In Vitro, Pharmacokinetic, Pharmacodynamic, and Safety Comparisons of Single and Combined Administration of Tiotropium and Salmeterol in COPD Patients Using Different Dry Powder Inhalers

Abstract

Abstract. In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 μm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 μg tiotropium/ 25 μg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18 μg of tiotropium (Spiriva® HandiHaler®) (TioHH) and 50 μg of salmeterol (Serevent® Diskus®) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, fourway crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss ) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and C max,ss . No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

“…Besides, it has been suggested that for lipophilic substances, such as salmeterol, delayed pulmonary dissolution may lead to a prolonged pulmonary absorption and also contribute to the later absorption phase observed for salmeterol (Horhota et al, ; Weber & Hochhaus, ). Likewise, the presence of flip‐flop kinetics in the later absorption phase and a possible mismatching of the estimated oral absorption rate constant with the disposition parameters cannot be excluded as well.…”

Essential criteria for pharmacokinetic studies supporting bioequivalence of inhaled tiotropium bromide products

“…These present a major challenge in bioanalytical method development and pharmacokinetic parameter estimation for bioavailability and bioequivalence studies . In earlier studies, the bioanalytical methodology that was used for analyzing tiotropium in plasma (liquid chromatography coupled to tandem mass spectrometry [LC‐MS/MS]) had a lower limit of quantitation (LLOQ) of 2.5 pg/mL . Table shows the numbers of subjects with plasma concentrations of tiotropium above the LLOQ (2.5 pg/mL) following a single administration of 18 μg tiotropium to healthy volunteers.…”

“…The reviews of the workshops, although comprehensive, do not address specific bioequivalence requirements for tiotropium bromide (trade name, Spiriva). Specifically for tiotropium, it was recently shown that the in vitro tests conducted for the development of a new OIP containing tiotropium were not predictive of the systemic exposure …”

“…Several clinical studies that include pharmacokinetics in healthy volunteers and patients with COPD and asthma have been performed by the innovator during the development of new tiotropium inhaled products for enhanced patient benefit . These trials have demonstrated that certain pharmacokinetic design elements are vital for conducting a valid and reproducible clinical bioavailability study with tiotropium, and these are described in the following sections.…”

Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference

“…The following review papers in this issue provide an integrated view of talks and discussions related to a given topic: & Application of the modified chi-square ratio statistic in a stepwise procedure for cascade impactor equivalence testing (by Ben Weber et al) (6) & Effect of device design and formulation on the in vitro comparability for multi-unit dose dry powder inhalers (by Jag Shur et al) (7) & In vitro, pharmacokinetic, pharmacodynamic, and safety comparisons of single and combined administration of tiotropium and salmeterol in COPD patients using different dry powder inhalers (by Stephen Horhota et al) (8) & Safety of β2-agonists in asthma: linking mechanisms, meta-analyses, and regulatory practice (by Sanjeeva Dissanayake) (9).…”