Atazanavir and lopinavir with ritonavir alone or in combination: Analysis of pharmacokinetic interaction and predictors of drug exposure

Objectives: Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure. Methods: Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300mg with ritonavir 100mg q24h (group A) or lopinavir/ritonavir 400/100mg q12h (group B) or atazanavir 300mg q24h with lopinavir/ritonavir 400/100mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded. Results: In group A (n=10), mean ± standard deviation atazanavir C min was 390 ± 460ng/mL, C max 3051 ± 1996ng/mL and AUC 24 29913 ± 17686ng/mL/h. In group B (n=9), lopinavir C min was 7562 ± 4292ng/mL, C max 12944 ± 4838ng/mL and AUC 0-12 122313 ± 38225ng/mL/h. In group C (n=7), atazanavir C min was 876 ± 460ng/mL (P=0.039 vs. group A), C max 3421 ± 3399ng/mL and AUC 0-24 65055 ± 49843ng/mL/h (two-sided P >0.05 for each comparison with group A), lopinavir C min was 7471 ± 3745ng/mL, C max 10143 ± 5217ng/mL and AUC 0-12 104501 ± 43565ng/mL/h (P >0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir C min and with lower lopinavir C max. Atazanavir C min showed a correlation with total bilirubin levels. Conclusions: Combination with lopinavir/ritonavir provides higher atazanavir C min than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure.