Bioequivalence study of a C1-esterase-inhibitor product (Cetor®) with optimised sampling design
RJ Keizer(1), E van Twuijver(2), JJ Marcar(2), PFW Strengers(2), ADR Huitema(1)
(1) Slotervaart Hospital, Amsterdam. Dept. of Pharmacy & Pharmacology; (2) Sanquin Plasma Products, Amsterdam
Objectives: Cetor is a concentrate of a highly purified C1-inhibitor concentrate prepared from human fresh frozen plasma, used in the treatment of hereditary and acquired angioedema (HAE/AAE). A change in the manufacturing process required a bioequivalence study to demonstrate that the change had not affected the pharmacokinetics of the product. The design of the clinical study was optimised by the use of trial simulations.
Methods: A population pharmacokinetic model built from retrospective data (9 patients) was used to optimise the sampling design and to investigate the bioequivalence of the two products. Data from total antigen and functional protein assays were simultaneously analysed in the pharmacokinetic model by defining functional protein as a fraction of total antigen (Ffunc). Trial-simulations were performed with a sample size of 10 patients and both a full (n=14) and a reduced (n=8) sampling design were tested. A randomised cross-over design, with an interval of 1 week between the administration of the two products, was used. The power of the study to detect a type I error of 0.05 was assessed using simulations of three scenarios, assuming the PK characteristics of both products are equal (a), Ffunc being 25% lower (b) or CL being 20% higher (c) than the reference compound, respectively. In the actual clinical trial, 13 HAE patients were included. Relative differences in PK properties induced by the adaptations in production process were estimated for CL, V, Ffunc. NONMEM V.1.1 was used in the PK analysis.
Results: For a full sampling schedule the power to detect differences in product characteristics were 92,2% and 47.8% for scenarios b and c, respectively. For the reduced sampling schedule these were 86.1% and 40.3. Only an increase in sample size led to an increase in power of the study. However, this could not be implemented due to the limited number of HAE patients. Data from the actual clinical trial were described with a linear one-compartment. No significant differences were found in PK characteristics and all confidence intervals of the relative differences in PK parameters were between 0.8 and 1.25.
Conclusions: Trial-simulation was successfully used to optimise the design of a bioequivalence study of two C1-esterase-inhibitor products. A reduced sampling design only had minimal influence on the power of the study. The results of the clinical trial showed that the adaptations in the production process did not lead to changes in PK parameters.
