A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects.

Sawittree Sahakijpijarn,Jay I Peters,Moeezullah Beg,Robert O Williams,Stephanie M Levine

doi:10.3390/pharmaceutics13050717

Sawittree Sahakijpijarn, Jay I Peters + Show 3 more

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https://doi.org/10.3390/pharmaceutics13050717

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Abstract

Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled TAC combined with 50% w/w lactose (LAC) was safe and effective for the treatment of lung transplant rejection in rodent models. In this study, we aimed to investigate the safety and tolerability of TFF TAC-LAC in human subjects. The formulation can be delivered to the lung as colloidal dispersions after reconstitution and as a dry powder. Healthy subjects inhaled TAC-LAC colloidal dispersions at 3 mg TAC/dose via a vibrating mesh nebulizer in the first stage of this study and TAC-LAC dry powder at 3 mg TAC/dose via a single dose dry powder inhaler in the second stage. Our results demonstrated that oral inhalation of TAC-LAC colloidal dispersions and dry powder exhibited low systemic absorption. Additionally, they were well-tolerated with no changes in CBC, liver, kidney, and lung functions. Only mild adverse side effects (e.g., cough, throat irritation, distaste) were observed. In summary, pulmonary delivery of TFF TAC-LAC would be a safe and promising therapy for lung transplant recipients.

Highlights

Published: 13 May 2021Lung transplantation has become a life-saving treatment option for patients with end-stage lung diseases
TAC was purchased from Teva Pharmaceutical Industries (Petah Tikva, Israel), while lactose monohydrate was purchased from Fisher Scientific (Pittsburgh, PA, USA)
The solution was dropped on a cryogenic drum that is filled with liquid nitrogen

Summary

Introduction

Lung transplantation has become a life-saving treatment option for patients with end-stage lung diseases. The number of lung transplants has steadily increased over the years worldwide [1]. According to the 2020 Registry of the International Society for Heart and Lung Transplantation, more than 4500 lung transplants were performed annually [2]. Almost 70,000 lung transplant cases have been reported worldwide between 1992 and. A median survival has been improved from 4.7 to 6.7 years over the last decade [3], long-term survival remained the lowest compared to other solid organ transplants [4]. The long-term survival rate is limited by acute and chronic rejection, infectious complications, drug toxicities, and malignancies [4]

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