Safety, Tolerability, and Pharmacokinetics of Single and Repeat Doses of Nemiralisib Administered via the Ellipta Dry Powder Inhaler to Healthy Subjects

Abstract

Purpose: Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.

Methods: This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 μg) and repeat (200 μg for 10 days) doses of inhaled nemiralisib in parts A (n = 12) and B (n = 12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n = 6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days.

Findings: 21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma C_max dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma C_max and AUC_0-24 values were 174.3 pg/mL (96.9-313.3) and 694.6 pg·h/mL (503.5-958.2) for 100 μg and 398.9 pg/mL (318.3-500.1) and 1699.6 pg·h/mL (1273.3-2268.7) for 200 μg, respectively. Repeat dosing for 10 days showed exposures ∼2- to 4-fold higher than on the single dose (peak, trough, and AUC_0-24 levels), achieving steady-state by day 6. Mean AUC_0-24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non-drug-related adverse events were observed; neither was serious or resulted in withdrawal.

Implications: Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ∼23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325.

Keywords: ellipta; healthy volunteers; nemiralisib; phramacokinetics; safety.