Population analysis of the pregnancy-related modifications in lopinavir pharmacokinetics and their possible consequences for dose adjustment.
OBJECTIVE
To investigate the possible necessity of an increase in lopinavir dose during pregnancy in order to achieve the concentrations previously defined as predictive of virological efficacy.


METHODS
Lopinavir pharmacokinetics were investigated by a population approach performed on 145 HIV-infected women, including 74 pregnant women. The final model was used to determine the probability of achievement of the target trough concentrations by Monte Carlo simulations.


RESULTS
The typical population estimates (inter-individual variability %) of apparent clearance (CL/F) and volume of distribution were 4.38 L/h (24%) and 58.4 L (59%), respectively. Pregnancy associated with a gestational age >15 weeks and delivery were found to increase lopinavir CL/F by 39% and 58%, respectively. With the standard 400 mg twice-a-day regimen, the probability of reaching the 1 mg/L target trough concentration for protease inhibitor (PI)-naive patients was 99% and 96% for non-pregnant and pregnant women, respectively. An important decrease in the probability of achieving the 5.7 mg/L target trough concentration for salvage therapy was observed for non-pregnant women (55%), this decrease being even greater for pregnant women (21%). Raising the lopinavir dose to 600 mg twice daily increased these probabilities to 87% and 53% for non-pregnant and pregnant women, respectively.


CONCLUSIONS
Modification of the lopinavir dose is unlikely to be required for PI-naive pregnant women; however, in pregnant women who have previously received a PI, therapeutic drug monitoring and/or empirical increasing of the dose should be considered.
Bouillon-Pichault
Marion
M
Université Paris Descartes, France.
Jullien
Vincent
V
Azria
Elie
E
Pannier
Emmanuelle
E
Firtion
Ghislaine
G
Krivine
Anne
A
Compagnucci
Alexandra
A
Taulera
Olivier
O
Finkielsztejn
Laurent
L
Chhun
Stéphanie
S
Pons
Gérard
G
Launay
Odile
O
Treluyer
Jean-Marc
JM
D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D061466:Lopinavir; D008657:Metabolic Clearance Rate; D009010:Monte Carlo Method; D010949:Plasma / Q000737:chemistry; D011247:Pregnancy; D011744:Pyrimidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution
D019380:Anti-HIV Agents; D011744:Pyrimidinones; D061466:Lopinavir