A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses

Abstract

Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty‐three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time‐dependent elimination due to autoinduction, concentration‐dependent clearance, and dose‐dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis–Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure–response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high‐dose rifampicin.

Forecasting Clinical Dose–Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin

“…All model components, i.e., the human rifampicin PK model, the epithelial lining fluid model (ELF) model, and the MTP model were developed earlier and linked in this work ( Figure ). All parameter values used for the translational predictions are presented in Table .…”

“…These predictions indicate that a further, but modest, increase in rifampicin EBA might be attainable at 50 mg/kg compared to 35 mg/kg. Although the concentrations achieved with a 50 mg/kg dose were covered by the PD side of our approach, PK was formally only studied up to 40 mg/ kg, 19 and hence our predictions represent a slight extrapolation out of the data space. As the maximum effects of all identified nonlinearities in rifampicin PK have been well captured, the accuracy of the extrapolation might be acceptable in this case.…”

“…The murine PK parameters were estimated from digitalized PK data from Jayaram et al 22 and are presented in Table 1. For prediction of the clinical phase IIa EBA study, the concentration-time profile in the epithelial lining fluid, predicted using the General Pulmonary Distribution model 20 and a human plasma PK model, 19 were linked to the MTP model. The covariates of the human PK rifampicin model (weight and height) were set to values typically observed in TB patients 19 and sampled from log-normal distributions with a geometric mean of 60 kg for weight and 1.75 m for height.…”

Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

“…Fat‐free mass (FFM) (derived from sex, bodyweight, and body mass index as suggested in recent studies) and total bodyweight were allometrically scaled to all clearance parameters (Eq. 2), and volume of distribution parameters (Eq.…”

“…Recent studies in pulmonary tuberculosis treatment suggest that much higher doses of rifampin (up to 40 mg/kg/day) can be given safely and result in increased drug exposure and bacterial killing. 4 Clinical and pharmacological studies conducted in Indonesian adults with TBM have suggested that survival increases with increased drug exposure and rifampin doses of at least 20 mg/kg, and possibly up to 35 mg/kg/day, may be required to improve outcomes. [5][6][7][8] Taken together, these studies suggest the rifampin dose used in our trial (15 mg/kg/day) may have been too low.…”