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|Title:||Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys||Authors:||Yu, KM
|Issue Date:||2018||Publisher:||Academic Press||Source:||Toxicology and applied pharmacology, 2018, v. 342, p. 39-49 How to cite?||Journal:||Toxicology and applied pharmacology||Abstract:||The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL-11 (PEG-IL11) showed a much prolonged circulating half-life of 67 h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~ 3 h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2 = 6.9 h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25 mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3 mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1–0.3 mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30–100 μg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.||URI:||http://hdl.handle.net/10397/77651||ISSN:||0041-008X||EISSN:||1096-0333||DOI:||10.1016/j.taap.2018.01.016|
|Appears in Collections:||Journal/Magazine Article|
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