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Session 111 Poster Abstracts
Pharmacology of NRTIs
Wednesday, 1:30 - 3:30 pm
Hall A


648
Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or Atazanavir/Ritonavir
S Kaul*1, C Olszyk1, P Ji1, J Xie1, D Whigan2, and S Rahim1
1Bristol-Myers Squibb, Princeton, NJ, USA and 2Bristol-Myers Squibb, New Brunswick, NJ, USA

Background:  A previous study demonstrated that the exposure of didanosine (ddI) was increased by 26% when 500 mg didanosine enteric coated capsules (ddI-EC) was given with 400 mg atazanavir (ATV) and food, compared with 400 mg ddI-EC in the fasted state. The dose of ddI-EC in combination with ATV and food was increased to 500 mg to overcome the negative food effect on ddI. This study was designed to investigate the exposure of 400 mg ddI-EC when given with 400 mg ATV or 300/100 mg ATV/ritonavir (RTV) and food.

Methods:  In the following protocol, 35 healthy subjects participated—day 1:  400 mg ddI-EC in the fasted state; days 2 to 7:  400 mg ATV once-daily with food; day 8:  400 mg ddI-EC + 400 mg ATV with food; days 9 to 18:  300/100 mg ATV/RTV once daily with food; day 19: 400 mg ddI-EC + 300/100 mg ATV/RTV with food. Serial blood samples were collected over a 24-hour period on days 1, 7, 8, 18, and 19 and ddI, ATV, or RTV were analyzed by LC/MS/MS. Pharmacokinetic parameters were calculated by non-compartmental analysis.

Results:

Pharmacokinetic Parameter

Geometric Mean Ratios (90% CI)

 

400 ddI-EC+400 ATV fed vs 400 ddI-EC fasted

400 ddI-EC+400 ATV fed vs 400 ATV fed

400 ddI-EC+300/100 ATV/RTV fed vs 400 ddI-EC fasted or 300/100 ATV/RTV fed

Cmax, ddI-EC

0.640 (0.550 to 0.743)

—

0.617 (0.516 to 0.737)

AUC, ddI-EC

0.662 (0.596 to 0.735)

—

0.658 (0.590 to 0.733)

Cmax, ATV

—

1.026 (0.927 to 1.137)

1.038 (1.009 to 1.068)

AUC, ATV

—

0.993 (0.914 to 1.078)

0.995 (0.962 to 1.031)

Cmax, RTV

—

—

1.032 (0.917 to 1.160)

AUC, RTV

—

—

1.021 (0.945 to 1.102)

Conclusions: Didanosine-EC has no effect on ATV or ATV/RTV exposure. Reduced ddI exposure is seen when ddI-EC is co-administered with ATV and food or ATV/RTV and food consistent with the known food effect seen with ddI. No dosage adjustments are required for ATV or ATV/RTV when co-administered with ddI-EC. Both drugs should be administered as per their current dosing recommendations: ddI-EC should be given in the fasted state and ATV administered with food; hence ddI-EC should be administered at different times than ATV. The drugs were generally safe and well-tolerated when administered alone or in combination.

 

Keywords: didanosine; atazanavir; drug interaction