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Antimicrobial Agents and Chemotherapy, June 2009, p. 2532-2538, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01374-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Population Pharmacokinetics of Lopinavir Predict Suboptimal Therapeutic Concentrations in Treatment-Experienced Human Immunodeficiency Virus-Infected Children
Natella Rakhmanina,1,2,4
John van den Anker,1,2,5,6
Aline Baghdassarian,4
Steven Soldin,3,4,5,7
Keetra Williams,1 and
Michael N. Neely8,9*
Division of Infectious Disease,1 Division of Pediatric Clinical Pharmacology,2 Department of Laboratory Medicine, Children's National Medical Center, Washington, DC,3 Departments of Pediatrics,4 Pathology,5 Pharmacology and Physiology, George Washington University School of Medicine, Washington, DC,6 Department of Pharmacology, Georgetown University and Georgetown Clinical Research Center, Washington, DC,7 Division of Pediatric Infectious Diseases,8 Laboratory of Applied Pharmacokinetics, University of Southern California, Los Angeles, California9
Received 13 October 2008/ Returned for modification 17 January 2009/ Accepted 14 February 2009
In adult protease inhibitor (PI)-experienced patients, a lopinavir (LPV) phenotypic inhibitory quotient (PIQ) of >15 has been associated with a higher likelihood of viral suppression. The aims of this study were to develop a population pharmacokinetic (PK) model of LPV in children and to estimate the probability of achieving a PIQ of >15. HIV-infected, PI-experienced children receiving LPV were intensively sampled for 12 h to measure plasma LPV. The data were fitted to candidate PK models (using MM-USCPACK software), and the final model was used to simulate 1,000 children to determine the probability of achieving an LPV PIQ of >15. In 50 patients (4 to 18 years old), the median LPV plasma 12-hour-postdose concentration was 5.9 mg/liter (range, 0.03 to 16.2 mg/liter) lower than that reported in adults. After a delay, LPV was absorbed linearly into a central compartment whose size was dependent on the weight and age of the patient. Elimination was dependent on weight. The regression line of observed versus predicted LPV had an R2 of 0.99 and a slope of 1.0. Visual predictive checks against all available measured concentrations showed good predictive ability of the model. The probability of achieving an LPV PIQ of >15 was >90% for wild-type virus but <10% for even moderately resistant virus. The currently recommended dose of LPV/ritonavir appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant human immunodeficiency virus (HIV). PI-experienced HIV-infected children will likely benefit from longitudinal, repeated LPV measurement in plasma to ensure that drug exposure is most often near the maximal end of the observed safe range.
* Corresponding author. Mailing address: University of Southern California, Division of Pediatric Infectious Diseases, Laboratory of Applied Pharmacokinetics, 1640 Marengo St., No. 300, Los Angeles, CA 90033. Phone: (323) 226-2330. Fax: (323) 226-2505. E-mail: mneely{at}usc.edu
Published ahead of print on 2 March 2009.
Antimicrobial Agents and Chemotherapy, June 2009, p. 2532-2538, Vol. 53, No. 6
0066-4804/09/$08.00+0 doi:10.1128/AAC.01374-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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