Pharmacokinetics and pharmacodynamics of a pasireotide subcutaneous depot (CAM4071) and comparison with immediate and long-acting release pasireotide

Purpose To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of subcutaneous depot CAM4071, a novel, ready-to-use pasireotide formulation. Methods This was a phase 1, randomised, open-label study in healthy volunteers. After a single 600 µg dose of pasireotide immediate release (IR), participants were randomised to one of eight groups to receive either a CAM4071 upper thigh (5, 10, 20, 40 or 80 mg) or buttock (20 mg) injection or multiple pasireotide IR 900 µg upper thigh injections twice daily or a single pasireotide long-acting release (LAR) 60 mg intramuscular buttock injection. Results Ninety-four participants were randomised. For all CAM4071 doses, initial pasireotide release was relatively rapid compared to pasireotide LAR and sustained over the 2-month observation period, with a slow decay in plasma concentrations. CAM4071 maximum plasma concentrations increased slightly greater than dose proportionally; area under the curve extrapolated to infinity increased approximately dose proportionally. Relative bioavailability of pasireotide for different doses of CAM4071 versus pasireotide IR 600 μg ranged from 0.752 (90% confidence interval [CI]: 0.58, 0.98) to 1.68 (1.32, 2.14), and versus pasireotide LAR: 0.517 (0.37, 0.72) to 1.15 (0.84, 1.58). CAM4071 doses >5 mg exhibited rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared to pasireotide LAR. Maximum IGF-1 inhibition was greatest for CAM4071 80 mg. CAM4071 injections ≤40 mg were well tolerated and comparable with currently available pasireotide formulations. Conclusion CAM4071 provided long-acting release of pasireotide over at least one month, with high bioavailability and onset and duration of IGF-1 suppression similar to pasireotide LAR. Trial registration EudraCT: 2014-003783-20.