Bioequivalence of two recombinant interferon alpha-2b liquid formulations in healthy male volunteers.
OBJECTIVE
Interferon (IFN) alpha-2b is a protein with antiviral, antiproliferative and immunoregulatory properties that is approved for several clinical indications. A new liquid, albumin-free, IFNalpha-2b formulation has recently been developed. This study aimed to evaluate the equivalence of the pharmacokinetic, pharmacodynamic and safety properties of the new formulation with a reference one in healthy male volunteers.


METHODS
A randomised, crossover, double-blind study with a 3-week washout period was performed in which Heberon Alfa R (formulation A) and Viraferon (formulation B) were compared. A single 20 x 10(6) IU IFNalpha-2b dose was administered subcutaneously to 14 apparently healthy male subjects. Serum IFN level was measured over 48 hours by enzyme immunoassay (EIA) and by antiviral activity titration. Clinical and laboratory variables were determined, as were pharmacodynamic and safety criteria.


RESULTS
Groups were homogeneous with regard to all demographic and baseline variables. Pharmacokinetic comparison by EIA did not show differences between the formulations: area under the curve (AUC) 2572 versus 2561 ng x h/L, maximum plasma concentration (Cmax) 318 versus 354 ng/L, time to Cmax (tmax) 8.2 versus 8.5 h, elimination half-life (t(1/2)) 5.87 versus 6.08 h, terminal elimination rate (lambda) 0.122 versus 0.118 h(-1), and mean residence time (MRT) 10.9 versus 12.0 h for formulations A and B, respectively. The differences never reached 20%, which is the clinically significant threshold. The 90% confidence interval of the ratio between them was in all cases within the 0.8, 1.25 range. The two formulations were clinically equivalent with regard to serum IFN antiviral activity titration (0.8, 1.25 criterion) regarding their pharmacokinetic parameters. There were no significant differences with respect to the pharmacodynamic variables: serum beta2-microglobulin and temperature increase. Heart rate and blood pressure changes did not differ either. Both products provoked similar haematological count decreases and had similar safety profiles. The most frequent adverse reactions were fever, tachycardia, headache and arthralgias.


CONCLUSIONS
The overall analysis strongly suggests the bioequivalence of these two products.
Garcia-Garcia
Idrian
I
Clinical Trials Division, Center for Biological Research, Havana, Cuba. idrian.garcia@cigb.edu.cu
Gonzalez-Delgado
Carlos Alberto
CA
Valenzuela-Silva
Carmen
C
Hernandez-Bernal
Francisco
F
Ferrero-Bibilonia
Joel
J
Soto-Hernandez
Ramon
R
Cervantes-Llano
Majel
M
Ducongé
Jorge
J
Correa-Fernandez
Armando
A
Olivera-Ruano
Lourdes
L
Lopez-Saura
Pedro
P
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001772:Blood Cell Count; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D011994:Recombinant Proteins; D013696:Temperature; D013810:Therapeutic Equivalency; D055815:Young Adult; D001613:beta 2-Microglobulin / Q000096:biosynthesis
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin