Dipyridamole Bioavailability in Subjects With Reduced Gastric Acidity
BACKGROUND AND PURPOSE
Dipyridamole (DP) is an antiplatelet agent that shows decreased oral bioavailability with increased gastric pH that occurs with commonly prescribed antacids. An extended-release (ER) formulation of DP that employs tartaric acid to improve bioavailability of DP in the presence of elevated gastric pH was developed as a combination antiplatelet product with immediate-release (IR) aspirin (ASA).
METHODS
This crossover-designed study examined the relative bioavailability of DP from the composite product compared to conventional DP tablets during reduced gastric acidity. Gastric pH was increased (pH > 4.0) in 20 healthy subjects with lansoprazole (30 mg/d for 5 days). Dipyridamole systemic exposure over 12 hours was compared after oral administration of a single composite ER capsule (200 mg DP + 25 mg aspirin) versus two 100-mg conventional DP tablets given 6 hours apart combined with 81 mg delayed-release (DR) ASA.
RESULTS
Mean Plasma Dipyridamole Profiles
Mean plasma profiles for the 20 evaluable subjects after each treatment are shown in the figure. DP bioavailability was clearly dampened with the immediate-release generic DP compared to the composite ER formulation in subjects with elevated gastric pH. DP relative bioavailability was reduced 53% with conventional tablets compared to the composite buffered ER capsule in reduced gastric acid conditions. Peak DP plasma concentrations were 57% lower with immediate-release tablets compared to the composite formulation with high stomach pH.
Reference:
Derendorf et al. J Clin Pharmacol 2005; 45 (7): 845-850.
Mean Plasma Dipyridamole Profiles in 20 Subjects with Elevated Gastric pH (> 4.0)
Pharmacokinetic Parameters for Dipyridamole
The extent of DP exposure that is reflected by the AUC0-12 with the immediate-release formulation was only 50% of the mean value after the composite buffered ER formulation. Total DP exposure was estimated from AUC0-48 values that were consistently higher from the buffered ER formulation 200-mg dose compared to the same dose given at the recommended 6-hour dosing interval as conventional tablets. The ratio of AUC0-48 values for conventional DP tablets compared to buffered ER formulation ranged from 0.65 to 0.88 for the 20 individuals. Peak DP concentrations (Cmax) measured with the immediate-release formulation were less than half those measured after the composite ER formulation, with a geometric mean ratio of 43% for individuals.
Reference:
Derendorf et al. J Clin Pharmacol 2005; 45 (7): 845-850.
Pharmacokinetic Parameters for Dipyridamole in Subjects With Low Gastric Acidity (pH > 4.0)
 |
|
|
| Parameter |
Composite Extended-Release Dipyridamole Capsule With Aspirin |
Immediate-Release Dipyridamole Plus Aspirin |
| AUC, ng*h/mL
|
7883
3976-12341 |
3943
994-7709 |
| AUC ng*h/mL
|
11896
4753-21188 |
9051
1389-25159 |
| Cmax, ng/mL
|
1842
1000-3302 |
848
202-1643 |
| C, ng/mL
|
237
66-621 |
362
78-909 |
| tmax, h
|
7883
3976-12341 |
3943
994-7709 |
| Parameter |
Ratio Immediate Release Versus Buffered Extended-Release Composite |
95% Confidence Interval |
| AUC, ng*h/mL
|
0.50a |
0.41, 0.59 |
| AUC ng*h/mL
|
0.76a |
0.65, 0.88 |
| Cmax, ng/mL
|
0.46a |
0.31, 0.61 |
| C, ng/mL
|
1.53a |
1.19, 1.87 |
| tmax, h
|
1.28 |
0.86, 1.69 |
a. Immediate release significantly different than extended-release composite,
P < 0.01.
CONCLUSION
Substituting generic DP plus low-dose aspirin may be less effective than the buffered DP composite product in patients with concomitant antacid therapies.
PubMed Abstract
References:
Derendorf et al. J Clin Pharmacol 2005; 45 (7): 845-850.
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