Pharmacokinetics of dipyridamole-β-cyclodextrin complex in healthy volunteers after single and multiple doses

Abstract

Dipyridamole is a well known anti-aggregating agent characterized by poor water solubility as well as scant and variable bioavailability. Recently, the compound was complexed with beta-cyclodextrin forming a molecular encapsulation resulting in better oral absorption and stronger biological activities in animals. In the present study, a randomized double blind cross-over comparison between dipyridamole-beta-cyclodextrin complex (dip-beta-CD) and dipyridamole was performed in 12 healthy subjects after single (75mg) and multiple oral treatments (75mg TID). Dip-beta-CD showed better bioavailability and less interindividual variability than dipyridamole either after single or multiple doses. In particular, dip-beta-CD had a greater AUC and Cmax, and a smaller Tmax even at the steady state. In addition, 100% of the subjects receiving a single dose of dip-beta-CD, as compared to 66.7% of those treated with dipyridamole, had plasma levels superior to 1 microgram/ml (which is the supposed anti-aggregating threshold level). In contrast, 0 and 33.03% of the subjects showed plasma levels superior to 2.5 micrograms/ml (which might cause the appearance of side-effects) on the 7th day of the multiple treatment with dip-beta-CD and dipyridamole, respectively. In fact, the subjects presenting higher levels after uncomplexed dipyridamole also complained of headache and/or dizziness on occasion. No adverse side effects were reported for dip-beta-CD.

The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development

“…Gastric pH related variability has been demonstrated in elderly patients81 and raised gastric pH significantly lowers the oral absorption of the drug 82. Dosing as a cyclodextrin formulation helps to reduce variability and increased bioavailability 83. In addition, the use of acidifying agents in an extended release formulation has been used to improve the pharmacokinetic variability 49, 82.…”

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

“…While these reports will not be extensively reviewed here, the subject of each publication will be addressed for the reader's information. Ricevuti et al 157 investigated the pharmacokinetics in healthy volunteers of dipyridamole and its -CD complex following single and multiple dosing and found better bioavailability from the complex. Yusuff et al 158 observed improved spironolactone bioavailability from a -CD complex and a micronized powder versus the commercial product, Aldactone.…”

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

“…The target dosing strategy was to scale down to the clinical dose administered with a glass of water (i.e., 75, 200, and 200 mg for dipyridamole, ketoconazole, and itraconazole, respectively, with 250 mL water) [22][23][24]. For the biphasic experiments, since 40 mL of aqueous medium was used, the dipyridamole, ketoconazole and itraconazole doses were estimated to be 12, 32, and 32 mg, respectively.…”