Effects of didanosine formulations on the pharmacokinetics of amprenavir.
OBJECTIVE
To determine the effects of concurrent, single doses of didanosine (both buffered and encapsulated enteric-coated bead formulations) on amprenavir steady-state pharmacokinetics, and to determine the effect of staggered dosing of the buffered formulation.


METHODS
Two-period, single-sequence, prospective, open-label drug interaction study with a 10-day washout interval.


METHODS
Clinical research unit.


METHODS
Sixteen healthy volunteers without human immunodeficiency virus infection.


METHODS
Amprenavir 600 mg twice/day was given for the first 4 days of each treatment period, with 12-hour pharmacokinetic evaluations conducted on the last 2 days of each period. Amprenavir was administered according to the following sequential treatments (all fasting): amprenavir alone, concurrent with buffered didanosine, 1 hour before buffered didanosine, and concurrent with the encapsulated enteric-coated bead formulation of didanosine.


RESULTS
Plasma was collected 0, 1, 2, 3, 4, 6, 8, and 12 hours after dosing and assayed for amprenavir by using high-performance liquid chromatography. Noncompartmental pharmacokinetic parameters were determined. Geometric mean ratios for each treatment relative to amprenavir alone were determined and reported with 90% confidence intervals (CIs). No significant trends were noted in predose concentrations measured during either period. Area under the concentration-time curve during one 12-hour dosing interval (AUC12) was found to be bioequivalent for all treatments. Peak drug concentration (Cmax) was reduced by 15% on average with concurrent administration of buffered didanosine, and bioequivalence was not demonstrated for this parameter. For concurrent enteric-coated didanosine, geometric mean ratios for Cmax and AUC12 were 0.93 and 0.94, respectively. For buffered didanosine given 1 hour after amprenavir, geometric mean ratios were 1.06 and 1.10 for the same parameters, respectively. No differences were observed in 12-hour concentration (C12) with concurrent administration of buffered or enteric-coated didanosine.


CONCLUSIONS
Amprenavir AUC12 and C12 are not significantly affected by concurrent administration of the buffered or enteric-coated formulations of didanosine. Therefore, amprenavir may be administered concurrently with either the buffered or the encapsulated enteric-coated bead formulation of didanosine in the fasting state.
Shelton
Mark J
MJ
GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA.
Giovanniello
Angela A
AA
Cloen
Denise
D
Berenson
Charles S
CS
Keil
Kim
K
DiFrancesco
Robin
R
Hewitt
Ross G
RG
D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002214:Capsules; D002219:Carbamates; D018592:Cross-Over Studies; D016049:Didanosine / Q000494:pharmacology*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005663:Furans; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D013608:Tablets, Enteric-Coated; D013997:Time Factors
D019380:Anti-HIV Agents; D002214:Capsules; D002219:Carbamates; D005663:Furans; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D013608:Tablets, Enteric-Coated; C095108:amprenavir; D016049:Didanosine