Bioequivalence of Two Recombinant Interferon ??-2b Liquid Formulations in Healthy Male Volunteers

García-García, Idrian; González-Delgado, Carlos A.; Valenzuela-Silva, Carmen; Hernández-Bernal, Francisco; Ferrero-Bibilonia, Joel; Soto-Hernández, Ramón; Cervantes-Llano, Majel; Ducongé, Jorge; Correa-Fernandez, Armando; Olivera-Ruano, Lourdes; López-Saura, Pedro

doi:10.2165/00126839-200405050-00003

Cited by 10 publications

(11 citation statements)

References 25 publications

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“…Our findings reveal a pharmacokinetic behavior of IFN alpha-2b quite similar to that reported by other authors [11]. Distribution to a wide range of tissues and organs and a very fast clearance are distinctive characteristics of IFNs [23–27]. …”

Section: Discussionsupporting

confidence: 87%

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

García-García

Hernández-González

Díaz-Machado

et al. 2016

BMC Pharmacol Toxicol

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BackgroundMore 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).MethodsA group of nine healthy male subjects received intramuscularly 24.5 × 106 IU of CIGB-128-A. IFN concentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (β2M) 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.ResultsConcerning 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 β2M 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 β2M 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.ConclusionsThe administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved pharmacodynamic properties that may be beneficial to treat several malignancies.Trial registrationCuban Public Registry of Clinical Trials RPCEC00000118, May 24, 2011.

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Section: Discussionsupporting

confidence: 87%

“…Although this last increment was reached in a similar population after administration of 20 ×10 6 IU of IFN alpha-2b [27], a slower return to initial levels was now observed.…”

Section: Discussionmentioning

confidence: 99%

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

García-García

Hernández-González

Díaz-Machado

et al. 2016

BMC Pharmacol Toxicol

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“…In a similar type of study with the native IFN alpha-2b the mean values for t 1/2 and MRT were 5.9 h and 10.9 h, respectively [12]. After "pegylation" these parameters were 64.8 h and 123 h, respectively, around 11 fold higher, consistent with previous studies of 40 Kd PEG IFN alpha-2a vs. its conventional IFN counterpart in healthy subjects [13,14].…”

Section: Discussionsupporting

confidence: 84%

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study

et al. 2010

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BackgroundInterferon (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.MethodsA 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.ResultsThe 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.ConclusionsBoth formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried out to confirm clinical similarity.Trial registrationRegistro Público Cubano de Ensayos Clínicos RPCEC00000039.

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“…Parameters as Tmax and t 1/2 were within the reported ranges for these conventional IFNs after systemic administration either in patients or healthy volunteers even considering the expected high variability [24-27]. For IFN alpha-2b Cmax was also very similar to a previous report ours in healthy male volunteers [21]. …”

Section: Discussionsupporting

confidence: 82%

“…In the case of PEG-IFN beta although half-life was greatly extended by pegylation, the neopterin response was not affected [18]. On the other hand, two times higher levels than baseline were recorded for serum β 2 M 24–48 hours after injection, superior to those increments detected by other authors, which were around 60% with natural or pegylated IFN-alpha [19-21]. For both pharmacodynamic markers their more slow return to initial levels has not been observed with conventional IFN in the reports above-cited.…”

Section: Discussionmentioning

confidence: 99%

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

García-Vega

García-García

Collazo-Caballero

et al. 2012

BMC Pharmacol Toxicol

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BackgroundThe 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.MethodsAn 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.ResultsThe 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.ConclusionsHeberPAG®possesses improved pharmacodynamic properties that may be very useful in the oncologic setting. Efficacy trials can be carried out to confirm these findings.Trial registrationRegistro Público Cubano de Ensayos Clínicos RPCEC00000130

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Bioequivalence of Two Recombinant Interferon ??-2b Liquid Formulations in Healthy Male Volunteers

Cited by 10 publications

References 25 publications

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

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

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study

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

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