title: Impact of adherence and anthropometric characteristics on nevirapine pharmacokinetics and exposure among HIV-infected Kenyan children.
abstract: 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.
authors.affiliation: *Department of Pediatrics, School of Medicine, Indiana University, Indianapolis, IN; †The Regenstrief Institute, Inc, Indianapolis, IN; ‡Academic Model Providing Access to Healthcare (AMPATH), Eldoret, Kenya; Departments of §Child Health and Paediatrics; ‖Medicine, School of Medicine, College of Health Sciences, Moi University, Eldoret, Kenya; ¶Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA; and #Department of Medicine (Clinical Pharmacology) and Molecular Pharmacology, School of Medicine, Stanford University, Stanford, CA.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Vreeman
authors.forename: Winstone M
authors.initials: WM
authors.lastname: Nyandiko
authors.forename: Edward A
authors.initials: EA
authors.lastname: Liechty
authors.forename: Naftali
authors.initials: N
authors.lastname: Busakhala
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.forename: Rada M
authors.initials: RM
authors.lastname: Savic
authors.forename: Michael L
authors.initials: ML
authors.lastname: Scanlon
authors.forename: Samual O
authors.initials: SO
authors.lastname: Ayaya
authors.forename: Terry F
authors.initials: TF
authors.lastname: Blaschke
mesh_terms: D000293:Adolescent; D000886:Anthropometry; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D049628:Body Size; D001834:Body Water; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007630:Kenya; D008297:Male; D055118:Medication Adherence; D019829:Nevirapine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009752:Nutritional Status; D011446:Prospective Studies
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine