Puberty is characterized by a significant increase in growth velocity, changes in body composition and the appearance of striking somatic changes. Those changes have a potential to significantly affect the pharmacokinetics (PK) and pharmacodynamics (PD) of antiretroviral (ARV) drugs, particularly those with a narrow therapeutic window. Among the ARV drugs Efavirenz (EFV) has the smallest window as well as a very low genetic barrier for the development of viral resistance and treatment failure. EFV is a substrate of the cytochrome (CYP) P450 metabolic pathway (primarily CYP2B6), and in vitro data of EFV metabolism suggest that 8-hydroxylation of EFV is a specific marker of CYP2B6 activity. We propose to evaluate the effect of physical and hormonal changes during puberty on biotransformation and clearance of EFV. We hypothesize that the developmental changes during puberty affect the disposition of EFV and have the potential to alter the clinical outcome of EFV based therapy in HIV-infected children and adolescents by influencing the dose-plasma concentration relationship.
Studv Aimi : Evaluate the relationship of developmental changes during puberty to clearance (CL/F) of EFV through a cross-sectional study of 44 children and adolescents in Tanner stages l-IV.
Studv Aim 2 : Evaluate the relationship of developmental changes during puberty (measured by somatic growth and sexual maturation) to CYP2B6 activity (determined by the formation clearance of EFV to its metabolite 8-hydroxyefavirenz) in the cross-sectional cohort of 44 children in study aim 1 and a longitudinal prospective cohort of 22 children in Tanner stages l-ll.
Studv Aim 3 : Explore the effect of developmental changes in CYP2B6 activity on the clinical outcome (measured by HIV-RNA viral load and CD4+ cell count) and toxicity (measured by CNS adverse events) of EFV based therapy in HIV-infected children and adolescents in a prospective cohort of 22 children in Tanner stages l-ll.

Public Health Relevance

The long-term goal of the proposed investigations is to improve dosing of EFV in HIV-infected children and adolescents, leading to improved outcome and decreased adverse drug reactions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HD060452-04
Application #
8306188
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mofenson, Lynne M
Project Start
2009-07-10
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$124,542
Indirect Cost
$8,792
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Kirmse, Brian; Baumgart, Stephen; Rakhmanina, Natella (2013) Metabolic and mitochondrial effects of antiretroviral drug exposure in pregnancy and postpartum: implications for fetal and future health. Semin Fetal Neonatal Med 18:48-55
Rakhmanina, Natella Y; Neely, Michael N; Capparelli, Edmund V (2012) High dose of darunavir in treatment-experienced HIV-infected adolescent results in virologic suppression and improved CD4 cell count. Ther Drug Monit 34:237-41
Rakhmanina, Natella Y; Neely, Michael N; Van Schaik, Ron H N et al. (2011) CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children. Ther Drug Monit 33:417-24
Best, Brookie M; Capparelli, Edmund V; Diep, Huy et al. (2011) Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Defic Syndr 58:385-91
Neely, Michael N; Rakhmanina, Natella Y (2011) Pharmacokinetic optimization of antiretroviral therapy in children and adolescents. Clin Pharmacokinet 50:143-89
Rakhmanina, Natella Y; van den Anker, John N (2010) Efavirenz in the therapy of HIV infection. Expert Opin Drug Metab Toxicol 6:95-103
Rakhmanina, Natella Y; van den Anker, John N (2010) Treating an HIV-infected paediatric patient: an easy task? Antivir Ther 15:293-6
Rakhmanina, Natella Y; van den Anker, John N; Soldin, Steven J et al. (2010) Can therapeutic drug monitoring improve pharmacotherapy of HIV infection in adolescents? Ther Drug Monit 32:273-81