Dose adjustments are required for weight based didanosine if used with tenofovir DF
Tenofovir Disoproxil Fumarate versus Didanosine
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Study Design
In a phase 1, open-label, multiple dose, one sequence, drug-drug interaction study of tenofovir disoproxil fumarate (TDF) 300 mg and didanosine EC (ddI-EC) 250 mg compared to ddI-EC 400 mg alone in healthy male and female subjects (>60 kg), subjects received the following treatments. On day one, ddI-EC 400 mg (fasted). On days 2-7, TDF 300 mg mwith morning meal. On day eight, ddI-EC 250 mg (fasted) plus TDF 300 mg 2 hours later with light meal. On day nine, ddI-EC 250 mg plus TDF 300 mg together with a light meal. On day ten, ddI-EC 250 mg plus TDF 300 mg together (fasted). Blood samples were collected over 24 hours following the administration of study drugs on days 1, 8, 9, and 10. The ratio of geometric means for AUC and Cmax and their 90% confidence intervals were derived for each drug when administered alone or together using a mixed model analysis.
Study Results
From the studies by Kearny, et al, the pharmacokinetics of tenofovir were unaffected by the coadministration with didanosine. However, didanosine concentrations were altered as seen in the table below.
Regimen ddI Cmax (mcg/mL) GMR (90% CI) ddI AUC (mcg*h / mL) GMR (90% CI)
ddI EC 400 mg alone 1.18 NA 2.75 NA
ddI EC 250 + TDF:
• Staggered (2h prior) 1.06 89.5 (78.1 – 103) 2.74 99.8 (89.2, 112)
• Together with light meal 0.84 71.1 (61.3 – 82.4) 2.44 88.6 (76.8, 102)Si
• Together Fasted 1.09 92.4 (81.2, 105) 3.14 114 (100, 131)
In healthy subjects a 44% increase in AUC of didanosine was found when the buffered tablet formulation was coadministered with tenofovir DF. Other studies have shown that when didanosine EC 400 mg was administered in the fasted state two hours before tenofovir DF, didanosine AUC was 48% higher relative to didanosine EC administered alone. Since administration with food lowers didanosine exposure, coadministration of didanosine EC with food and tenofovir was also evaluated. Contrary to expectations, simultaneous administration of didanosine EC 400 mg with TDF and food resulted in a 60% increase in didanosine AUC relative to administration alone in the fasted state.
Study Conclusions
The authors concluded that didanosine administered as either the buffered tablet or the enteric coated formulation (didanosine EC) has been shown not to have an effect on tenofovir pharmacokinetics, but does cause increases in didanosine AUC and Cmax. Please follow current dosing guidelines, which recommend that in patients using concomitant tenofovir (CrCl 60 mL/min or more): delayed-release capsules or oral solution of didanosine should be used in a weight based fashion. For patients weighing ess than 60 kg: 200 mg orally once a day, and for patients who weigh 60 kg or more: 250 mg orally once a day. The delayed-release capsules should be taken together with tenofovir and a light meal (400 kilocalories or less, 20% fat or less) or in the fasted state. The oral solution and tenofovir may be taken together in the fasted state. Alternatively, if tenofovir is taken with food, the oral solution should be taken on an empty stomach.
References
Kearney BP. Drug‐drug and drug‐food interactions between tenofovir disoproxil fumarate and didanosine. Journal Of Clinical Pharmacology. 2005; 12: 1360-1367.
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