Pharmacokinetics of generic and trade formulations of lamivudine, stavudine and nevirapine in HIV-infected Malawian children.
BACKGROUND
The aim of this study was to evaluate the pharmacokinetics of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in HIV-infected Malawian children receiving quartered tablet multiples of Triomune 40 (generic tablet [GT]) compared with individual generic liquid (GL) and trade liquid (TL).


METHODS
This was a prospective randomized three-way crossover study. Patients (8-<12 kg, 18-<22 kg or 28-<32 kg body weight) taking Triomune 40 were recruited and randomized to receive GT twice daily (one-quarter, one-half or three-quarter tablets using Malawi treatment guidelines), GL twice daily (in the equivalent dose of GT) or TL twice daily (dosed using weight and age from US Department of Health and Human Services paediatric treatment guidelines). After 10 days of one formulation, 6-h pharmacokinetic sampling was performed, and patients were crossed over to subsequent formulations. Baseline concentration (C(0 h)), area under the curve (AUC)(0-6 h), maximum plasma concentration (C(max)) and time to C(max) were generated for each antiretroviral treatment.


RESULTS
A total of 7 males and 11 females (6 in each GT dosing group) with a median (range) age of 7.2 years (1.3-13.6), weight of 19 kg (9.0-30.5) and height of 109 cm (75-132) were recruited. Combining all patients, no difference in pharmacokinetics was noted among the formulations for all drugs. However, patients in the one-quarter GT dosing group (8-<12 kg) had lower 3TC exposures than with the GL or TL (3TC AUC(0-6 h) 1,102, 1,720 and 2,060 h*ng/ml, respectively; P<0.005) and had more subtherapeutic NVP C(0 h) (10 of 13 occasions versus the one-half and three-quarter tablet groups). Compared with Western paediatric cohorts, Malawians had concentrations 30-40% lower for 3TC and d4T and 50% higher for NVP.


CONCLUSIONS
Quartered multiples of Triomune 40 are appropriate for children 18-<22 kg and 28-<32 kg in weight; however, alternative formulations are suggested in children weighing 8-<12 kg.
Corbett
Amanda H
AH
University of North Carolina Schools of Pharmacy, Medicine and Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ahcorbet@email.unc.edu
Hosseinipour
Mina C
MC
Nyirenda
Jean
J
Kanyama
Cecelia
C
Rezk
Naser L
NL
Mkupani
Pax
P
Sichali
Dorothy
D
Tien
Hsiao
H
Kashuba
Angela Dm
AD
Mwansambo
Charles
C
Weigel
Ralf
R
Kazembe
Peter
P
D000293:Adolescent; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D004304:Dosage Forms; D004334:Drug Administration Schedule; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006678:HIV; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007223:Infant; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008295:Malawi; D008297:Male; D019829:Nevirapine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011446:Prospective Studies; D018119:Stavudine / Q000008:administration & dosage / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D004304:Dosage Forms; D016568:Drugs, Generic; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine