caa a22 4500 477056733 CHVBK 20180405111347.0 cr unu---uuuuu 170330e19961001xx s 000 0 eng 10.1007/s002280050181 doi (NATIONALLICENCE)springer-10.1007/s002280050181 Multiple dose pharmacokinetics of tiludronate in healthy volunteers [Elektronische Daten] [H. R. Schwietert, P. A. M. Peeters, J. Dingemanse, J. F. Thiercelin, J. Necciari, H. de Bruin, J. H. G. Jonkman] Objectives: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. Methods: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. Results and conclusions: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (Cmin) ranged between 0.19 and 1.5 mg ⋅ l−1, and maximal plasma concentrations (Cmax) between 1.1 and 7.8 mg⋅l−1 for the lowest and highest doses, respectively. A supra-proportional increase in Cmax, AUC24 and Ae 24 with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in Cmax and AUC24 with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D3 and intact PTH (1-84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way. Springer-Verlag Berlin Heidelberg, 1996 Key words Tiludronate nationallicence healthy volunteers nationallicence bisphosphonates nationallicence pharmacokinetics nationallicence calcium metabolism nationallicence bone resorption nationallicence adverse events nationallicence Schwietert H. R. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut Peeters P. A. M. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut Dingemanse J. F. Hoffmann-La Roche Ltd., Department of Clinical Pharmacology, CH-4002 Basel, Switzerland, CH aut Thiercelin J. F. Sanofi Recherche, Department of Metabolism and Pharmacokinetics, 371, Rue du Professeur J. Blayac, F-34184 Montpellier Cedex 04, France, FR aut Necciari J. Sanofi Recherche, Department of Metabolism and Pharmacokinetics, 371, Rue du Professeur J. Blayac, F-34184 Montpellier Cedex 04, France, FR aut de Bruin H. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut Jonkman J. H. G. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut https://doi.org/10.1007/s002280050181 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050181 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Schwietert H. R. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut NATIONALLICENCE 700 1- Peeters P. A. M. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut NATIONALLICENCE 700 1- Dingemanse J. F. Hoffmann-La Roche Ltd., Department of Clinical Pharmacology, CH-4002 Basel, Switzerland, CH aut NATIONALLICENCE 700 1- Thiercelin J. F. Sanofi Recherche, Department of Metabolism and Pharmacokinetics, 371, Rue du Professeur J. Blayac, F-34184 Montpellier Cedex 04, France, FR aut NATIONALLICENCE 700 1- Necciari J. Sanofi Recherche, Department of Metabolism and Pharmacokinetics, 371, Rue du Professeur J. Blayac, F-34184 Montpellier Cedex 04, France, FR aut NATIONALLICENCE 700 1- de Bruin H. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut NATIONALLICENCE 700 1- Jonkman J. H. G. Pharma Bio-Research International B.V., P.O. Box 200, NL-9470 AE Zuidlaren, The Netherlands, NL aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer