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Tiotropium Pharmacokinetics and Pharmacodynamics - What are Drivers for Systemic Levels and Local Pulmonary Responses?

Weber B, Borghardt JM, Parra-Guillen ZP, Sharma A, Retlich S, Staab A, Troconiz IF.

Respiratory Drug Delivery 2016. Volume 1, 2016: 45-54.

Abstract:

Tiotropium is a once-daily inhaled long-acting muscarinic receptor antagonist (LAMA) approved for the management of chronic obstructive pulmonary disease (COPD) and asthma. Tiotropium plasma and urine concentrations have historically been analyzed with non-compartmental approaches to evaluate systemic pharmacokinetics and safety aspects. The objective of this work was to investigate the pulmonary pharmacokinetics of tiotropium in healthy subjects after inhalation via the Respimat^® Soft Mist™ inhaler by applying non-linear mixed effects modeling techniques to tiotropium plasma and urine data after intravenous administration and inhalation. The key findings were that: 1) three parallel pulmonary absorption processes were identified to best describe the data; and 2) tiotropium exhibits an extended pulmonary residence time (65.4 hour absorption half-life) of the majority (86.4%) of the pulmonary bioavailable fraction and only a small portion of the pulmonary bioavailable fraction is fast absorbed. Thereby, the three absorption processes not only define the pulmonary fate of tiotropium but are also driving the plasma concentration time profiles of inhaled tiotropium. The fast absorbed portion (3.69% of the pulmonary bioavailable fraction) contributes to the sharp plasma concentration peak that is observed after tiotropium inhalation whereas the slowly absorbed fraction contributes to the phase of slowly declining plasma concentrations and the accumulation after multiple inhalations. Also, the small contribution of systemically available drug to plasma concentration peak positively impacts systemic safety aspects often associated with maximum plasma concentrations. In conclusion, the extended pulmonary residence time of tiotropium appears to be a key factor in contributing to its once-daily dosing regimen/long-lasting efficacy in addition to the previously demonstrated slow receptor off-kinetics.