90) was 16 (44) ng/mL for atazanavir and 173 (44) ng/mL for lopinavir. The median IQ (min, max), calculated as the ratio of C-min to individual baseline PBA-EC90, was 35 (4, 77) for atazanavir and 34 (11, 129) for lopinavir. The C-max for ritonavir was 46% higher, while AUC(0-24) and Cmin were 16% and 72% lower in the atazanavir regimen compared with the lopinavir regimen. Tenofovir exposures were similar with both treatments. Conclusions: Atazanavir (300 mg once daily) and lopinavir (400 mg twice daily), each with low-dose ritonavir, achieved similar IQs in HIV-infected, treatment-naive patients. These results are supportive of the main clinical finding of the CASTLE Study, that the atazanavir/ritonavir-based regimen is non-inferior in antiviral efficacy to the lopinavir/ritonavir-based regimen in antiretroviral-naive subjects.