Impact of adherence and anthropometric characteristics on nevirapine pharmacokinetics and exposure among HIV-infected Kenyan children
Journal of Acquired Immune Deficiency Syndromes
Department of Pediatrics, School of Medicine, Indiana University, 410 W, 10th Street, Indianapolis, IN, United States; Regenstrief Institute, Inc, Indianapolis, IN, United States; Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya; Department of Child Health and Paediatrics, College of Health Sciences, Moi University, Eldoret, Kenya; Department of Medicine, College of Health Sciences, Moi University, Eldoret, Kenya; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States; Department of Medicine (Clinical Pharmacology) and Molecular Pharmacology, School of Medicine, Stanford University, Stanford, CA, United States
Background: There are insufficient data on pediatric antiretroviral therapy (ART) pharmacokinetics (PK), particularly for children in low- and middle-income countries. Methods: We conducted a prospective nevirapine (NVP) PK study among HIV-infected Kenyan children aged 3-13 years initiating an NVP-based ART regimen. NVP dose timing was measured through medication event monitors. Participants underwent 2 inpatient assessments: 1 at 4-8 weeks after ART initiation and 1 at 3-4 months after ART initiation. Allometric scaling of oral clearance (CL)/bioavailability (F) and volume of distribution (Vd)/F values were computed. Nonlinear mixed-effects modeling using the first-order conditional estimation with interaction method was performed with covariates. The impact of adherence on time below minimum effective concentration was assessed in the final PK model using medication event monitors data and model-estimated individual parameters. Results: Among 21 children enrolled, mean age was 5.4 years and 57% were female. CL/F was 1.67 L/h and Vd/F was 3.8 L for a median child weighing 15 kg. Participants' age had a significant impact on CL/F (P < 0.05), with an estimated decrease in CL of 6.2% for each 1-year increase in age. Total body water percentage was significantly associated with Vd/F (P < 0.001). No children had >10% of time below minimum effective concentration when the PK model assumed perfect adherence compared with 10 children when adherence data were used. Conclusions: Age and body composition were significantly associated with children's NVP PK parameters. ART adherence significantly impacted drug exposure over time, revealing subtherapeutic windows that may lead to viral resistance. Copyright © 2014 by Lippincott Williams & Wilkins.
nevirapine; anti human immunodeficiency virus agent; nevirapine; adolescent; age; allometry; anthropometry; antiviral therapy; apparent distribution volume; arm circumference; Article; body composition; body weight; child; childhood disease; clinical article; drug absorption; drug bioavailability; drug clearance; drug distribution; drug dose increase; drug exposure; drug monitoring; elimination rate constant; female; follow up; human; Human immunodeficiency virus infected patient; Human immunodeficiency virus infection; Kenyan; male; malnutrition; medication compliance; minimum plasma concentration; oral clearance; patient compliance; priority journal; prospective study; total body water; volume of distribution; anthropometry; bioavailability; body size; body water; HIV Infections; Kenya; metabolism; nutritional status; preschool child; Adolescent; Anthropometry; Anti-HIV Agents; Biological Availability; Body Size; Body Water; Child; Child, Preschool; Female; HIV Infections; Humans; Kenya; Male; Medication Adherence; Nevirapine; Nutritional Status; Prospective Studies