Bioequivalence of dispersed stavudine: opened versus closed capsule dosing.
BACKGROUND
Stavudine, a nucleoside reverse transcriptase inhibitor, is used commonly to treat HIV-infected children in the developing world. The paediatric liquid formulation presents major logistical difficulties in rural and resource-limited areas, and prescribers are frequently forced to employ off-label 'opened capsule' dosing methods using the adult capsule. The South African Department of Health (DoH) has advised that caregivers should be instructed to disperse the contents of an adult capsule in 5 ml water and then withdraw the required dose using a syringe. The bioavailability of stavudine using the opened capsule dosing method has not previously been validated.


METHODS
This was a randomized crossover pharmacokinetic study with each subject serving as his/her own control. A total of 28 healthy HIV-negative adult volunteers were randomized on a 1:1 basis to receive one of the two generic preparations typically available in state hospitals. They were then further randomized to receive either intact or opened 30 mg capsules. After 1 week, those who initially received intact capsules, were given opened capsules and vice versa. The capsule dispersion technique used was identical to that prescribed by the DoH. Serial blood samples were collected and plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Stavudine pharmacokinetics were analysed using non-compartmental methods and formulations were compared using ANOVA.


RESULTS
Plasma drug exposure after stavudine administration as a solution using an opened capsule dosing method was found to be bioequivalent to intact capsule administration. This was true for both generics tested.


CONCLUSIONS
The opened capsule dosing technique is bioequivalent to intact capsule dosing for stavudine in HIV-seronegative adults.
KID-CRU (Children's Infectious Diseases Clinical Research Unit), Tygerberg Children's Hospital and Stellenbosch University, Tygerberg, South Africa. innes@sun.ac.za
Steve
S
Innes
Jennifer
J
Norman
Pete
P
Smith
Marlize
M
Smuts
Edmund
E
Capparelli
Bernd
B
Rosenkranz
Mark
M
Cotton
D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002214:Capsules; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D018119:Stavudine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency
D019380:Anti-HIV Agents; D002214:Capsules; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine