Effects of Didanosine Formulations on the PK of Amprenavir
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 (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.
Conclusion: 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.
Amprenavir is a human immunodeficiency virus (HIV) protease inhibitor that, in combination with nucleoside reverse transcriptase inhibitors, is effective in the treatment of HIV infection. Systemic availability of amprenavir may be influenced by cytochrome P450 (CYP) 3A4 metabolism, drug transport processes (i.e., P-glycoprotein), and concomitant food administration. In combination with other antiretroviral agents, currently approved regimens consist of amprenavir 1200 mg twice/day as a single protease inhibitor and two regimens in combination with ritonavir: amprenavir 600 mg and ritonavir 100 mg twice/day, and amprenavir 1200 mg and ritonavir 200 mg once/day. In contrast to other HIV protease inhibitors, such as nelfinavir and saquinavir, amprenavir can be given with or without food, although a high-fat meal may reduce amprenavir absorption and should be avoided.
Didanosine is a reverse transcriptase inhibitor approved, in combination with other antiretroviral agents, for the treatment of HIV infection. Didanosine is an acid-labile nucleoside presently available in various formulations to prevent intragastric degradation (by gastric buffering or enteric coating). All didanosine formulations should be taken in a fasting state, since high-fat meals reduce absorption by 20-50%.
Because of the limited number of antiretroviral regimens, concurrent administration of both amprenavir and didanosine occurs frequently in patients who are HIV positive. Concurrent administration of these agents is not recommended owing to the potential for gastric buffers to reduce amprenavir absorption as a result of reduced aqueous solubility. Whereas concurrent administration of buffered didanosine reduces systemic exposure to indinavir and delavirdine, staggered administration represents a strategy to avoid the interaction. This issue has not been evaluated fully for amprenavir in a pharmacokinetic study. At present, combination antiretroviral regimens containing both amprenavir and didanosine represent an adherence barrier because of the recommended 1-hour separation of doses and the fasting requirement for didanosine. Use of the encapsulated enteric-coated bead formulation of didanosine may avoid this potential interaction, as has been shown for the HIV protease inhibitor indinavir.
The present study was designed to determine the effects of two didanosine formulations (buffered vs encapsulated enteric-coated bead formulation) on the pharmacokinetics of amprenavir and to determine the effect of staggered buffered didanosine dosing on the pharmacokinetic exposure to amprenavir in healthy volunteers.