Steady state pharmacokinetics and dose equivalents of oral clodronate in renal failure.

OBJECTIVE: Clodronate is used in the treatment of osteoporosis, and malignancy-associated bone disease. The steady state pharmacokinetics and the dose equivalents of oral clodronate were assessed in subjects with various degrees of renal failure. MATERIALS AND METHODS: 1,600 mg of clodronate was given orally mornings for 11 days to 14 healthy volunteers (creatinine clearance, CLCr, > 80 ml/min), and 18, 12 and 16 subjects with mild (50 - 80 ml/min), moderate (30 - 50 ml/min) and severe (< 30 ml/min) renal failure, respectively. Trough drug levels at 4, 7 and 11 days, and concentration-time curves for 72 h after the last dose were followed. RESULTS: In all study groups, the trough drug levels achieved the kinetic steady state within 11 days. The area under the 24-h concentration-time curve (AUC0-24) enlarged and the elimination half-life (t1/2elim) prolonged progressively when the renal function was impaired. The maximum drug level and the time to maximum were not changed significantly in the renal failure. In the steady state phase, the diurnal drug excretion (E0-24) was not changed by the kidney function, but the renal drug clearance (CLD) decreased in close correlation with CLCr. The normal-to-failed AUC0-24 ratios in mild, moderate, and severe renal failure were 0.53, 0.43 and 0.31, respectively, when the ideally-matched counterpart was assumed as the normal reference to each renal failure group. CONCLUSIONS: In mild, moderate and severe renal failure, 53%, 43% and 31% oral clodronate doses, respectively, resulted in drug AUCs similar to those in controls with normal (> 80 ml/min) CLCR.

Comparison of pharmacokinetics of clodronate after single and repeated doses.

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.

Pharmacokinetics of clodronate in haemodialysis patients.

BACKGROUND: Clodronate is a bisphosphonate used in the treatment of hypercalcaemia of various aetiologies. The major route of elimination of clodronate is renal excretion. The aim of the study was to derive data for the adjustment of dosage in haemodialysis patients. METHODS: The pharmacokinetic parameters describing the fate of an intravenous infusion of 300 mg clodronate disodium were studied in 10 haemodialysis patients. Clodronate disodium in serum, urine and dialysate samples was analysed by capillary gas chromatography with mass-selective detection. RESULTS: Of the 300 mg clodronate infused, 159 mg (53%) was excreted into dialysate within 4 h. Clearance by haemodialysis (CLD) was 87.8+/-16.2 ml/min, accounting for 84% of total serum clearance (CLtot). Non-renal, non-dialysis clearance (CL(NRD)) represents the removal of the drug via other routes than dialysis or kidneys. The greatest CL(NRD) was observed in patients with most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH concentration. CONCLUSIONS: According to the present findings, standard haemodialysis removes clodronate effectively from the circulation, and total clearance in haemodialysis patients on a dialysis day is not very different from that in healthy subjects. The regimen of dosing intravenous clodronate in hypercalcaemia can also be used in haemodialysis patients. The portion of clodronate eliminated by routes other than via dialysate or kidneys, i.e. predominantly via skeletal deposition, was related to the severity of hyperparathyroidism.

Pharmacokinetics of clodronate in peritoneal dialysis patients.

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.

Pooling of clodronate urinary excretion data: a new pharmacokinetic method to study drugs with highly variable gastrointestinal absorption.

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.

Propofol infusion anaesthesia and immune response in minor surgery.

This study was set up to evaluate the effects of propofol infusion anaesthesia on immunological function in minor surgery. Twenty-seven patients (median age 51 years, ASA 1-2) scheduled for minor breast surgery were randomly assigned to two groups. Anaesthesia was induced in group 1 with propofol 2.5 mg.kg-1 and maintained with propofol 12 mg.kg-1 x h-1 and 30% O2 in air, whereas in group 2 anaesthesia was induced with thiopentone 4 mg.kg-1 and maintained with 70% N2O in O2. Fentanyl and vecuronium were used in both groups. The percentages of T cells (p < 0.001), B cells (p < 0.01) and memory T cells increased (p < 0.01) in both groups. T helper cell percentages increased in the propofol but not in the thiopentone group (p < 0.05). The percentages of natural killer cells decreased from pre-induction values in both groups (p < 0.001). No changes were seen in lymphocyte proliferative responses. Minor breast surgery under propofol or conventional combined anaesthesia had only minor effects on the immune response. The higher percentage of T helper cells after propofol anaesthesia compared to conventional combined anaesthesia is beneficial, but its clinical importance remains to be determined.