Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults.

Abstract

We evaluated the pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) in Ugandan adults. The study design was a three-period crossover study (3 tablets [600 mg of lopinavir/150 mg of ritonavir {600/150 mg}], 4 capsules [533/133 mg], and 2 tablets [400/100 mg] twice a day [BD]; n = 40) of lopinavir-ritonavir with NNRTIs and a parallel one-period study (2 tablets BD; n = 20) without NNRTIs. Six-point pharmacokinetic sampling (0, 2, 4, 6, 8, and 12 h) was undertaken after observed intake with a standardized breakfast. Ugandan DART trial participants receiving efavirenz (n = 20), nevirapine (n = 18), and no NNRTI (n = 20) had median ages of 41, 35, and 37 years, respectively, and median weights of 60, 64, and 63 kg, respectively. For the no-NNRTI group, the geometric mean (percent coefficient of variation [%CV]) lopinavir area under the concentration-time curve from 0 to 12 h (AUC<sub>0-12</sub>) was 110.1 (34%) µg·h/litre. For efavirenz, the geometric mean lopinavir AUC<sub>0-12</sub> (%CV) values were 91.8 µg·h/litre (58%), 65.7 µg·h/litre (39%), and 54.0 µg·h/litre (65%) with 3 tablets, 4 capsules, and 2 tablets BD, respectively, with corresponding (within-individual) geometric mean ratios (GMR) for 3 and 2 tablets versus 4 capsules of 1.40 (90% confidence interval [CI], 1.18 to 1.65; P = 0.002) and 0.82 (90% CI, 0.68 to 0.99; P = 0.09), respectively; the apparent oral clearance (CL/F) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC<sub>0-12</sub> (%CV) values were 112.9 µg·h/litre (30%), 68.1 µg·h/litre (53%), and 61.5 µg·h/litre (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88; P 12) were observed with 3 tablets and efavirenz-nevirapine (P = 0.04 and P = 0.0005, respectively), and marginally lower C<sub>12</sub> values were observed with 2 tablets and efavirenz-nevirapine (P = 0.08 and P = 0.26, respectively). These data suggest that 2 tablets of lopinavir-ritonavir BD may be inadequate when dosed with NNRTIs in Ugandan adults, and the dosage should be increased by the addition of an additional adult tablet or a half-dose tablet (100/25 mg), where available.

Citation

Antimicrobial Agents and Chemotherapy (2010) 54 (7) 2965-2973 [doi:10.1128/AAC.01198-09].

Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults.

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