JAC Advance Access first published online on April 22, 2009
This version published online on April 27, 2009
Journal of Antimicrobial Chemotherapy, 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.
Key Words: HIV , protease inhibitors , PK
The original version was incorrect. Figure 1 should have appeared in colour and in Table 1, the last line of data was incorrectly aligned
The first two authors contributed equally to this study.
The last two authors contributed equally to this study.