Pharmacokinetics and plasma protein binding of a single dose of clodronate disodium are similar for juvenile sheep and horses

Abstract

OBJECTIVE To determine the single-dose pharmacokinetics of clodronate disodium (CLO) in juvenile sheep and the plasma protein binding (PPB) of CLO in juvenile sheep and horses. ANIMALS 11 juvenile crossbred sheep (252 ± 6 days) for the pharmacokinetic study. Three juvenile crossbred sheep (281 ± 4 days) and 3 juvenile Quarter Horses (599 ± 25 days) for PPB analysis. METHODS CLO concentrations were determined using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis from plasma samples obtained at 0, 0.5, 1, 3, 6, 12, 24, 48, and 72 hours after CLO administered IM at 0.6 mg/kg. PPB was determined using equine and ovine plasma in a single-use rapid equilibrium dialysis system. RESULTS The mean and range for maximum plasma concentration (Cmax: 5,596; 2,396–8,613 ng/mL), time of maximal concentration (Tmax: 0.5; 0.5–1.0 h), and area under the curve (AUCall: 12,831; 7,590–17,593 h X ng/mL) were similar to those previously reported in horses. PPB in sheep and horses was moderate to high, with unbound fractions of 26.1 ± 5.1% in sheep and 18.7 ± 7.5% in horses, showing less than a 1.4-fold difference. CLINICAL RELEVANCE The pharmacokinetic parameters and PPB of CLO in juvenile sheep were similar to those previously reported in horses. The results suggest that juvenile sheep can be utilized as an animal model for studying the potential risks and/or benefits of bisphosphonate use in juvenile horses.

Clodronate disodium does not produce measurable effects on bone metabolism in an exercising, juvenile, large animal model

“…This may be due to the lower dose used in large animals compared to humans. We used a dose in sheep that resembled the pharmacokinetic values of therapeutic CLO administered in horses [ 48 ]. The dose used in horses (1.8 mg/kg) has shown clinical efficacy in reducing musculoskeletal pain in multiple studies [ 20 , 46 , 47 , 77 ].…”

“…The dose of CLO was selected based on a pilot study which compared plasma concentrations of CLO following 3 different doses of CLO (0.6, 1.8, 3.0 mg/kg i.m.) over 48 hours in 12 adult sheep ( n = 4/treatment group) [ 48 ]. CLO administered at 0.6 mg/kg i.m.…”

“…resulted in similar pharmacokinetic parameters to those observed with a dose of CLO at1.8 mg/kg i.m. for horses [ 48 ].…”

“…Given the existing knowledge gap regarding the skeletal effects of bisphosphonates on juvenile populations engaged in exercise, this study aimed to investigate the effects of clodronate disodium (CLO) administration on bone formation and remodeling using juvenile sheep subjected to forced exercise. CLO was selected as it is an FDA-approved bisphosphonate for use in a large animal species [ 46 ], has shown clinical efficacy for musculoskeletal disease [ 46 , 47 ], and the pharmacokinetics have been described in sheep [ 48 ]. Outcome measures included physical examinations, lameness evaluations, SBB, advanced imaging methods, biomechanical testing (BT), and sulfated glycosaminoglycan content (GAG) in cartilage.…”