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

Kityo, C., Walker, A. S., Dickinson, L., Lutwama, F., Kayiwa, J., Ssali, F., Nalumenya, R., Tumukunde, D., Munderi, P., Reid, A., Gilks, C. F., Gibb, D. M. and Khoo, S. (2010) Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults. Antimicrobial Agents and Chemotherapy, 54 7: 2965-2973. doi:10.1128/AAC.01198-09

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Author Kityo, C.
Walker, A. S.
Dickinson, L.
Lutwama, F.
Kayiwa, J.
Ssali, F.
Nalumenya, R.
Tumukunde, D.
Munderi, P.
Reid, A.
Gilks, C. F.
Gibb, D. M.
Khoo, S.
Title Pharmacokinetics of Lopinavir-Ritonavir with and without Nonnucleoside Reverse Transcriptase Inhibitors in Ugandan HIV-Infected Adults
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
Publication date 2010-07-01
Year available 2010
Sub-type Article (original research)
DOI 10.1128/AAC.01198-09
Open Access Status File (Publisher version)
Volume 54
Issue 7
Start page 2965
End page 2973
Total pages 9
Place of publication Washington, DC United States
Publisher American Society for Microbiology
Language eng
Abstract High rates of sustained virologic response at post-treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA
Formatted 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 (AUC0-12) was 110.1 (34%) μg·h/liter. For efavirenz, the geometric mean lopinavir AUC0-12 (%CV) values were 91.8 μg·h/liter (58%), 65.7 μg·h/liter (39%), and 54.0 μg·h/liter (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, and the apparent oral clearance (CL/F) values were reduced by 58% and 1%, respectively. For nevirapine, the geometric mean lopinavir AUC0-12 (%CV) values were 112.9 μg·h/liter (30%), 68.1 μg·h/liter (53%), and 61.5 μg·h/liter (52%), respectively, with corresponding GMR values of 1.66 (90% CI, 1.46 to 1.88; P < 0.001) and 0.90 (90% CI, 0.77 to 1.06; P = 0.27), respectively, and the CL/F was reduced by 57% and 7%, respectively. Higher values for the lopinavir concentration at 12 h (C12) were observed with 3 tablets and efavirenz-nevirapine (P = 0.04 and P = 0.0005, respectively), and marginally lower C12 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. 
Keyword direct-acting antiviral
interferon-free therapy
sustained virologic response
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID G0600344
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Public Health Publications
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