Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV-1-infected patients

Abstract

Aims: To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening.

Methods: This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis.

Results: Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (C(max)) and concentration at the end of the dosing interval (C(24 h)) after am and pm dosing was, respectively, 143 (116-214) mg l(-1) h, 12.8 (10.3-17.2) mg l(-1), 1.34 (0.58-3.25) mg l(-1), and 171 (120-232) mg l(-1) h, 12.9 (8.22-16.3) mg l(-1), 1.15 (0.59-1.98) mg l(-1). The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), C(max), and C(24 h) was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir C(max) after am and pm dosing was 1.05 and 0.90 mg l(-1), respectively. The GMR (95% CI) of the RTV AUC(0,24 h), C(max), and C(24 h) was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated.

Conclusions: No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.

Figure 1

Mean (± SD) steady-state plasma lopinavir (A) and ritonavir (B) concentration vs time profile after administration of lopinavir/ritonavir 800/200 mg once daily with a standardized meal in the morning (open circles) and in the evening (closed circles) in 14 HIV-1-infected male individuals

Figure 2

Individual changes in lopinavir concentration at 24 h postdose (C_24h; Figure 2A) and maximum ritonavir concentration (C_max; Figure 2B) after steady-state administration of lopinavir/ritonavir 800/200 mg once daily with food in the morning (am) or in the evening (pm) in 14 HIV-1-infected male individuals. The horizontal lines indicate the median