Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis
- 3 May 2019
- journal article
- review article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 58 (9), 1103-1129
- https://doi.org/10.1007/s40262-019-00764-2
Abstract
The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8–12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 μg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 μg/mL and area under the concentration–time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 μg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.Keywords
This publication has 167 references indexed in Scilit:
- A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis PatientsAntimicrobial Agents and Chemotherapy, 2012
- Skin manifestations of drug allergyBritish Journal of Clinical Pharmacology, 2011
- Effects of Tuberculosis, Race, and Human Gene SLCO1B1 Polymorphisms on Rifampin ConcentrationsAntimicrobial Agents and Chemotherapy, 2010
- Pharmacokinetics of Antituberculosis Drugs in Pulmonary Tuberculosis Patients with Type 2 DiabetesAntimicrobial Agents and Chemotherapy, 2010
- Paradoxical Effect of Isoniazid on the Activity of Rifampin-Pyrazinamide Combination in a Mouse Model of TuberculosisAntimicrobial Agents and Chemotherapy, 2009
- Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in LungsAntimicrobial Agents and Chemotherapy, 2009
- Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by RifampinAntimicrobial Agents and Chemotherapy, 2007
- Effects of Rifampin and Multidrug Resistance Gene Polymorphism on Concentrations of MoxifloxacinAntimicrobial Agents and Chemotherapy, 2007
- Pharmacokinetics and Tolerability of a Higher Rifampin Dose versus the Standard Dose in Pulmonary Tuberculosis PatientsAntimicrobial Agents and Chemotherapy, 2007
- Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis PatientsAntimicrobial Agents and Chemotherapy, 2006