A tolerability and pharmacokinetic study of a new injectable formulation of disodium clodronate in healthy female volunteers.
Disodium clodronate (dichloromethylene bisphosphonic acid, disodium salt; CAS 22560-50-5) is a bisphosphonate that has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption. Intramuscular clodronate can determine pain at the injection site, it is therefore particularly useful to co-administer a local anaesthetic with clodronate to reduce pain at the injection site. The tolerability and pharmacokinetic of a new formulation of 100 mg disodium clodronate containing 1% lidocaine (test formulation, Chiesi Farmaceutici S.p.A) were investigated in comparison to the same formulation without the local anaesthetic (Clody) and a marketed formulation containing 1% benzyl alcohol (Clasteon). Thirty healthy female volunteers were treated according to a single dose, double-blind, randomised, three-way cross-over design. The local tolerability was investigated by assessing reddening and hardening at the injection site, and plasma CPK levels. Pain intensity was investigated on the VAS (visual analogue scale) and on the VRS (verbal rating score). Urinary clodronic acid concentrations were determined using a validated specific GC/MS/NCI assay. The statistical analysis on pain assessment showed a significant reduction of pain intensity immediately and up to 2 hours after administration of the new formulation compared to the marketed ones. CPK levels and occurrence of hardening at the injection site did not show statistically significant differences between formulations. No local redness was reported. Clodronate urinary excretion during the 48 h collection interval was not statistically different among the formulations and the 95% confidence intervals were inside the bioequivalence acceptance region, demonstrating comparable bioavailability. It was concluded that the investigated new formulation of 100 mg disodium clodronate was better tolerated than the reference marketed formulations.
Poli
Gianluigi
G
Chiesi Farmaceutici S.p.A., Pharmacokinetics Department, Parma Italy.
Mariotti
Fabrizia
F
Corrado
Mario Ermanno
ME
Acerbi
Daniela
D
D000779:Anesthetics, Local / Q000008:administration & dosage / Q000627:therapeutic use; D019905:Benzyl Alcohol / Q000008:administration & dosage / Q000627:therapeutic use; D004002:Clodronic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D004890:Erythema / Q000139:chemically induced; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007273:Injections, Intramuscular; D008012:Lidocaine / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D010147:Pain Measurement; D012867:Skin / Q000473:pathology
D000779:Anesthetics, Local; D004338:Drug Combinations; D004002:Clodronic Acid; D008012:Lidocaine; D019905:Benzyl Alcohol