Population pharmacokinetic model for Ritonavir (RTV) in HIV-infected patients treated with Lopinavir (LPV)/RTV (KaletraTM)
A. Martin-Suarez (1), D. Santos Buelga (1), E. Lopez (2), S. Cabrera (3), R. Lopez (4), E. Ribera (5), A. Dominguez-Gil (1,2), M.J. Garcia (1).
(1) Department of Pharmacy and Pharmaceutical Technology and (2) Pharmacy Service, University Hospital, University of Salamanca; (3) University Austral of Chile; (4) Service of Biochemistry (section of pharmacology), Clinic Hospital of Barcelona; and (5) Service of infectious diseases Vall´d Hebron. Barcelona. Spain
Objectives: Having the population model previously obtained for LPV with the same data-set (Santos Buelga D. PAGE 2009), the aim of this study was to develop and validate a population pharmacokinetic (PK) model for RTV in HIV-infected patients treated with KaletraTM.
Methods: 201 ambulatory HIV-infected adult patients from two Spanish hospitals, treated with LPV/RTV (dose 400/100 twice daily) were included. 686 LPV and RTV plasma concentrations at a single time-point and 62 full PK profiles were available, resulting in a database of 1110 LPV and RTV steady-state plasma concentrations. The patients were divided randomly into two groups for model building (n=954 RTV plasma concentrations) and model validation (n=156). RTV and LPV plasma concentrations were determined by HPLC with UV detector. The population PK parameters of RTV were estimated using the NONMEM software package version V.1, and FOCE method with INTERACTION. The influence of different patient characteristics (age, gender, height, weight, body mass index, total bilirrubin, hepatitis C co-infection, PK behaviour of LPV and concomitant treatment with saquinavir (SQV), tenofovir and atazanavir) on the PK of RTV was explored.
Results: RTV plasma concentration-time data were modeled using a one-compartment PK model with first-order absorption and elimination including lag-time. The model was parameterized in terms of clearance (CL/F, for unknown true bioavailability) and volume of distribution (V/F). An additive statistical model was selected to describe the residual error and a proportional model for the interindividual variability. The inclusion of the CL/F of LPV in the basic model produced a decrease from -658.66 to -801.18 in the objective function value and a decrease from 45% to 29% (CV%) in the interindividual variability of clearance. RTV clearance was also influenced significantly by SQV concomitant treatment. No covariates were found to explain the high variability of other parameters estimated.
Final model (mean parameters (SE)):
CL/F (L/h) = 2.15 (2.46%) *CLLPV*1.25 (7.50%)**SQV(0/1); CVCL = 30.07% (14.16 %)
V/F (L) = 303.00 (12.01%); CVVd = 86.02% (19.02%)
Ka (h-1) = 2.06 (14.66%); CVKA = 65.12% (61.69%)
Lag-time (h) = 2.44 (4.96%);
Residual variability (SD) = 0.12 mg/L (5.68%)
Conclusions: The clearance of LPV and the concomitant use of SQV significantly influence the PK of RTV. Validations results obtained confirm the adequacy of the proposed model.
References:
[1] BS Kappelhoff et als. Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients. Br J Clin Pharmacol 59(2):174-182,2004.
[2] J Moltó et als. Simultaneous population pharmacokinetics model for lopinavir and ritonavir in HIV-infected adults. Clin Pharmacokinet 46(1):85-92,2007.
[3] E Ribera et als. Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults Antimicrob Agents Chemother 48:4256-62,2004.
[1] N von Henting. Lopinavir/Ritonavir: appraisal of its use in HIV therapy. Drugs Today 43(4):221-47,2007.
