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Lopinavir Population Pharmacokinetics on HIV-infected Pregnant Women
Marion Bouillon Pichault*1, V Jullien1,2, E Azria1,2, E Panier1,2, G Firtion2, A Krivine1,2, A Compagnucci2, O Taulera2, O Launay1,2, J M Treluyer1,2, and EA 3620
1Univ Paris Descartes, France and 2Hosp Cochin, Paris, France
Background: Lopinavir (LPV) is a protease inhibitor (PI) used in HIV-infection
treatment with a current recommended dosing regimen of 400 mg with 100 mg
ritonavir (r) twice daily. It was previously evidenced that pregnancy increased
LPV clearance but, the possible consequences of these modifications on LPV dose
is still under debate. Target efficacy threshold values of LPV trough
concentrations (Ctrough) of 1 and 5.7 mg/L were previously evidenced
for PI-naïve and PI-experienced patients, respectively. However, the influence
of pregnancy-related change in LPV pharmacokinetics on the probabilities to
achieve these target Ctrough was not determine to date. We therefore
conducted a pharmacokinetic study highlighting the possible influence of
pregnancy on the achievement of LPV target Ctrough.
Methods: The
pharmacokinetics of LPV were investigated using a population approach performed
with NONMEM on 412 samples coming from therapeutic drug monitoring of 180
HIV-1-infected women (77 pregnant, 103 non-pregnant). Monte Carlo simulations
were performed using the final model in order to estimate the probability to
achieve target Ctrough for 2 dosing regimens (400 mg twice daily,
and 600 mg twice daily).
Results: LPV
pharmacokinetics was well described by a 1-compartment model with a first-order
absorption rate, with typical population estimates (interindividual variability
percentage) of 4.35 L/h (24%) and 65.9 L (56%) for apparent clearance and distribution volume, respectively. Second and third trimesters of pregnancy, as
well as delivery were found to influence LPV pharmacokinetics, increasing
apparent clearance by 39 an 59%, respectively. Probability to achieve the 1 mg/L
target Ctrough with the recommended dose of 400/100 LPV/r twice
daily was >90% for pregnant and non-pregnant women. On the contrary, the
probability to achieve the 5.7 mg/L target Ctrough was 21.1% and
55.3%, respectively, for pregnant and non-pregnant women. These probabilities
to achieve the 5.7 mg/L value were raised to 53.3% and 86.4%, respectively, for
the 600 mg twice daily regimen.
Conclusions: The LPV/r 400 mg/100 mg twice daily regimen is efficient to reach a
minimal concentration of 1 mg/L for PI-naïve pregnant women, but may not be
suitable for PI-pre-treated pregnant women. Pregnancy and delivery influence LPV
Ctrough. Higher LPV dose safety and efficacy could be investigated
for PI-pre-treated pregnant women.
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