Open Access Research article

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

Yanelda García-Vega1, Idrian García-García1, Sonia E Collazo-Caballero2, Egla E Santely-Pravia2, Alieski Cruz-Ramírez1, Ángela D Tuero-Iglesias1, Cristian Alfonso-Alvarado2, Mileidys Cabrera-Placeres2, Nailet Castro-Basart2, Yaquelín Duncan-Roberts1, Tania I Carballo-Treto3, Josanne Soto-Matos3, Yoandy Izquierdo-Toledo4, Dania Vázquez-Blomquist4, Elizeth García-Iglesias1 and Iraldo Bello-Rivero1*

Author Affiliations

1 Clinical Investigation Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6332, Havana, Cuba

2 “Hermanos Ameijeiras” Hospital, Dermatology Service, Havana, Cuba

3 “Hermanos Ameijeiras” Hospital, Clinical Laboratory Service, Havana, Cuba

4 Genomics Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba

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BMC Pharmacology and Toxicology 2012, 13:20  doi:10.1186/2050-6511-13-20

Published: 28 December 2012

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 × 106 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 (t1/2): 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.

Trial registration

Registro Público Cubano de Ensayos Clínicos RPCEC00000130