Minimal food effect on steady-state pharmacokinetics of lopinavir when administered as a tablet formulation in Ugandan HIV- positive patients
Background:
Recently, a
film-coated tablet formulation of lopinavir plus ritonavir (LPV/r) was
introduced in sub-Saharan Africa. Here, we present steady-state
pharmacokinetics of LPV under different meal conditions in Ugandan patients.
Methods:
An open-label, three-phase,
crossover study was conducted in HIV-infected patients on second-line therapy
containing LPV/r tablets (Aluvia®) 400 mg twice daily. Sampling was
performed on Day1 and repeated seven and 14 days later (Day8 and Day15). Two LPV/r
tablets (400mg/100mg) were administered with a standardized moderate fat breakfast
(local Ugandan meal, 20g fat), and a standardized high fat western breakfast
(36g fat) on Day1 and Day8, respectively. Patients took LPV/r in the fasted
state on Day15.
On each sampling
occasion, venous samples were collected pre-dose and 0,1,2,3,4,6,8,12 hours
post-LPV/r dosing. Plasma concentrations were determined by a validated HPLC-MS/MS
assay. Pharmacokinetic parameters (Cmax and AUC0-12) were
calculated by non-compartmental methods (WinNonlin). Geometric means (GM), GM ratios
(GMR) with Day15 data as reference, and 90% confidence intervals (CI) were
calculated.
Results:
Twelve patients
(6 female) completed the study. Median (interquartile range) age and weight
were 48 (44-49) years and 62 (59-68) kg, respectively.
On Day1, Day8
and Day15 LPV AUC0-12 (GM, 90% CI) were 89047 ng.h/mL, 77201 ng.h/mL
and 90276 ng.h/mL, respectively. Corresponding Cmax values were 9905
ng/mL, 8747 ng/mL and 10165 ng/mL.
For LPV, Day15
versus Day1 GMR (90% CI) for AUC0-12 and Cmax were 0.99
(0.90-1.08) and 0.97 (0.88-1.06), respectively. For Day15 versus Day8, AUC0-12
and Cmax were significantly lower (0.86 [0.77-0.95] and 0.86 [0.81-0.92],
respectively).
Conclusion:
Lopinavir
exposure and peak concentrations were similar in fasted state and with a local
Ugandan (moderate fat) meal. Paradoxically, mild reductions in LPV
pharmacokinetics were observed (< 15%) with high fat meal but this is unlikely
to be clinically significant. This LPV/r formulation can be taken without
regard to meals.
M. Lamorde1,2, P. Byakika-Kibwika1,2,3, L. Nabukeera1, A. Amara4, A. Hughes4, J. Tjia4, M. Boffito5, S. Khoo4, D. Back4, C. Merry1,2,6
1Infectious Diseases Institute, Makerere University, Kampala, Uganda, 2School of Medicine, Trinity College Dublin, Dublin, Ireland, 3Infectious Disease Network for Treatment and Research in Africa, Kampala, Uganda, 4Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom, 5Chelsea & Westminster Hospital, London, United Kingdom, 6St James' Hospital, Dublin, Ireland