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Pharmacokinetic and pharmacodynamic characterization of a novel formulation containing co-formulated interferons alpha-2b and gamma in healthy male volunteers

Abstract:

Background: More potent antitumor activity is desired in Interferon (IFN)-treated cancer patients. This could be achieved by combining IFN alpha and IFN gamma. The aim of this work was to characterize the pharmacokinetics and pharmacodynamics of a novel formulation containing a co-formulated combination of IFNs alpha-2b and gamma (CIGB-128-A). Methods: A group of nine healthy male subjects received intramuscularly 24.5 × 10<sup>6</sup> IU of CIGB-128-A. IFN concentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (β<inf>2</inf>M) and 2'-5' oligoadenylate synthetase (2'-5' OAS), classical IFN-inducible serum markers, were measured during 192 h by enzyme immunoassay and body temperature was used as pharmacodynamic variable as well. Results: Concerning pharmacokinetics, serum IFNs' profiles were better fitted to a mono-compartmental model with consecutive zero order and first order absorption, one bioavailability value. No interferences by simultaneous administered IFNs were observed in their typical similar systemic profiles. Neopterin and β<inf>2</inf>M time profiles showed a delay that was efficiently linked to pharmacokinetics by means of a zero order absorption rate constant. Neopterin level was nine-fold higher than initial values, 48 h post-administration, an increment not described before. At this time, mean serum β<inf>2</inf>M peaked around the double from baseline. Serum concentrations of the enzyme 2'-5' OAS was still elevated on the 8 day post-injection. The formulation was well tolerated. Most frequent adverse reactions were fever, headache, arthralgia and lymphopenia, mostly mild. Conclusions: The administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved pharmacodynamic properties that may be beneficial to treat several malignancies. Trial registration: Cuban Public Registry of Clinical Trials RPCEC00000118 , May 24, 2011.