An evaluation of the pharmacokinetics of tiotropium following a single-dose inhalation in healthy subjects using an ultra-sensitive bioanalytical method

Abstract

Objective and significance: The systemic bioavailability of tiotropium following administration via inhalation is known to be very low. A validated ultra-sensitive bioanalytical method with the lowest lower limit of quantitation (LLOQ) was developed and used to evaluate the complete pharmacokinetic profile of tiotropium.

Methods: This was a pharmacokinetic study performed in 18 healthy subjects. Each subject was administered a dose of 18 mcg of tiotropium from a dry powder inhaler (DPI). The subjects’ plasma tiotropium concentrations were assayed with LLOQ of 0.1 pg/mL.

Results: The results showed a mean C_max of 4.98 ± 3.55 pg/mL, and a median (t_max) of 3.6 minutes (range: 1.8–12 minutes). The means for area under the concentration–time curve (AUC) from time zero hours to infinity (AUC_inf) and AUC from time zero hours to the time of the last measurable tiotropium concentration (AUC_t) were 51.11 ± 27.4 pg*h/mL and 37.37 ± 23.38 pg*h/mL, respectively. The mean apparent elimination half-life (t_1/2) was 68.02 ± 24.55 hours. This calculated half-life is longer than what others have reported where a less sensitive LLOQ was used.

Conclusion: The lower LLOQ enabled further insight into the pharmacokinetics of tiotropium that was not possible with other analytical methods. With this method, we were able to quantify tiotropium concentrations as early as one minute following drug administration and up to 144 hours after dosing. The application of this method will allow for studies to be designed properly and enable further investigations into the pharmacokinetics of tiotropium.

Keywords:

• Tiotropium
• pharmacokinetics
• lower limit of quantitation
• sensitivity
• inhalation

Acknowledgments

The authors acknowledge the assistance provided by Ashraf El Sheikh Ali in the preparation of the manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol and informed consent form were approved by Salus Institutional Review Board (IRB), Texas, USA.

Informed consent

Informed consents were obtained from all individual participants included in the study, prior to any activity in the trial.

Disclosure statement

The authors declare that they do not have any conflict of interest.

Additional information

Funding

This study was funded by Pharma Medica Research Inc.