Fifty human immunodeficiency virus (HIV)-infected children participated in an area-under-the plasma concentration-time curve (AUC)-controlled trial of efavirenz and nelfinavir. Pharmacokinetic evaluations were performed at weeks 2, 6, and 56. Efavirenz and nelfinavir doses were adjusted to achieve AUC values of 60-120 and ≥10mgh/l, respectively. Thirty-seven (74%) children met the efavirenz target and 41 (82%) the nelfinavir by week 10. Children with AUC values for both drugs above the first quartile were more likely to reach <400 copies/ml of HIV RNA at week 8. Efavirenz and nelfinavir oral clearance increased 37 and 62% from weeks 2 to 56, respectively, in 34 children who continued on therapy at week 56. AUC values at week 56 were not different between children who did or did not have HIV RNA <400 copies/ml. Dose adjustment to achieve specific AUC values in these children reduced the risk of suboptimal exposure and achieved high rates of virologic suppression.We designed an open-label evaluation of the pharmacokinetics, safety, and anti-human immunodeficiency virus (HIV) effect of efavirenz and nelfinavir, in combination with nucleoside reverse transcriptase inhibitors (NRTIs), in HIV-infected children. This trial employed a concentration-controlled paradigm to adjust the doses of efavirenz and nelfinavir to meet predetermined area-under-the plasma concentration-time curve (AUC) target ranges. The safety and anti-viral effect of this study have been previously reported. 1 This paper reports the pharmacologic characteristics of efavirenz and nelfinavir in the HIV-infected children who participated in this trial.
© 2007 American Society for Clinical Pharmacology and TherapeuticsCorrespondence: CV Fletcher (courtney.fletcher@uchsc.edu).
CONFLICT OF INTERESTThe authors declared no conflict of interest.
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Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2010 April 1.
RESULTSPharmacokinetic studies for both efavirenz and nelfinavir were performed on 50 children at weeks 2 and 6. At week 2, the mean and median age of these children were 7.9 and 7 years, respectively, with a range of 3-16 years. These children had a mean and median body weight of 28.1 and 24 kg, respectively, with a range of 13.4-98 kg; the mean and median body surface area were 1 and 0.9m 2 and ranged from 0.6 to 2.1m 2 . Sixteen children discontinued the study before or at week 48: 10 children completed the initial 48-week study and chose not to continue past this primary observation end point; three children met the end point for virologic failure before week 48; one child was withdrawn before week 48 at the request of the family; one child was lost to follow-up before week 48; and one child had to be withdrawn at week 48 because of the lack of availability of the study drug. Thirty-four children remained on study at week 56, and pharmacokinetic evaluations for efavirenz and nelfinavir were repeated. The physical characteristics of these 34 children were (mean, median, and range) : age, 8.5, 8, and ...