Pharmacokinetics of lopinavir-ritonavir with and without nonnucleoside reverse transcriptase inhibitors in Ugandan HIV-infected adults.
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(0-12)) was 110.1 (34%) microg x h/liter. For efavirenz, the geometric mean lopinavir AUC(0-12) (%CV) values were 91.8 microg x h/liter (58%), 65.7 microg x h/liter (39%), and 54.0 microg x 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 AUC(0-12) (%CV) values were 112.9 microg x h/liter (30%), 68.1 microg x h/liter (53%), and 61.5 microg x 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 (C(12)) were observed with 3 tablets and efavirenz-nevirapine (P = 0.04 and P = 0.0005, respectively), and marginally lower C(12) 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.
Kityo
C
C
Joint Clinical Research Centre, Kampala, Uganda.
Walker
A S
AS
Dickinson
L
L
Lutwama
F
F
Kayiwa
J
J
Ssali
F
F
Nalumenya
R
R
Tumukunde
D
D
Munderi
P
P
Reid
A
A
Gilks
C F
CF
Gibb
D M
DM
Khoo
S
S
D000328:Adult; D000368:Aged; D000480:Alkynes; D048588:Benzoxazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000493:pharmacokinetics / Q000627:therapeutic use; D011744:Pyrimidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014454:Uganda
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D019829:Nevirapine; C098320:efavirenz; D019438:Ritonavir