title: Pharmacokinetic and pharmacodynamic characterization of a new formulation containing synergistic proportions of interferons alpha-2b and gamma (HeberPAG) in patients with mycosis fungoides: an open-label trial.
abstract: BACKGROUND
  The synergistic combination of interferon (IFN) alpha-2b and IFN gamma results in more potent in vitro biological effects mediated by both IFNs. The aim of this investigation was to evaluate by first time the pharmacokinetics and pharmacodynamics of this combination in patients with mycosis fungoides.
  
  
  METHODS
  An exploratory, prospective, open-label clinical trial was conducted. Twelve patients, both genders, 18 to 75 years-old, with mycosis fungoides at stages IB to III, were eligible for the study. All of them received intramuscularly a single high dose (23 × 10(6) IU) of a novel synergistic IFN mixture (HeberPAG) for pharmacokinetic and pharmacodynamic studies. Serum IFN alpha-2b and IFN gamma concentrations were measured during 96 hours by commercial enzyme immunoassays (EIA) specific for each IFN. Other blood IFN-inducible markers and laboratory variables were used as pharmacodynamics and safety criteria.
  
  
  RESULTS
  The pharmacokinetic evaluation by EIA yielded a similar pattern for both IFNs that are also in agreement with the well-known described profiles for these molecules when these are administered separately. The average values for main parameters were: Cmax: 263 and 9.3 pg/mL; Tmax: 9.5 and 6.9 h; AUC: 4483 and 87.5 pg.h/mL, half-life (t(1/2)): 4.9 and 13.4 h; mean residence time (MRT): 13.9 and 13.5 h, for serum IFN alpha-2b and IFN gamma, respectively. The pharmacodynamic variables were strongly stimulated by simultaneous administration of both IFNs: serum neopterin and beta-2 microglobulin levels (β2M), and stimulation of 2'-5' oligoadenylate synthetase (OAS1) mRNA expression. The most encouraging data was the high increment of serum neopterin, 8.0 ng/mL at 48 h, not been described before for any unmodified or pegylated IFN. Additionally, β2M concentration doubled the pre-dose value at 24-48 hours. For both variables the values remained clearly upper baseline levels at 96 hours.
  
  
  CONCLUSIONS
  HeberPAG possesses improved pharmacodynamic properties that may be very useful in the oncologic setting. Efficacy trials can be carried out to confirm these findings.
  
  
  BACKGROUND
  Registro Público Cubano de Ensayos Clínicos RPCEC00000130.
authors.forename: Yanelda
authors.initials: Y
authors.lastname: García-Vega
authors.forename: Idrian
authors.initials: I
authors.lastname: García-García
authors.forename: Sonia E
authors.initials: SE
authors.lastname: Collazo-Caballero
authors.forename: Egla E
authors.initials: EE
authors.lastname: Santely-Pravia
authors.forename: Alieski
authors.initials: A
authors.lastname: Cruz-Ramírez
authors.forename: Angela D
authors.initials: AD
authors.lastname: Tuero-Iglesias
authors.forename: Cristian
authors.initials: C
authors.lastname: Alfonso-Alvarado
authors.forename: Mileidys
authors.initials: M
authors.lastname: Cabrera-Placeres
authors.forename: Nailet
authors.initials: N
authors.lastname: Castro-Basart
authors.forename: Yaquelín
authors.initials: Y
authors.lastname: Duncan-Roberts
authors.forename: Tania I
authors.initials: TI
authors.lastname: Carballo-Treto
authors.forename: Josanne
authors.initials: J
authors.lastname: Soto-Matos
authors.forename: Yoandy
authors.initials: Y
authors.lastname: Izquierdo-Toledo
authors.forename: Dania
authors.initials: D
authors.lastname: Vázquez-Blomquist
authors.forename: Elizeth
authors.initials: E
authors.lastname: García-Iglesias
authors.forename: Iraldo
authors.initials: I
authors.lastname: Bello-Rivero
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002626:Chemistry, Pharmaceutical; D003462:Cuba; D004338:Drug Combinations; D004355:Drug Stability; D004357:Drug Synergism; D005260:Female; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D019798:Neopterin / Q000819:agonists / Q000097:blood; D011994:Recombinant Proteins / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D004338:Drug Combinations; C573415:IFNG protein, human; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D019798:Neopterin; D007371:Interferon-gamma