Impact of Adherence and Anthropometric Characteristics on Nevirapine Pharmacokinetics and Exposure Among HIV-Infected Kenyan Children

Vreeman, Rachel C. MD, MS*,†,‡; Nyandiko, Winstone M. MBChB, MMED, MPH‡,§; Liechty, Edward A. MD*; Busakhala, Naftali MBChB, MMED‡,‖; Bartelink, Imke H. PhD; Savic, Rada M. PhD; Scanlon, Michael L. MPH*,‡; Ayaya, Samual O. MBChB, MMED‡,§; Blaschke, Terry F. MD¶,#

JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0000000000000300
Clinical Science
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.

Author Information

*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.

Correspondence to: Rachel C. Vreeman, MD, MS, Children's Health Services Research, Department of Pediatrics, School of Medicine, Indiana University, 410 W, 10th Street, HITS Suite 1000, Indianapolis, IN 46202 (e-mail: rvreeman@iu.edu).

Supported in part by a career development award to R.C.V. from the Indiana CTSI (KL2RR025760-01) and by the President's Emergency Plan for AIDS Relief (PEPFAR) through USAID under the terms of Cooperative Agreement No. AID-623-A-12-0001. Grant (1K23MH087225).

The primary author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors have no conflicts of interest to disclose.

The views expressed in this article are those of the authors and do not necessarily represent the view of the Indiana University School of Medicine or the Moi University School of Medicine.

Received February 27, 2014

Accepted July 11, 2014

© 2014 by Lippincott Williams & Wilkins