Particle size and gastrointestinal absorption influence tiotropium pharmacokinetics: a pilot bioequivalence study of PUR0200 and Spiriva HandiHaler

Abstract

AIMSPlasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva ® HandiHaler ® (HH). The ratio of tiotropium lung-to-oral deposition in PUR0200 was varied to investigate the impact of particle size on tiotropium pharmacokinetics, and the contribution of oral absorption to tiotropium exposure was assessed using charcoal block. METHODSA seven-period, single-dose, crossover study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in five periods and Spiriva HH in two periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8 h after inhalation. RESULTSPUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung-to-oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3 μg tiotropium) lung deposition was similar to Spiriva HH (18 μg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The C max and AUC 0-0.5h of Spiriva HH with and without charcoal block were bioequivalent; however, Spiriva HH AUC 0-8h was lower when gastrointestinal absorption was inhibited with oral charcoal administration. CONCLUSIONSPharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC 0-t than Spiriva HH due to reduced absorption of drug from the gastrointestinal tract. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 580-589 580• Tiotropium is a commonly used bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). • Tiotropium is used in clinical practice as Spiriva HandiHaler (HH), a lactose blend formulation with an 18 μg nominal dose, or Spiriva Respimat, a soft mist inhaler with a 5 μg nominal dose. • PUR0200 is a spray dried formulation of tiotropium that results in efficient lung delivery and similar bronchodilation to Spiriva HH with a 3 μg nominal dose. WHAT THIS STUDY ADDS• Tiotropium exposure following inhalation results from both lung and gastrointestinal absorption.• Tiotropium lung deposition and exposure is predicted by in vitro impactor sized mass as determined by cascade impaction.• Particle engineering approaches, such as PUR0200, enable multiple options for achieving bioequivalence, including formulations with similar lung doses and lower total systemic exposure. PUR0200 and tiotropium pharmacokinetics Br J Clin Pharmacol (2019) 85 580-589 581 PUR0200 and tiotropium pharmacokinetics Br J Clin Pharmacol (2019) 85 580-589 583

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