Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years

Abstract

The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.Lopinavir is a protease inhibitor (PI) used for the treatment of human immunodeficiency virus (HIV) infection in children and adults. Lopinavir can be administered to children older than 6 months of age by the use of a liquid formulation as well as by the use of a solid oral formulation, both of which contain ritonavir for pharmacokinetic enhancement, at recommended lopinavir/ritonavir doses of 12/3 mg/kg of body weight (BW) twice daily (BID) for children with BWs between 7 and 14 kg and 10/2.5 mg/kg BID for children with BWs between 15 and 40 kg. For children with body weights greater than 40 kg, the 400/100-mg BID adult dosage regimen is recommended. Children younger than 6 months of age were not investigated in previously published studies (3,27). This lack of data can explain to some extent why lopinavir is not recommended for use in children younger than age 6 months. Nevertheless, there are clinical situations, such as the presence of a viral strain less sensitive to the other antiretrovirals, which could require the administration of lopinavir to very young children. Another pediatric population for which pharmacokinetic data are lacking is children with BWs greater than 40 kg. However, this lack of data for adolescents is a very common phenomenon and is relevant not only to lopinavir. Frequently, adolescents are considered similar to adults from a pharmacokinetic point of view, which explains why adolescents often receive the recommended adult dosage regimen. However, adolescence is characterized by physiological and hormonal changes (26, 30), the possible consequences of which on the pharmacokinetics and metabolism of drugs are still unknown. Because pharmacokinetic data for children younger than age 6 months and adolescents are lacking, the relationships between lopinavir pharmacokinetic parameters and the individual characteristics of children are also not known. These relationships are nevertheless important for optimization of the lopinavir dosage regimen, as several studies perform...

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