Coadministration of lopinavir-ritonavir, an antiretroviral protease inhibitor, at the standard dose (400/100 mg twice a day [BID]) with the antituberculous agent rifampin is contraindicated because of a significant pharmacokinetic interaction due to induction of cytochrome P450 3A by rifampin. In the present study, two adjusted-dose regimens of lopinavir-ritonavir were tested in combination with rifampin. Thirty-two healthy subjects participated in a randomized, two-arm, open-label, multiple-dose, within-subject controlled study. All subjects were treated with lopinavir-ritonavir at 400/100 mg BID from days 1 to 15. From days 16 to 24, the subjects in arm 1 received lopinavir-ritonavir at 800/200 mg BID in a dose titration, and the subjects in arm 2 received lopinavir-ritonavir at 400/400 mg BID in a dose titration. Rifampin was given at 600 mg once daily to all subjects from days 11 to 24. The multiple-dose pharmacokinetics of lopinavir, ritonavir, and rifampin were assessed. Twelve of 32 subjects withdrew from the study. For nine subjects lopinavir-ritonavir combined with rifampin resulted in liver enzyme level elevations. Pharmacokinetic data for 19 subjects were evaluable. Geometric mean ratios for the lopinavir minimum concentration in serum and the maximum concentration in serum (C max ) on day 24 versus that on day 10 were 0.43 (90% confidence interval [CI], 0.19 to 0.96) and 1.02 (90% CI, 0.85 to 1.23), respectively, for arm 1 (n ‫؍‬ 10) and 1.03 (90% CI, 0.68 to 1.56) and 0.93 (90% CI, 0.81 to 1.07), respectively, for arm 2 (n ‫؍‬ 9). Ritonavir exposure increased from days 10 to 24 in both arms. The geometric mean C max of rifampin was 13.5 mg/liter (day 24) and was similar between the two arms. Adjusteddose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.

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Lopinavir is one of the most-widely used protease inhibitors in the treatment of HIV-1 infected patients. Concentration-effect relationships have been described for both antiviral activity and toxicity. Less is known about patient characteristics that may determine interpatient variability in lopinavir plasma concentrations. A database was created containing all Therapeutic Drug Monitoring (TDM) results collected at our Department. Patients were included if they were using lopinavir twice daily for at least two weeks; subjects who were known to be nonadherent (based on either a lopinavir concentration <0.2 mg/L or suspected by the physician) were excluded. Demographic data were collected from TDM application forms and patient charts. Patients attending one of the 22 HIV treatment centers in The Netherlands. The Department of Clinical Pharmacy is a national referral center for TDM of antiretroviral agents. Lopinavir concentration ratios (CRs) were calculated for each patient by dividing the individual plasma concentration by the time-adjusted population value. Relationships with lopinavir CRs were tested using regression analysis and analysis of variance. A total of 802 patients were included (607 males; 150 females; 45 unknown). The age and body weight of the patients ranged from 18 to 74 years (mean 42) and 42 to 121 kg (mean 72), respectively. Race was known for 756 persons: Caucasian 76%, African 18% and Asian 6%. The median (+ interquartile range, IQR) lopinavir CR was 0.98 (IQR: 0.67-1.31). Body weight showed an inverse relationship with lopinavir CR (F = 23.1; P < 0.001). Age was not related with lopinavir CR (P = 0.99). Female patients had a significantly higher lopinavir CR than males: 1.18 vs. 1.03 (P = 0.005); race was not associated with differences in lopinavir CR. In a multivariate regression analysis body weight, but not gender, remained significantly related to lopinavir CR. Body weight is the only demographic factor that could be related to lopinavir exposure; clinicians should be alert for an increased risk of suboptimal antiviral efficacy in patients with high body weight, and for an increased risk of toxicity in patients with a low body weight.

This novel association between CAR rs2307424 and efavirenz plasma concentrations now requires validation in other cohorts.