Comparison of pharmacokinetics of clodronate after single and repeated doses

Pharmacokinetics of orally given clodronate disodium, a drug for the treatment of hypercalcemia and bone resorption, were studied after a single dose of 400, 800 and 1600 mg given randomly to 11 healthy volunteers in a crossover manner, in 7-14 hospitalized cancer patients given 400, 800 and 1600 mg twice daily, each dosage for one week, and during the customary therapy in 15 additional cancer patients treated in hospital with 400 mg thrice daily for > or = 2 weeks.

Clodronate concentrations in serum and urine were measured by capillary gaschromatography with mass-selective detection. Pharmacokinetic parameters were calculated with a three-compartmental model.

After a single oral dose to healthy volunteers the absolute clodronate concentrations increased almost dose-dependently. The mean cumulative excretion in urine was 1.72-2.77% of the dose, an interindividual range being from 0.92% to 5.52%. With 800 and 1600 mg twice daily for one week to cancer patients the serum drug concentrations increased almost progressively with increasing the dose. In cancer patients serum drug concentrations were clearly higher and renal drug clearances (mean 25-62 ml/min) lower than in healthy volunteers (mean 123-149 ml/min). The mean urinary excretions were 2.24-3.14% of the dose and interindividual ranges from 0.18% to 19.0%. During the routine cancer therapy with 400 mg thrice daily, the clodronate excretions in urine on two successive days were on an average 3.26% (range 0.0-10.5%).

Absolute concentrations in serum and excretions in urine of orally given clodronate increase dose-dependently, but during the maintenance therapy in hospitalized cancer patients the renal drug clearances seem to be lower than in healthy volunteers. This and the large interindividual variation in kinetics propose therapeutic monitoring of clodronate for optimizing the oral dose of the drug.