Interferon pharmacokinetics

Gutterman, J.U., Fine, S., Quesada, J., Homing, S.J., Levine, J.F., Alexanian, R., Bernhardt, L., Kramer, M., Speigal, H., Colburn, W., Trown, R, Merigan, T. and Dziewanawska, Z. (1982). Recombinant leukocyte A interferon Pharmacokinetics, single-dose tolerance, and biological effects in cancer patients. Ann. Intern. Med. 96 549-556. 

Gutterman, J.U., S. Pine, J. Quesada, S.J. Horning, IP. Levine, R. Alexanian, L. Bernhardt, M. Kramer, H. Spiegel, W. Colburn, P. Trown, T. Merigan, and Z. Dziewanowski, Recombinant leukocyte A interferon pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann Intern Med, 1982. 96(5) 549-56. 

Gutterman J U, Eine S, Quesada J, et al. (1984). Recombinant lenkocyte A interferon Pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Cancer Res. 44 4164-4171. 

Bain VG, Kaita KD, Yoshida EM, Swain MG, Heathcote EJ, Neumann AU, FisceUa M, Yu R, Osborn BE, Cronin PW, Ereimuth WW, McHutchison JG, Subramanian GM (2006) A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 44 671-678... 

Osborn BL, Olsen HS, NardeUi B, Murray JH, Zhou JX, Garcia A, Moody G, Zaritskaya LS, Sung C (2002) Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 303 540-548 Ozes ON, Reiter Z, Klein S, Blatt LM, Taylor MW (1992) A comparison of interferon-Conl with natural recombinant interferons-alpha antiviral, antiproliferative, and natural kiUer-inducing activities. J Interferon Res 12 55-59... 

HCV-796 is a non-nucleosidic NS5B polymerase inhibitor with potent antiviral activity in vitro. A phase lb study was performed to determine the antiviral activity, pharmacokinetics, and safety of HCV-796 in patients with chronic HCV infection. Maximum antiviral effects were achieved after 4 days of treatment with a mean reduction of HCV-RNA of 1.4 loglOIU/ml. Combination of HCV-796 with pegylated interferon-a led to a greater reduction of viral RNA load (3.3-3.5 loglO lU/ml) after a 14 days treatment interval. 

Jen, J.F. et al., Population pharmacokinetic analysis of pegylated interferon alfa-2b and interferon alfa-2b in patients with chronic hepatitis C, Clin. Pharmacol. Then, 69, 407, 2001. 

In patients with lymphocytic CSF cytological syndromes, elevation of CSF C4 concentrations was observed. Leakage of several proteins across the blood-CSF barrier was also found. Leakage of C4 complement into CSF depends on the functional state of the barrier to a certain extent, being partially selective. Under pathological circumstances, the rate of penetration of protein fractions across the blood-CSF barrier can be modified selectively, which has been proved in CSF acute-phase reactants. They are highly influenced by the production of cytokines. These considerations evoke the question as to whether similar mechanisms of penetration can be expected in cytokines. Elucidation of the pharmacokinetics of interferons in CSF could substantially influence our approach not only to MS patients but to others as well (A18). 

Pharmacokinetics Interferon beta-la-. After IM administration, peak serum levels attained in 3-15 hr. Biologic markers increase within 12 hr and remain elevated for 4 days. Half-life 10 hr (IM). Interferon beta-lb Half-life 8 min-4.3 hr. 

Pharmacokinetics The pharmacokinetic properties of Infergen have not been evaluated in patients with chronic hepatitis C. Pharmacokinetic profiles were evaluated in normal, healthy volunteer subjects after subcutaneous injection of interferon alfacon-1 at doses up to 9 j,g. Plasma levels of interferon alfacon-1 at any dose were too low to be detected. However, analysis of Infergen-induced cellular products— induction of 2 5 oligoadenylate synthetase and (beta)-2 microglobulin—after treatment in these subjects revealed a statistically significant, dose-related increase in the area under the curve (AUC). 

Pharmacokinetics A mean elimination half-life of approximately 5 hours has been reported after intravenous doses of Roferon-A. Pharmacokinetic parameters are similar in healthy subjects and cancer patients after intramuscular doses. Dose-proportionate increases in serum levels occur with doses up to 198 MIU. The bioavailability of interferon alfa-2a after intramuscular administration is 80% to 83%, and its volume of distribution is 0.223 to 0.748 liter/kg. The total body clearance of interferon alfa-2a has been reported to range from 2.14 to 3.62ml/min per kg. 

Pharmacokinetics The elimination half-life of interferon alfa-2b after subcutaneous or intramuscular administration is 2 to 3 hours. 

Pharmacokinetics The bioavaUabUity of subcutaneous interferon beta-lb is 50%. In patients receiving single intravenous Betaseron doses up to 2.0 mg, increases in serum concentrations of interferon beta-lb were dose proportional. Mean serum clearance values ranged from 9.4ml/min per kg to 28.9 ml/minperkg and were independent of dose. Mean terminal elimination half-life values ranged from 8.0 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 liter/kg to 2.88 hters/kg. Three-times-a-week intravenous dosing for 2 weeks resulted in no accumulation of interferon beta-lb in the serum of patients. 

Pharmacokinetics According to product label, interferon gamma-lb is rapidly cleared after intravenous administration (1.41iters/min) and slowly absorbed after intramuscular or subcutaneous injection. After intramuscular or subcutaneous injection, the apparent fraction of dose absorbed was greater than 90%. The mean elimination half-life after intravenous administration in healthy male subjects was 38 minutes. The mean elimination half-lives after intramuscular or subcutaneous dosing were 2.9 and 5.9 hours, respectively. Pharmacokinetic studies in patients with chronic granulomatous disease have not been performed. 

Pharmacokinetics Pegylation of interferon alfa-2b produces a product whose clearance is substantially lower that than of nonpegylated interferon alfa-2b. The mean absorption half-life of peginterferon alfa-2b following a single subcutaneous injection of PEG-Intron is 4.6 hours. Time to peak concentration is variable and may... 

Pharmacokinetics The pharmacokinetics of interferon beta-la (Rebif) in patients with multiple sclerosis have not been evaluated. In healthy subjects, a single injection resulted in a peak serum concentration at about 16 hours after administration. The mean serum elimination half-life was 69 hours but varied widely. Following every-other-day subcutaneous injections, an increase in the area under the serum concentration versus time curve (AUC) of approximately 240% was observed. Clearance has been estimated at 33 to 55 liters/h. 

Lewis, D., Cole, B. F., Wallace, P. K., Fisher, J. L., Waugh, N., Guyre, P. M., Fanger, M. W., Curnow, R. T., Kaufman, P. A., and Ernstoff, M. S. 2001. Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma A multiple-dose phase-I study in patients with advanced cancer which overexpresses HER-2/wew. J. Immunol. Methods. 248 149-165. 

Deres and co-workers (Bayer) [21] have reported a series of non-nucleosidic Biginelli-derived inhibitors 13, 14, 15 (Figure 11.2) of the hepatitis B virus (HBV). Chronic infection is a major cause of liver disease, and to date only interferon-a and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. The lead compound, Bay 41-4109 13 has a specific mechanism of action inhibiting capsid maturation and may be useful in combination therapies. In addition to efficacy in HBV transgenic mice [22], the compound possesses satisfactory pharmacokinetic and toxicology profiles. Efficacy in a clinical setting of HBV infection is under investigation. 

Pedder, S. C. PEGylation of interferon alfa Structural and pharmacokinetic properties. Semin. Liver Dis. 23 (suppl l) 19-22. 2003. 

Halme, M., P. Maasilta, K. Mattson, and K. Cantell. 1994. Pharmacokinetics and toxicity of inhaled human natural interferon-beta in patients with lung cancer. Respiration 61 105-107. 

K. Cantell. 1995. Inhaled recombinant interferon gamma in patients with lung cancer pharmacokinetics and effects on chemiluminescence responses of alveolar macrophages and peripheral blood neutrophils and monocytes. Int. 

Fig. 11.11 Pharmacokinetic (upper panel) and pharmacodynamic (lower panel) behaviors of native and PEGylated interferon administered subcutaneously to humans. Interferon-PEG 12 kDa and interferon-PEG2 40 kDa doses were 1.5 ig/kg and 180 4g, respectively. The native interferon dose was 3 M LN units. The interferon amounts reported here correspond...

J. Hoffman, S. Pedder and M. Brunda. 1999. Pharmacokinetic properties of five polyfethylene glycol) conjugates of interferon alfa-2a. Antivir. Then A. 27—17. 

A. Gibas N.E. Martin, M.L. Shiffman, and L.S. Marsano. 2000. The pharmacokinetic behaviour of pegylated (40 kDa) interferon alfa-2a (Pegasys) in chronic hepatitis C patients after multiple dosing. Hepatology 32 394A. 

C. Raffanel, R. Sabo, S.K. Gupta, M. Salfi, and S. Jacobs. 2000. Pegylated interferon-a2b pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin. Pharmacol. Then 68 ... 

Pharmacokinetics Interferons are well absorbed after intramuscular injections. Being proteins, they are probably degraded by proteases. 

---