Abstract
BackgroundHX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway. Therefore, in order to demonstrate the bioequivalence of HX575 to an existing epoetin alfa, the pharmacokinetic and pharmacodynamic response to steady state circulating concentrations of HX575 and a comparator epoetin alfa were compared following multiple intravenous administrations.MethodsAn open, randomised, parallel group study was conducted in 80 healthy adult males. Subjects were randomised to multiple intravenous doses of 100 IU/kg body weight of HX575 or of the comparator epoetin alfa three-times-weekly for four weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratio of haematological characteristics were used as surrogate parameters for efficacy evaluation.ResultsThe haematological profiles of both treatments were similar, as determined from their population mean curves and the AUECHb ratio and 90% confidence interval (99.9% [98.5–101.2%]), the primary pharmacodynamic endpoint of this study. The pharmacokinetic parameters after the treatments showed minor differences after single dosing, but not at steady state doses. After multiple doses, HX575 was bioequivalent to the comparator with respect to the rate and extent of exposure of exogenous epoetin (AUCτ ratio and 90% confidence interval: 89.2% [82.5–96.2%]). Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected.ConclusionHX575 and the comparator epoetin alfa were bioequivalent at steady state circulating drug concentrations with respect to their pharmacokinetic profile and pharmacodynamic action. This supports the conclusion that HX575 and the comparator epoetin alfa, when administered intraveneously, will be equally efficacious and may be interchangeable as therapy.
Highlights
HX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway
A minimum of 36 subjects per treatment group had to complete the study in order to determine the relative pharmacodynamic efficiency in terms of the area under the effect curve (AUEC) ratio (HX575/comparator) with adequate precision in an analogous way to a bioequivalence study; the 90% confidence interval (CI) of the AUECHb ratio should fall within a range of 96.8–103.2% with a power of > 80%, provided the true ratio was 100%
The HX575 treatment group was comprised of 37 subjects and the comparator treatment group was comprised of 39 subjects
Summary
HX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway. Patients with chronic renal failure have impaired epoetin production, which is the primary cause of their anaemia [2,3]. Human recombinant epoetin or erythropoiesis stimulating agents (ESA) has been shown to stimulate erythropoiesis in anaemic patients with chronic renal failure, both in those who do, and those who do not, require regular dialysis [3,4,5,6,7,8,9,10,11,12]. ESA are indicated for treatment of chemotherapy-induced anaemia in cancer patients, and to reduce the need for allogenic blood transfusions in patients with moderate anaemia scheduled to undergo elective surgery [13,14,15]. Human recombinant epoetin is indicated for patients at high risk for perioperative transfusions with significant, anticipated blood loss. Except for paracetamol, all other concomitant use of drugs was restricted
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