Published in:
Open Access 01-10-2016 | Original Research Article
Pharmacokinetic Modeling and Dose Selection in a Randomized, Double-Blind, Placebo-Controlled Trial of a Human Recombinant Alkaline Phosphatase in Healthy Volunteers
Published in: Clinical Pharmacokinetics | Issue 10/2016
Login to get accessAbstract
Background and Objective
Previous clinical trials have suggested that bovine intestinal alkaline phosphatase has renal protective effects in patients with sepsis-associated acute kidney injury. We conducted a first-in-human study to investigate the pharmacokinetics, safety and tolerability of a novel human recombinant alkaline phosphatase (recAP), and we developed a population pharmacokinetic model to support dose selection for future patient studies.
Methods
In a randomized, double-blind, placebo-controlled, phase I trial, healthy volunteers received a single dose of recAP (200, 500, 1000 or 2000 U/kg; n = 33; 3:1 ratio) or multiple doses of recAP (500 or 1000 U/kg; n = 18; 2:1 ratio) via a 1-h intravenous infusion on three consecutive days. Serum recAP concentrations, alkaline phosphatase (AP) activity levels and anti-drug antibodies were measured, and safety parameters were monitored. A population pharmacokinetic model was developed, and simulations were performed to guide dose selection for a phase IIa/b trial.
Results
Peak concentrations of recAP and peak AP activity were reached at the end of the 1-h infusion and showed a rapid decline, with about 10 % of the maximum concentration remaining at 4 h and less than 5 % remaining 24 h post-start. RecAP treatment was generally well tolerated, and anti-drug antibodies could not be detected in the serum up to 2 weeks post-injection after a single dose, or up to 3 weeks post-injection after multiple doses. A four-compartment model best described the pharmacokinetics of recAP administration, with moderate inter-individual variability on the central volume of distribution and elimination rate constant. Simulations showed that 1-h intravenous infusions of 250, 500 and 1000 U/kg recAP once every 24 h for three consecutive days constituted the dosing regimen that best met the criteria for dose selection in patient studies.
Conclusion
RecAP did not raise any safety concerns when administered to healthy volunteers. A population pharmacokinetic model was developed to support dose selection for patient studies.
Trial Registration
2013-002694-21 (EudraCT).