Pharmacokinetic, tolerability, and bioequivalence comparison of three different intravenous formulations of recombinant human erythropoietin in healthy Korean adult male volunteers: an open-label, randomized-sequence, three-treatment, three-way crossover study.
BACKGROUND
Existing formulations of recombinant human erythropoietin (rhEPO) in Korea contain human serum albumin. To avoid the potential risk of infection by human serum albumin, a new albumin-free rhEPO has been developed.


OBJECTIVE
This study was conducted to characterize and compare the pharmacokinetic and safety profiles and the bioequivalence of a newly developed albumin-free rhEPO (Aropotin [TS Corporation, Seoul, South Korea]) with 2 existing rhEPO formulations (Espogen [LG Life Sciences, Seoul, South Korea]; Recormon [Roche, Basel, Switzerland]) with albumin in healthy Korean subjects.


METHODS
This was an open-label, randomized-sequence, 3-treatment, 3-way crossover study in which healthy, nonobese (+/-20% of ideal weight), male volunteers between the ages of 19 and 50 years were assigned to 1 of 2 dose levels (50 IU/kg or 100 IU/kg) of 3 formulations. Blood was collected over 32 hours and plasma rhEPO concentrations were determined using a validated enzyme immunoassay. There was a 14-day washout between periods. The pharmacokinetic parameters of the 3 formulations were compared using the bioequivalence criteria of the US Food and Drug Administration, which requires that the 90% CIs of the geometric mean ratios for AUC(0-t), AUC(0-infinity), and C(max) fall within 0.80 to 1.25. Tolerability was evaluated by physical examination with measurements of vital signs, clinical laboratory tests, and electrocardiogram. Subjects were followed up for 2 weeks after the last administration of study drug.


RESULTS
Twelve Korean male volunteers were enrolled and completed the study. Six subjects (mean [SD] age, 22.0 [1.7] years; weight, 63.3 [6.2] kg; height, 172.3 [3.5] cm) received a single 50 IU/kg IV bolus dose of study drug and the remaining 6 subjects (mean [SD] age, 23.7 [1.5] years; weight, 66.3 [4.8] kg; height, 174 [4.7] cm) received 100 IU/kg. After a single 50 IU/kg dose, the geometric mean ratio (90% CI) for Aropotin/Espogen was 1.04 (0.91-1.19) IU/L/h for AUC(0-t) and 1.02 (0.89-1.17) IU/L for C(max). The geometric mean ratio (90% CI) for Aropotin/Recormon was 1.01 (0.88-1.15) IU/L/h for AUC(0-t) and 1.01 (0.89-1.16) IU/L for C(max). After a single 100-IU/kg dose, the geometric mean ratio (90% CI) for Aropotin/ Espogen was 0.98 (0.86-1.13) IU/L/h for AUC(0-t) and 0.99 (0.87-1.13) IU/L for C(max). The geometric mean ratio (90% CI) for Aropotin/Recormon was 0.99 (0.861.14) IU/L/h for AUC(0-t) and 0.96 (0.84-1.10) IU/L for C(max). The most frequent adverse events (AEs) were 3 occurrences of elevated serum creatine phosphokinase and serum lactate dehydrogenase levels in the Recormon 100-IU/kg group (n = 3), 3 events of elevated serum lactate dehydrogenase levels in the Espogen 100-IU/kg group (n = 3), and 4 events of elevated serum total bilirubin levels in the Aropotin 100-IU/kg group (n = 3). All formulations were well tolerated with no serious AEs.


CONCLUSIONS
The new formulation of rhEPO met the regulatory criteria for bioequivalence in these healthy Korean adult male volunteers. All formulations were generally well tolerated.
Cho
Sang-Heon
SH
Department of Clinical Pharmacology & Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea.
Lim
Hyeong-Seok
HS
Ghim
Jong-Lyul
JL
Choe
Sangmin
S
Kim
Un-Jib
UJ
Jung
Jin Ah
JA
Bae
Kyun-Seop
KS
D000328:Adult; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D003402:Creatine Kinase / Q000097:blood / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D005500:Follow-Up Studies; D006397:Hematinics / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D007770:L-Lactate Dehydrogenase / Q000097:blood / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012016:Reference Values; D013810:Therapeutic Equivalency
D006397:Hematinics; D011994:Recombinant Proteins; D004921:Erythropoietin; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D001663:Bilirubin