PMID- 19539105 OWN - NLM STAT- MEDLINE DCOM- 20090828 LR - 20140730 IS - 0149-2918 (Print) IS - 0149-2918 (Linking) VI - 31 IP - 5 DP - 2009 May TI - 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. PG - 1046-53 LID - 10.1016/j.clinthera.2009.05.013 [doi] AB - 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. CONCLUSION: The new formulation of rhEPO met the regulatory criteria for bioequivalence in these healthy Korean adult male volunteers. All formulations were generally well tolerated. FAU - Cho, Sang-Heon AU - Cho SH AD - Department of Clinical Pharmacology & Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea. FAU - Lim, Hyeong-Seok AU - Lim HS FAU - Ghim, Jong-Lyul AU - Ghim JL FAU - Choe, Sangmin AU - Choe S FAU - Kim, Un-Jib AU - Kim UJ FAU - Jung, Jin Ah AU - Jung JA FAU - Bae, Kyun-Seop AU - Bae KS LA - eng PT - Clinical Trial PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Hematinics) RN - 0 (Recombinant Proteins) RN - 11096-26-7 (Erythropoietin) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 2.7.3.2 (Creatine Kinase) RN - RFM9X3LJ49 (Bilirubin) SB - IM MH - Adult MH - Area Under Curve MH - Bilirubin/blood MH - Creatine Kinase/blood/drug effects MH - Cross-Over Studies MH - Dose-Response Relationship, Drug MH - Erythropoietin/blood/*pharmacokinetics/toxicity MH - Follow-Up Studies MH - Hematinics/blood/*pharmacokinetics/*toxicity MH - Humans MH - Immunoenzyme Techniques MH - L-Lactate Dehydrogenase/blood/drug effects MH - Male MH - Middle Aged MH - Recombinant Proteins MH - Reference Values MH - Therapeutic Equivalency EDAT- 2009/06/23 09:00 MHDA- 2009/08/29 09:00 CRDT- 2009/06/23 09:00 PHST- 2009/04/15 00:00 [accepted] PHST- 2009/06/23 09:00 [entrez] PHST- 2009/06/23 09:00 [pubmed] PHST- 2009/08/29 09:00 [medline] AID - S0149-2918(09)00159-3 [pii] AID - 10.1016/j.clinthera.2009.05.013 [doi] PST - ppublish SO - Clin Ther. 2009 May;31(5):1046-53. doi: 10.1016/j.clinthera.2009.05.013.