Population Pharmacokinetics of Lopinavir (Kaletra) in HIV-Infected Patients
D. Santos Buelga (1), E. López (2), S. Cabrera (3), R. López (4), E. Ribera (5), A. Domínguez-Gil (1,2), M.J. García (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) and (5)Clinic Hospital of Barcelona and Service of infectious diseases Vall´d Hebron. Barcelona. Spain
Objectives: To develop and validate a population pharmacokinetic (PK) model of lopinavir (LPV) associated to ritonavir (RTV) (KaletraÒ) in HIV-infected patients.
Methods: The study was carried on ambulatory HIV-infected adult patients from two Spanish hospitals, treated with lopinvir/ritonavir (dose 400/100 twice daily). From 201 patients, 686 lopinavir plasma concentrations at a single time-point and 62 full pharmacokinetic profiles were available, resulting in a database of 1110 LPV steady-state plasma concentrations. Samples were analysed by HPLC, UV detector. Pharmacokinetic analysis was performed with NONMEM. The first-order conditional estimation (FOCE) with Laplace approximation was used throughout. Age, gender, height, total body weigth (TBW), body mass index (BMI), ritonavir through concentration (RTC), total bilirrubin, VHC, gender and concomitant administration of saquinavir (SQV), tenofovir (TFV) and atazanvir (ATV) , were explored using GAM implemented in Xpose.A total of 954 and 156 LPV concentrations were included in two datasets for model building and model validation, respectively.
Results: A one -compartment model with first-order absorption (with lag-time) and elimination, specified to NONMEM by the routines (ADVAN2, TRANS2) with proportional and additive error models for interinditivual and residual varaibilities, respectively, best described the pharmacokinetics of lopinavir.
LPV clearance was influenced by patient BMI, RTC and ATV concomitant administration. No covariates were found to influence the other PK parameters. Thus final regression model for LPV was as follows:
CL (L/h) = 0.29*BMI*e-0.48*RTC*e-0.34*ATV; V (L) = 170; Ka (h-1) = 0.68; ALAG (h) = 0.69
CVCL = 26.9 %; CVV= 72.5 %; CVKA = 44.7 %; CVALAG = 52.1 %
Residual variability = 3.2 mg/L
Validation results in another dataset confirm the adequacy of the proposed model, as MPE ± SD and SMPE ± SD were -0.20 ± 2.72 and -0.05 ± 0.91
Conclusions: The population model proposed, adequately describe the lopinavir pharmacokinetics. Concomitant use of ritonavir and atazanavir significantly influence its elimination. This model could be used to estimate LPV appropriate dosage guidelines. Moreover their simple structure will allow an easy implementation in clinical PK software and their application in dosage individualization by Bayesian approach.
References:
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