Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2

Abstract

Interleukin-2 (IL-2) is a hormone of the immune system responsible for control of the proliferation and cytotoxicity of T lymphocytes and natural killer cells as well as the proliferation of B lymphocytes. Recombinant IL-2 has been only minimally to modestly successfully to date in the treatment of cancer and infectious diseases, largely because the drug is associated with toxicity and a narrow therapeutic index. Quantitative measurement of IL-2 can be quickly done by enzyme immunoassay. IL-2 bioassay provides an index of biologically active cytokine. IL-2 action and pharmacokinetics can be understood in the context of the effect IL-2 on high (alpha, beta, gamma trimer) vs intermediate (alpha, beta) vs low (beta only or alpha only) affinity IL-2 receptors on various cells of the immune system. IL-2 undergoes rapid renal elimination. The route of administration is important to determine the provision of sustained drug concentrations adequate to support the proliferation and cytotoxicity of immune cells. When IL-2 is given intravenously it has rapid elimination pharmacokinetics with an initial elimination half-life and terminal elimination half-life (t1/2 beta) of 6 to 12 minutes and 40 to 80 minutes, respectively. Subcutaneous or intramuscular administration of IL-2 results in sustained systemic absorption and approximately 30% of the injected dose is absorbed. Because IL-2 is less rapidly cleared from the site of intracavitary injection, when the drug is given by these less traditional routes (e.g. intraperitoneal, intrapleural, intrathecal, intraventricular, intravesicular, and inhalational administration) sustained local IL-2 activity can result. In some cases this has resulted in an improved therapeutic index compared with that resulting after administration of the drug by high dose intravenous bolus or continuous infusion. Depot IL-2 preparations may offer more convenient administration (e.g. t1/2 beta of polyethylene glycolated IL-2 is approximately 10-fold higher than that of recombinant IL-2) or more favourable biodistribution (e.g. IL-2 liposomes are more potent against lung metastases) compared with IL-2 administered by more conventional routes. An understanding of IL-2 clinical pharmacokinetics in relation to immunobiology of this central cytokine should lead to less toxicity and more effective clinical use.

Propagation and Control of T Cell Responses by Heparan Sulfate-Bound IL-2

“…Twenty-four hours after the injection of IL-2, no free IL-2 was detectable in the blood, consistent with its brief half-life (23). However, IL-2 deposits were detected in the perifollicular regions of the spleen (Fig.…”

Enhanced Activity of Hu14.18-IL2 Immunocytokine against Murine NXS2 Neuroblastoma when Combined with Interleukin 2 Therapy

“…6 The half-life of IL-2 is shorter (ϳ45 min) after a bolus i.v. injection (23)(24)(25). However, giving the same dose of IL-2 as a c.i., rather than as a bolus, results in prolonged in vivo exposure to IL-2 and greater in vivo activation of NK cells (18) ϩ effectors by soluble IL-2, which could not be realized with the modest dose increase (from 5 g up to 22 g) of ICs (Fig.…”

Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

“…Unfortunately, the clinical development of rIL-2 has been compromised by frequently associated toxicities and a narrow therapeutic index [22][23][24]. Regarding pulmonary toxicity, rIL-2 given intravenously is commonly complicated by NCPE.…”

“…The feasibility and the safety of longterm administration of subcutaneous rIL-2 at conventional 155 Cancer-Therapy-Related Noncardiogenic Pulmonary Edema doses of 4.5 million IU/day, three times weekly, has been well established [33] while novel locoregional administration strategies, such as the inhalation of nebulized rIL-2, are being investigated with the aim of improving its therapeutic index [34]. The more favorable toxicity profile of subcutaneous, compared with intravenous, bolus administration of rIL-2, is possibly attributed to a lower systemic absorption (30% of the injected dose) and a better pharmacokinetic profile (sustained systemic exposure and lower peak levels) associated with this route [22].…”