Human Fibroblast Interferon for Clinical Trials: Pharmacokinetics and Tolerability in Experimental Animals and Humans

Abstract

Human fibroblast interferon (F-interferon) purified by adsorption on controlled-pore glass was given intramuscularly to patients at daily dosages of up to 20 x 106 units. Serum levels of antiviral activity were low or undetectable. In contrast, reasonably high serum titers were found in patients receiving interferon prepared from leukocytes (L-interferon). Similarly, in rabbits lower serum titers were seen with F-interferon than with L-interferon. These results are at variance with those obtained earlier

Antiviral Effects of Human Fibroblast Interferon from Escherichia coli against Encephalomyocarditis Virus Infection of Squirrel Monkeys

“…Blood concentrations reach approximately 100 U/ml serum at 4 to 6 h after intramuscular administration of either interferon, a finding very similar to that reported for natural IFN-fl in Cercopithecus monkeys (Billiau et al, 1981). Following intravenous injection, both the natural and bacteria-derived material are cleared at essentially the same rate with a rapid initial half-life of 15 to 20 min and a slower second phase with a half-life of approximately 2 h. These findings are in close agreement with previous reports for a natural IFN-fl administered to rabbits (Billiau et al, 1979;Vilcek et al, 1980). The low circulating levels of human fibroblast interferon activity following intramuscular administration have been attributed to intramuscular degradation ' (Hanley et al, 1979), the presence of inactivators in human serum (Cesario et al, 1979) or the rapid removal from serum through uptake by organs.…”

“…The calculated HMS for the saline-treated group was 4.4 days, whereas it was 11.3 and 15.7 days for the 106 and 3 x 104 U/kg treatment regimens, respectively. Intramuscular administration of human fibroblast interferon to monkeys or humans results in very low or undetectable levels of interferon in the serum (Billiau et al, 1979(Billiau et al, , 1981. In order to determine whether IFN-fl might be efficacious when given by this route, we examined the effects of fibroblast interferon treatments by the intramuscular and intravenous routes in EMC virus-infected squirrel monkeys of the Guyanan strain.…”

Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination

“…In addition, there was evidence for accumulation of peak drug levels late in the treatment courses in the interferontreated patients. Mean levels rose to 3.23 ± 1.90 (SD), 3.93 ± 2.77 (SD), 6.09 ± 1.87 (SD), and 7.98 ± 0.93 (SD) ,ug/ml for doses of 5, 7.5, 10, and 15 mg/kg per day respectively. Comparing these early and late peak levels in patients on combination therapy, then, accumulation is statistically significant (P < 0.05 (15 mg/kg per day), P < 0.01 (7.5 mg/kg per day), P < 0.1 (10 mg/kg per day), P < 0.001 (15 mg/kg per day)) by Student's t test.…”

Spontaneous production of human interferon.

“…In view of the marked pharmacokinetic distinctions observed between human leukocyte and fibroblast interferons (7)(8)(9), it is tempting to speculate that such distinct fonrns of lymphoid interferons could have importantly different pharmacologic properties. Therefore, it seems worthwhile to produce and evaluate each of the distinct molecular forms of human interferons.…”

“…Present sources of human interferons are suspensions of virusinduced human peripheral blood leukocytes (2), monolayer cultures of human diploid fibroblasts induced with doublestranded polyribonucleotides (3), and virus-induced human lymphoblastoid cells (4)(5)(6). The interferon produced by human leukocyte suspensions appears to have pharmacologically advantageous properties in comparison with that produced by human fibroblast cultures (7)(8)(9), but its supply is predictably restricted by the availability of fresh human blood. Virus-induced human lymphoblastoid (Namalva) cell interferon is predominantly leukocyte type in terms of its antigenicity (10,11), cross-species activity (12), and pharmacologic properties (unpublished data).…”