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


METHODS
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.


RESULTS
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).


CONCLUSIONS
These results support lopinavir therapeutic drug monitoring and the use of higher lopinavir doses for PI-pretreated patients.
Bouillon-Pichault
Marion
M
Université Paris Descartes, Paris, France.
Jullien
Vincent
V
Piketty
Christophe
C
Viard
Jean-Paul
JP
Morini
Jean-Pierre
JP
Chhun
Stéphanie
S
Krivine
Anne
A
Salmon
Dominique
D
Dupin
Nicolas
N
Weiss
Laurence
L
Lortholary
Olivier
O
Pons
Gérard
G
Launay
Odile
O
Treluyer
Jean-Marc
JM
D000293:Adolescent; D000328:Adult; D000368:Aged; D001835:Body Weight; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011159:Population Surveillance; D011744:Pyrimidinones / Q000493:pharmacokinetics*; D013607:Tablets
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D013607:Tablets; D061466:Lopinavir