Search

Objective: 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., Methods: Clodronate concentrations in serum and urine were measured by capillary gaschromatography with mass-selective detection. Pharmacokinetic parameters were calculated with a three-compartmental model., Results: 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%)., Conclusions: 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.

Objective: To study the pharmacokinetics of clodronate in patients on continuous ambulatory peritoneal dialysis (CAPD)., Design: A single intravenous dose pharmacokinetic study., Setting: University hospital., Patients: Ten CAPD patients (3 female, 7 male, age 39-79 year, median 55)., Methods: Clodronate disodium in serum, urine, and dialysate was collected for 24 hours and analyzed by capillary gas chromatography with mass-selective detection., Results: Only 7% of the infused dose of clodronate was eliminated through peritoneal dialysis during 24 hours. Clearance via CAPD (CL[CAPD]) was 2.4 +/- 0.6 mL/min, which was less than 10% of the total serum clearance (CL(tot), 26.0 +/- 19.3 mL/min). Even the kidneys were a more important route of elimination than CAPD in those patients with residual diuresis of more than 500 mL/24 hr. However, in all patients most of the clodronate serum clearance (77% +/- 13%) took place via routes other than peritoneal dialysis or kidneys, that is, via nonrenal-non-CAPD clearance (CL[NRD]). CL(NRD) most likely represents the part of the drug deposited in the skeleton. There was a positive correlation between CL(NRD) and the plasma intact parathyroid hormone concentration., Conclusions: CAPD removed clodronate poorly from the circulation. Most clearance took place via routes other than CAPD or kidneys. This CL(NRD) most likely represents the skeletal deposition of the drug, and this is related to the severity of hyperparathyroidism. When treating CAPD patients with hyperparathyroid bone disease, the administration of clodronate should be adjusted as in those subjects with severe renal failure.

Gastrointestinal absorption of bisphosphonates is highly variable from individual to individual (between-subject variation) and from day to day (within-subject variation), a fact that creates problems both in research and in clinical use of these drugs. We conducted a randomized, two-period cross-over pharmacokinetic (phase I) study to assess the relative bioavailability of two different clodronate preparations: an 800 mg tablet and a 400 mg capsule. Urinary excretion of clodronate correlates with gastrointestinal absorption. To minimize the confounding effect of the high variability of gastrointestinal absorption, we chose as the primary parameter the cumulative amount of clodronate excreted into urine (A(e0-t)) during 9 days (7 days of treatment, 2 days of follow-up). The 90% confidence interval calculated for the population medians of A(e0-t) was 0.83-1.09, well within the 90% confidence interval stipulated for bioequivalence for the area under the curve values (0.80-1.25). This new procedure for pooling urinary excretion data offered a clear advantage over previous methods, and thus could presumably be used to study other drugs as well that are not metabolized and may show highly variable gastrointestinal absorption.