A population analysis of weight-related differences in lopinavir pharmacokinetics and possible consequences for protease inhibitor-naive and -experienced patients

• Published in: Antiviral therapy 2009, Vol.14 (7), p.923-929
• Main Authors: BOUILLON-PIEHAULT, Marion, JULLIEN, Vincent, LORTHOLARY, Olivier, PONS, Gérard, LAUNAY, Odile, TRELUYER, Jean-Marc, PIKETTY, Christophe, VIARD, Jean-Paul, MORINI, Jean-Pierre, CHHUN, Stéphanie, KRIVINE, Anne, SALMON, Dominique, DUPIN, Nicolas, WEISS, Laurence
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Body Weight; Female; HIV Infections - drug therapy; HIV Protease Inhibitors - pharmacokinetics; Human immunodeficiency virus; Human viral diseases; Humans; Infectious diseases; Lopinavir; Male; Medical sciences; Middle Aged; Models, Statistical; Pharmacology. Drug treatments; Population Surveillance; Pyrimidinones - pharmacokinetics; Tablets; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 1359-6535; 2040-2058
• DOI: 10.3851/imp1414

Lopinavir is a potent protease inhibitor (PI) used for the treatment of HIV infection. Different lopinavir target trough concentrations (C(troughs)) were previously determined according to patient treatment histories: 1 mg/l for PI-naive patients, and 4 and 5.7 mg/l for PI-experienced patients. However, the probability to achieve these target C(troughs) with the current 400 mg twice-daily or 800 mg once-daily doses of the new tablet form, and the influence of body weight on this probability are unknown. A population pharmacokinetic model for lopinavir was developed using data from 424 HIV type-1-infected patients, and the final model was used to estimate the probability to achieve target C(troughs) via Monte Carlo simulations. A one-compartment model adequately described the data. Mean population estimates (percentage interindividual variability) were 4.61 l/h (36%) for apparent clearance (CL/F) and 63.2 l (70%) for apparent distribution volume. Body weight was found to explain the interindividual variability of lopinavir CL/F. Probability to achieve the 1 mg/l target C(trough) was >96% for the twice-daily dose and comprised between 80% and 90% for the once-daily dose. The probability to achieve the 4 and 5.7 mg/l target C(troughs) with the twice-daily dose significantly decreased when body weight increased (from 76% to 61% and from 56% to 37% respectively, for body weights increasing from 50 to 90 kg). These results support lopinavir therapeutic drug monitoring and the use of higher lopinavir doses for PI-pretreated patients.