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Effects of Didanosine Formulations on the Pharmacokinetics of Amprenavir
Author(s) -
Shelton Mark J.,
Giovanniello Angela A.,
Cloen Denise,
Berenson Charles S.,
Keil Kim,
DiFrancesco Robin,
Hewitt Ross G.
Publication year - 2003
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1592/phco.23.7.835.32724
Subject(s) - amprenavir , didanosine , pharmacokinetics , bioequivalence , cmax , pharmacology , dosing , crossover study , medicine , chemistry , virology , viral load , human immunodeficiency virus (hiv) , placebo , antiretroviral therapy , biochemistry , alternative medicine , pathology , hiv 1 protease , protease , enzyme
Study Objectives. 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. Design. Two‐period, single‐sequence, prospective, open‐label drug interaction study with a 10‐day washout interval. Setting. Clinical research unit. Subjects. Sixteen healthy volunteers without human immunodeficiency virus infection. Intervention. 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. Measurements and Main 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 (AUC 12 ) was found to be bioequivalent for all treatments. Peak drug concentration (C max ) 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 C max and AUC 12 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 (C 12 ) with concurrent administration of buffered or enteric‐coated didanosine. Conclusion. Amprenavir AUC 12 and C 12 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.