title: Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study.
abstract: BACKGROUND
  Interferon (IFN) alpha conjugation to polyethylene glycol (PEG) results in a better pharmacokinetic profile and efficacy. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of a new, locally developed, 40-kDa PEG-IFN alpha-2b preparation with a reference, commercially available PEG-IFN alpha-2a in healthy male volunteers.
  
  
  METHODS
  A randomized, crossover, double-blind study with a 3-weeks washout period, was done. A single 180 micrograms PEG-IFN alpha-2 dose was administered subcutaneously in both groups. Sixteen apparently healthy male subjects were included. Serum PEG-IFN concentration was measured during 336 hours by an enzyme immunoassay (EIA). Other clinical and laboratory variables were used as pharmacodynamic and safety criteria.
  
  
  RESULTS
  The pharmacokinetic comparison by EIA yielded a high similitude between the formulations. In spite of a high subject variability, the parameters' mean were very close (in all cases p > 0.05): AUC: 53623 vs. 44311 pg.h/mL; Cmax: 333 vs. 271 pg/mL; Tmax: 54 vs. 55 h; half-life (t1/2): 72.4 vs. 64.8 h; terminal elimination rate (lambda): 0.011 vs. 0.014 h(-1); mean residence time (MRT): 135 vs. 123 h for reference and study preparations, respectively. There were no significant differences with respect to the pharmacodynamic variables either: serum neopterin and beta-2 microglobulin levels, stimulation of 2'5' oligoadenylate synthetase expression, and serum IFN antiviral activity. A strong Spearman's rank order correlation (p < 0.01) between the pharmacokinetic and pharmacodynamic concentration-time curves was observed. Both products caused similar leukocyte counts diminution and had similar safety profiles. The most frequent adverse reactions were leukopenia, fever, thrombocytopenia, transaminases increase and asthenia, mostly mild.
  
  
  CONCLUSIONS
  Both formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried out to confirm clinical similarity.
authors.affiliation: Clinical Trials Division, Center for Biological Research, Havana, Cuba. idrian.garcia@cigb.edu.cu
authors.forename: Idrian
authors.initials: I
authors.lastname: García-García
authors.forename: Carlos A
authors.initials: CA
authors.lastname: González-Delgado
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Valenzuela-Silva
authors.forename: Alina
authors.initials: A
authors.lastname: Díaz-Machado
authors.forename: Marisol
authors.initials: M
authors.lastname: Cruz-Díaz
authors.forename: Hugo
authors.initials: H
authors.lastname: Nodarse-Cuní
authors.forename: Orlando
authors.initials: O
authors.lastname: Pérez-Pérez
authors.forename: Cimara H
authors.initials: CH
authors.lastname: Bermúdez-Badell
authors.forename: Joel
authors.initials: J
authors.lastname: Ferrero-Bibilonia
authors.forename: Rolando
authors.initials: R
authors.lastname: Páez-Meireles
authors.forename: Iraldo
authors.initials: I
authors.lastname: Bello-Rivero
authors.forename: Fidel R
authors.initials: FR
authors.lastname: Castro-Odio
authors.forename: Pedro A
authors.initials: PA
authors.lastname: López-Saura
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood / Q000235:genetics; D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D015415:Biomarkers / Q000097:blood; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D019798:Neopterin / Q000097:blood; D011092:Polyethylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D055815:Young Adult; D001613:beta 2-Microglobulin / Q000097:blood
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D011092:Polyethylene Glycols; D019798:Neopterin; D015088:2',5'-Oligoadenylate Synthetase; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a