Predictions of Bedaquiline and Pretomanid Target Attainment in Lung Lesions of Tuberculosis Patients using Translational Minimal Physiologically Based Pharmacokinetic Modeling

BACKGROUND: Site-of-action concentrations for bedaquiline and pretomanid from tuberculosis patients are unavailable. The objective of this work was to predict bedaquiline and pretomanid site-of-action exposures using a translational minimal physiologically based pharmacokinetic (mPBPK) approach to understand the probability of target attainment (PTA). METHODS: A general translational mPBPK framework for the prediction of lung and lung lesion exposure was developed and validated using pyrazinamide site-of-action data from mice and humans. We then implemented the framework for bedaquiline and pretomanid. Simulations were conducted to predict site-of-action exposures following standard bedaquiline and pretomanid, and bedaquiline once-daily dosing. Probabilities of average concentrations within lesions and lungs greater than the minimum bactericidal concentration for non-replicating (MBC(NR)) and replicating (MBC(R)) bacteria were calculated. Effects of patient-specific differences on target attainment were evaluated. RESULTS: The translational modeling approach was successful in predicting pyrazinamide lung concentrations from mice to patients. We predicted that 94% and 53% of patients would attain bedaquiline average daily PK exposure within lesions (C(avg)-lesion) > MBC(NR) during the extensive phase of bedaquiline standard (2 weeks) and once-daily (8 weeks) dosing, respectively. Less than 5% of patients were predicted to achieve C(avg)-lesion > MBC(NR) during the continuation phase of bedaquiline or pretomanid treatment, and more than 80% of patients were predicted to achieve C(avg)-lung >MBC(R) for all simulated dosing regimens of bedaquiline and pretomanid. CONCLUSIONS: The translational mPBPK model predicted that the standard bedaquiline continuation phase and standard pretomanid dosing may not achieve optimal exposures to eradicate non-replicating bacteria in most patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-023-01217-7.