JAC Advance Access originally published online on April 22, 2009
Journal of Antimicrobial Chemotherapy 2009 63(6):1223-1232; doi:10.1093/jac/dkp123
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Original research |
Population analysis of the pregnancy-related modifications in lopinavir pharmacokinetics and their possible consequences for dose adjustment
1 Université Paris Descartes, Paris, France 2 Assistance Publique-Hôpitaux de Paris, Paris, France 3 Service de Pharmacologie Clinique, Hôpital Cochin—Saint-Vincent de Paul, Paris, France 4 EA 3620, Paris, France 5 Service de Gynécologie-Obstétrique II, Hôpital Cochin, Paris, France 6 Service de Virologie, Hôpital Cochin—Saint-Vincent de Paul, Paris, France 7 Pôle de Médecine Interne, Hôpital Cochin, Paris, France
Received 27 November 2008; returned 3 January 2009; revised 2 March 2009; accepted 5 March 2009
* Corresponding author. Service de Pharmacologie Clinique, Groupe Hospitalier Cochin—Saint-Vincent de Paul, 74-82 Avenue Denfert-Rochereau, 75674 Paris Cedex 14, France. Tel: +33-1-4048-8209; Fax: +33-1-4048-8223; E-mail: vincent.jullien{at}svp.aphp.fr
Objectives: 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.
Patients and 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.
Keywords: HIV , protease inhibitors , PK
The first two authors contributed equally to this study. 
The last two authors contributed equally to this study.