Comparable pharmacokinetics and pharmacodynamics of two epoetin alfa formulations Eporon ® and Eprex ® following a single subcutaneous administration in healthy male volunteers

• Published in: Drug design, development and therapy development and therapy, 2017-01, Vol.11, p.3127-3135
• Main Authors: Yoon, Sumin, Rhee, Su-Jin, Heo, Sun Ju, Oh, Tae Young, Yoon, Seo Hyun, Cho, Joo-Youn, Lee, SeungHwan, Yu, Kyung-Sang
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Anemia; Antibodies; Blood; Clinical trials; Cross-Over Studies; Dosage; Dosage and administration; Dose-Response Relationship, Drug; Double-Blind Method; Drug Compounding; Drug dosages; Drug therapy; Drug Tolerance; Epoetin alfa; Epoetin Alfa - administration & dosage; Epoetin Alfa - adverse effects; Epoetin Alfa - pharmacokinetics; Erythrocytes; Erythropoietin; Formulations; Health aspects; Healthy Volunteers; Hematocrit; Hemoglobin; Humans; Immunogenicity; Injections, Subcutaneous; Kidney diseases; Male; Males; Markers; Mathematical analysis; Middle Aged; Original Research; Parameters; Pharmacodynamics; Pharmacokinetics; Pharmacology; Quality of life; Review boards; Risk factors; Time lag; Young Adult
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S142673

This study aimed to assess and compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties following a single subcutaneous injection of epoetin alfa (Eporon ) with those of the comparator (Eprex ) in healthy male subjects. A randomized, double-blind, two-sequence, crossover study was conducted. Subjects were randomly assigned to receive a single dose, that is, 4,000 IU, of the test or comparator epoetin alfa. After 4 weeks, all subjects received the alternative formulation. The primary PK parameters, maximum observed concentration (C ) and area under the curve extrapolated to infinity (AUC ), were calculated with the serum erythropoietin (EPO) concentrations from blood samples collected for 144 h after dosing. The reticulocyte, hematocrit, hemoglobin and red blood cell counts were measured up to 312 h as PD markers. The primary PD parameters, maximum observed effect (E ) and area under the effect curve (AUEC), were obtained from the baseline-corrected reticulocyte count. The serum EPO concentration and the reticulocyte count were used to assess the concentration-response relationship. The tolerability and immunogenicity profiles were assessed together. Forty-two subjects completed the study. The mean EPO concentration-time profiles were comparable between the two formulations. The geometric mean ratios (90% CI) of the C and AUC were 0.908 (0.843-0.978) and 1.049 (0.999-1.101), respectively, both of which were within the regulatory range of 0.80-1.25. Additionally, the PD and tolerability profiles were similar between the two formulations. The time-matched serum EPO concentration and PD markers presented a counterclockwise hysteresis, suggesting a time delay between the measured concentration and the response. Both formulations were well tolerated, and production of anti-drug antibodies was not observed. The two epoetin alfa formulations had similar PK, PD and tolerability profiles. Furthermore, both formulations had a similar time-matched serum EPO concentration and erythropoietic response profile. Thus, the two formulations are expected to be used interchangeably in clinical settings.