Pharmacokinetics and absorption, distribution, metabolism and excretion profiling of tanimilast following an intravenous 14C-microtracer coadministered with an inhaled dose in healthy male individuals.

Tanimilast is an inhaled phosphodiesterase-4 inhibitor currently in phase III clinical development for treating chronic obstructive pulmonary disease and asthma. This trial aimed to characterize the pharmacokinetics, mass balance, and metabolite profiling of tanimilast. Eight healthy male volunteers received a single dose of nonradiolabeled tanimilast via powder inhaler (Chiesi NEXThaler [3200 μg]), followed by a concomitant intravenous infusion of a microtracer ([¹⁴C]-tanimilast: 18.5 μg and 500 nCi). Plasma, whole blood, urine, and feces samples were collected up to 240 hours after dose to quantify nonradiolabeled tanimilast, [¹⁴C]-tanimilast, and total-[¹⁴C]. The inhaled absolute bioavailability of tanimilast was found to be approximately 50%. Following intravenous administration of [¹⁴C]-tanimilast, plasma clearance was 22 L/h, the steady-state volume of distribution was 201 L, and the half-life was shorter compared to inhaled administration (14 vs 39 hours, respectively), suggesting that plasma elimination is limited by the absorption rate from the lungs. Seventy-nine percent (71% in feces; 8% in urine) of the intravenous dose was recovered in excreta as total-[¹⁴C]. [¹⁴C]-tanimilast was the major radioactive compound in plasma, whereas no recovery was observed in urine and only 0.3% was recovered in feces, indicating predominant elimination through metabolic route. Importantly, as far as no metabolites accounting for more than 10% of the circulating drug-related exposure in plasma or the administered dose in excreta were detected, no further qualification is required according to regulatory guidelines. This study design successfully characterized the absorption, distribution, and elimination of tanimilast, providing key pharmacokinetic parameters to support its clinical development and regulatory application. SIGNIFICANCE STATEMENT: This trial investigates pharmacokinetic and absorption, distribution, metabolism and excretion profile of tanimilast, an inhaled phosphodiesterase-4 inhibitor for chronic obstructive pulmonary disease and asthma. Eight male volunteers received a dose of nonradiolabeled tanimilast via Chiesi NEXThaler and a microtracer intravenous dose. Results show pivotal pharmacokinetic results for the characterization of tanimilast, excretion route and quantification of significant metabolites, facilitating streamlined clinical development and regulatory approval.