Co-administration of Tacrolimus Suppresses Pharmacokinetic Modulation of Multiple Subcutaneously Administered Human Interferon-alpha in Beagle Dogs

Abstract

Specific antibody production is an important issue in crossover pharmacokinetic (PK) studies of protein-based formulations. We recently reported that intravenous co-administration of tacrolimus with multiple human interferon-alpha (h-IFN) administrations successfully suppressed the production of anti-h-IFN antibodies in rats. Since crossover PK studies are preferentially carried out using larger animals such as dogs or monkeys that are capable of accepting the same dosage formulations as those for clinical use, we extended our study of co-administration of tacrolimus with multiple h-IFN administrations to beagle dogs in the present study. Beagle dogs were subcutaneously administered 0.5 million IU/kg of h-IFN once a week for 4 weeks. In some experiments, tacrolimus at 0.01 or 0.1 mg/kg was intravenously co-administered at the same time as the h-IFN administration. Co-administration of the lower dose of tacrolimus (0.01 mg/kg) failed to suppress the anti-h-IFN IgG responses, while co-administration of the higher dose (0.1 mg/kg) successfully suppressed these responses. Moreover, co-administration of tacrolimus had little effect on the serum creatinine concentrations, suggesting that multiple administrations of tacrolimus at the concentrations examined did not cause severe renal disorders. Taken together, the present data confirm that co-administration of tacrolimus is a promising way to assess crossover PK studies of human or humanized proteinic formulations in beagle dogs.

Cutaneous anaphylactoid reaction to polyoxyethylene hydrogenated castor oil in dogs

“…The PEG-derivativecontaining drugs for injection, especially those containing high concentrations, such as Prograf and Sandimmune (Table 1), should be prescribed for careful use because adverse reactions have been reported with drugs containing the same PEG derivatives or the drug itself. 10,[12][13][14] Although it is used as an infusion fluid (50 mg HCO-60 dissolved at 250-500 mL) in small animal practices in Japan, Multamin elicited skin reactions in the present study (Table 1). It has been described that male beagle dogs (n = 5) did not show any clinical signs of abnormalities after receiving total parenteral nutrition with Multamin-dissolved infusion solution, with concentration 50 mg HCO-60 dissolved at 5 mL, 0.1 mL/kg for 40 days (including a vitamin washout period).…”

“…We examined not only injections, but also capsules, eye drops and ointments. The PEG‐derivative‐containing drugs for injection, especially those containing high concentrations, such as Prograf and Sandimmune (Table 1), should be prescribed for careful use because adverse reactions have been reported with drugs containing the same PEG derivatives or the drug itself 10,12‐14 . Although it is used as an infusion fluid (50 mg HCO‐60 dissolved at 250–500 mL) in small animal practices in Japan, Multamin elicited skin reactions in the present study (Table 1).…”

“…HCO ethoxylates induced anaphylactoid reactions, whose potential was confirmed by the threshold concentration. Because polyoxyethylene hydrogenated castor oils are utilised as nonionic solubilisers in the formulations of lipophilic drugs, including steroid hormones, antibiotics, immunosuppressants and vitamins, 4,7,9,14 adverse effects from HCO ethoxylates should be considered when anaphylactoid reactions are encountered with these drug formulations.…”

“…This anaphylactoid reaction was specifically observed in beagle dogs, and not in monkeys, rabbits, guinea pigs or rats 11 . Drugs containing PEG derivatives carry the risk of anaphylactoid reaction in dogs and cats; 10,12–14 however, little is known about the safe amount of HCO ethoxylates in drugs containing PEG to avoid anaphylactoid reactions. The use of PEG in drugs used for people is increasing; therefore, the risk of anaphylactoid reaction may increase if dogs are administered human medications containing PEG derivatives.…”

Polish Journal of Veterinary Sciences

“…Advances in science and technology in recent decades have provided an increasing number of tools and opportunities for the development of peptides and proteins as drugs. For treatment, most peptide and protein drugs are usually applied through invasive pathways such as IV, SC or IM injections, due to the low bioavailability and high enzymatic degradation rates in the stomach and small intestine (Yamazaki et al 2010). Additionally, some supportive evidence indicates that the route of administration, namely, the behavior of drug treatments, is a significant factor affecting the efficacy of treatment (Wills 1990).…”