Amikacin exposure and its association with ototoxicity and efficacy in nontuberculous mycobacterial pulmonary disease treatment.

PURPOSE: Amikacin (AMK) is a widely used therapeutic drug monitoring (TDM)-recommended treatment for nontuberculous mycobacterial pulmonary disease (NTM-PD). However, its optimal dosage and TDM target remain unclear. In this study, we aimed to clarify the relationship between AMK exposure, ototoxicity, and efficacy.

METHODS

Patients with NTM-PD treated with AMK at Fukujuji Hospital were retrospectively included in this study. The correlation between AMK exposure, measured by peak and trough levels and the area under the concentration-time curve (AUC), ototoxicity, and culture conversion was analyzed using the Mann-Whitney U test and Cox regression analysis. A population pharmacokinetic/pharmacodynamic (PPK/PD) model was developed to predict ototoxicity using TDM measurements.

RESULTS

A total of 185 patients were enrolled. The median AMK dose and observation period were 500 (interquartile range [IQR], 500-600) mg/day and 45.8 (IQR, 31.3-76.5) months, respectively. Ototoxicity and culture conversion were observed in 39% and 54% of the enrolled patients, respectively, after initiating AMK. The median time to the development of ototoxicity was 69 (IQR; 43-97) days. Neither ototoxicity nor culture conversion was associated with pharmacokinetic parameter of AMK exposure, including its minimum inhibitory concentration. However, the cumulative AUC was significantly higher in patients who developed ototoxicity (P < 0.001) than in those without ototoxicity. The developed PPK/PD model enabled calculation of cumulative AUC from TDM data and prediction of ototoxicity onset.

CONCLUSION

Cumulative AMK exposure was associated with ototoxicity, and our findings allow prediction of ototoxicity onset using AMK TDM data.