(W1030-04-26) Tigecycline Pharmacokinetics after Intrapulmonary Administration in Mice

Purpose: Cystic Fibrosis (CF) patients commonly experience chronic pulmonary infections, with Mycobacterium abscessus being a frequent culprit. Treatment of M. abscessus infections is challenging and often requires combination therapy, but nevertheless has high failure and relapse rates. Tigecycline (TGC), a broad-spectrum antibiotic, has shown promise in treating M. abscessus infections. In the clinic, TGC administered intravenously (IV) at a dose of 50 mg every 12 hours has limited penetration into the lungs and therefore limited efficacy against M. abscessus, but higher doses result in unacceptable gastrointestinal toxicity. Hence, pulmonary administration is an attractive alternative for treating respiratory infections with M. abscessus, which allows direct delivery of the antibiotic to the lungs and reduces systemic exposure and serious side effects. However, data on the intrapulmonary pharmacokinetics of tigecycline at different doses is limited. Therefore, this study aimed to assess the pharmacokinetics of TGC after intrapulmonary administration (IPA) of various doses in C57B6/J mice.

Methods: C57B6/J mice were separated into three groups of 24 animals: 10, 50 and 70 mg/kg IPA doses, were given once daily for 5 days using the PennCentury micro spray device and compared with a single IV dose at 10 mg/kg. Plasma, bronchoalveolar lavage fluid (BALF) and lungs were collected at different time intervals after the last dose of the dosing series by destructive sampling (n=3 per sampling point). TGC concentrations were measured in the collected samples by liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters of TGC were calculated using non-compartmental analysis.

Results: The study found that the IPA route resulted in a significant increase in the lung-to-plasma exposure ratio compared to the intravenous (IV) route. With IPA delivery, lung exposure was approximately 90, 50-fold, and 65-fold higher than plasma exposure for the low, medium, and high doses, respectively, while only a 6-fold difference was observed with IV administration. The half-life of TGC was around 6-8 hours for all three doses. Total plasma exposure quantified as area under the concentration-time curve (AUC_0-24) was 1.55, 11.0, and 24.4 µg*hr/mL, while lung exposure was 144, 468, and 1233 µg*hr/g for 10, 50, and 70 mg/kg dose levels, respectively. The maximum concentration (C_max) of TGC in plasma was 1.39, 11.1, and 8.38 µg/mL for the 10, 50, and 70 mg/kg dose levels, respectively, while the C_max in the lungs was 160, 325, and 579 µg/mL for the 10, 50, and 70 mg/kg dose levels, respectively. Urea correction was applied to bronchoalveolar lavage fluid (BALF) to estimate TGC concentration in epithelial lining fluid (ELF). The area under the concentration-time curve (AUC0-24) for ELF was 92, 105, and 120 µg*hr/mL for 10, 50, and 70 mg/kg dose levels, respectively. The C_max of TGC in ELF was 43.7, 55.6, and 64.2 µg/mL for the 10, 50, and 70 mg/kg dose levels, respectively.

Conclusion: IPA administration resulted in higher exposure of TGC in lung tissue compared to the IV route, which may be beneficial for the treatment of M. abscessus infections. Further studies are needed to evaluate the in vivo efficacy of IPA TGC at different doses in murine infection models to evaluate its full potential.

Acknowledgements: All Authors Do not have any conflict of interest.