JAC Advance Access published online on March 13, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn112
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Original research |
Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children
1 Department of Immunodeficiency Diseases, Childrens Hospital of the Ludwig Maximilians University, Munich, Germany 2 HIV Laboratory Therapia GmbH, Immunologisches Tagesklinik, Berlin, Germany 3 Department of Clinical Pharmacy, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Received 4 November 2007; returned 11 December 2007; revised 26 January 2008; accepted 18 February 2008
* Correspondence address. Department of Clinical Pharmacy, 864 Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. Tel: +31-24-3616405; Fax: +31-24-3668755; E-mail: d.burger{at}akf.umcn.nl
Objectives: To obtain data on the pharmacokinetics of efavirenz in children in clinical practice.
Methods: HIV-1-infected children received efavirenz capsules or tablets in accordance with manufacturer's dosing recommendations. Plasma was collected at regular visits and analysed by HPLC. The therapeutic range of efavirenz was defined as 1.0–4.0 mg/L.
Results: Thirty-three children were included. Median (range) age, body weight, dose and dose/kg were 8.2 (2.1–16.7) years, 24 (12–62) kg, 300 (200–800) mg and 13.3 (9.7–22.5) mg/kg, respectively. Median (range) efavirenz plasma concentration at first sampling was 2.8 (0.13–11.6) mg/L. Plasma concentrations were not dependent on age (P = 0.97) or dose/kg (P = 0.87). A total of 307 efavirenz plasma concentrations were determined. Forty-five samples (14.7%) contained >4.0 mg/L, and 27 samples (8.8%) contained <1.0 mg/L. Eight children (24%) reported persistent adverse events probably caused by efavirenz [concentration problems (5), sleep disorder (1), psychotic reaction (1) and seizure (1)]; six discontinued efavirenz for this reason. A non-significant trend existed towards a higher proportion of toxic efavirenz plasma concentrations (>4.0 mg/L) in subjects who reported efavirenz adverse events: 25.9% versus 12.8% (P = 0.23; t-test). Viral load was <50 copies/mL in all 27 subjects who continued efavirenz, despite occasional subtherapeutic efavirenz plasma concentrations in 12 children. The occasional subtherapeutic levels suggest that temporal non-adherence was present.
Conclusions: Efavirenz as part of highly active antiretroviral therapy was highly effective in children able to tolerate the drug. Therapeutic drug monitoring (TDM) as part of toxicity management may prevent discontinuation in a subset of patients. Temporal non-adherence occurs frequently. TDM may allow initiation of adherence interventions before viral load becomes detectable.
Key Words: non-nucleoside reverse transcriptase inhibitor , paediatrics , therapeutic drug monitoring
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