Timing of food intake has a marked effect on the bioavailability of clodronate

Because of the low and variable bioavailability of bisphosphonates and the huge effect of food on their gastrointestinal absorption, it is of utmost i mportance to know the optimal timing of drug intake in relation to food int ake, We investigated the effect of time on the bioavailability of clodronat e when the drug was administered 2, 1, or 0.5 h before breakfast, with brea kfast, or 2 h after breakfast tin the middle of a 4-h fast). The study was conducted as a single-center, open, balanced, randomized, crossover pharmac okinetic study in 31 healthy subjects aged 21 to 34 years, The volunteers p articipated in five different sessions with 800 mg of oral clodronate, and these sessions were separated by washout phases, each for at least 1 week. The primary pharmacokinetic variables were the area under the serum concent ration time curve in 24 h (AUC(0-24)) for clodronate and the maximal concen tration of clodronate in serum (C-max). Clodronate was absorbed rather simi larly when taken in the morning on an empty stomach 2, 1, or 0.5 h before b reakfast, but because the best absorption occurred las expected) when the d rug was taken 2 h before breakfast, this scheme served as the reference tre atment. As evaluated by area ender the serum concentration time curves, the dose-breakfast interval of 1 h scarcely reduced absorption from the refere nce treatment level (relative absorption 91%, p = 1.0). Compared with the r eference treatment, clodronate was absorbed with 69% efficacy (p = 0.65) wh en breakfast followed only 0.5 h later. The dose-breakfast intervals of 0.5 and 1 h did not differ significantly from each other (p = 0.85). Absorptio n was, however, only 34% (p < 0.0001) of the optimum when the drug was take n 2 h after breakfast, and only 10% of optimal when clodronate was taken wi th breakfast (p < 0.0001). In conclusion, it can be recommended to take Bon efos capsules in the morning on an empty stomach at least 0.5 h before brea kfast. (C) 2000 by Elsevier Science Inc. All rights reserved.