Pharmacokinetic/pharmacodynamic parameters and the choice of high-dosage rifamycins

SETTING: Clinical trials and the behaviour of bacterial persisters.

OBJECTIVE: To explain why the efficacies of isoniazid (INH) and rifamycins during the treatment of tuberculosis (TB) are related not to the area under the curve (AUC)/minimum inhibitory concentration (MIC), but to peak drug concentrations.

DESIGN: We examined the response in clinical trials with patients treated with INH alone and divided into slow and rapid acetylators of INH.

RESULTS: The efficacy of INH is best related to peak concentrations, as repeated peaks can kill low-degree resistant mutants. A similar process might result in repeated peak concentrations of rifamycins killing low-tolerance persisters.

CONCLUSIONS: If the efficacy of rifamycins is best related to peak concentrations, we can explain the discrepancy between mouse studies on daily rifapentine (RPT) and the failure to accelerate elimination of TB from sputum in the TBTC Study 29A, as daily RPT greatly increases the AUC but not the peak concentrations. High dosage rifampicin may be better able than RPT to cause high peaks.