Pharmacokinetics and linear exposure of AFRESA™ compared with the subcutaneous injection of regular human insulin

Abstract

AFRESA [Technosphere Insulin (TI); MannKind Corporation, Valencia, CA], a dry powder preparation of regular human insulin (RHI), utilizes a novel and versatile drug carrier platform that enables pulmonary administration of medications typically administered by injection. The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of three different inhaled doses of TI with those of subcutaneous (s.c.) RHI. This randomized, open-label, four-way crossover study of 11 healthy, non-smoking volunteers evaluated PK and PD profiles following single inhalations of 25, 50 or 100 U TI and 10 IU RHI administered subcutaneously using a euglycaemic clamp technique. Following inhalation of TI, peak insulin concentrations (C(max)) were achieved approximately 2 h earlier than with RHI (12-17 min for TI vs. 134 min for RHI). Area under the insulin concentration-time curve (AUC) and insulin C(max) values increased with increasing TI dose. Insulin exposure, as measured by AUC, was found to be linear over the dose range studied. Compared with s.c. RHI, TI at doses of 25, 50 and 100 U showed a relative bioavailability of 25, 23 and 21%, respectively. The maximum bioeffect, as measured by the glucose infusion rate, occurred approximately 2 h earlier for all three TI doses (42, 50 and 58 min, respectively) than for s.c. RHI (171 min). No treatment-related adverse events were reported with TI. TI is an inhaled insulin with a more rapid absorption and a more rapid elimination than subcutaneously administered RHI, resulting in a quick onset and short duration of action. Insulin exposure following TI administration was found to be linear over the dose range of 25-100 U.