Higher Dose of Rifampicin for Tuberculosis: Practical Issues

Drug-susceptible tuberculosis (TB) is currently treated with drugs based on recommendations by the WHO in 1971.[1,2] During the first 2 months (intensive phase) daily doses of isoniazid 5 mg/kg, rifampicin 10 mg/kg, pyrazinamide 25 mg/kg, and ethambutol 15 mg/kg are given, followed by a continuation phase of isoniazid and rifampicin.[1] This 6-month multidrug regimen is intended to cure TB and at the same time prevent acquired drug resistance, therapy failure, and relapse.[3] In the National TB Elimination Program in India weight-banded fixed-dose combination of all four drugs is given in the intensive phase and three drugs barring pyrazinamide are given in the continuation phase maintaining the same dose. This is followed because of the high rates of INH monoresistance in India. When the weight-banded dosing is selected rifampicin dose reaches 900 mg/day in the higher weight category. The optimal dosing strategy for rifampicin in treating drug-susceptible TB is still highly debated. Current rifampicin dosing is implemented based on “outdated” knowledge and has remained suboptimal. The recommended dose of rifampicin for treating TB in adults is 10 mg/kg (8–12 mg) once daily with a maximum dose capped at 600 mg/day and in pediatric patients, the range is 10–20 mg/kg, with a maximum of 600 mg/day. The long treatment duration increases the chance of noncompliance; hence, shorter and more effective regimens with preserved safety profiles are needed to eliminate TB. Due to highly variable pharmacokinetic properties and a short half-life, suboptimal concentrations have been associated with decreased 2-month sputum culture conversion and increased treatment failure and relapse rates. A higher rifampicin dose may be needed to achieve therapeutic concentrations, particularly in younger children, underweight adults, patients with TB meningitis, and immunocompromised HIV-infected TB patients. Recent clinical trials have explored the use of higher doses of rifampicin,[4,5] to increase its bactericidal activity with the potential to shorten TB treatment duration. This was corroborated by results from pharmacokinetic-pharmacodynamic modeling and simulation.[6,7] “RIFASHORT,” a recently reported phase 3 trial, demonstrated that 4-month high-dose rifampicin regimens using flat doses of 1200 mg and 1800 mg daily did not have dose-limiting toxicities but failed to meet noninferiority criteria compared with the standard 6-month control regimen.[8] A new dose individualization approach using measured plasma concentrations coupled to Bayesian forecasting including dose predictions for high‐dose rifampicin TB treatment, recommends a rifampicin dose of 35 mg/Kg.[7] The efficacy profile is superior while the safety profile is not predictable. Rifampicin doses of at least three times the standard dose combined with isoniazid, pyrazinamide, and ethambutol were safely administered to 63 patients with pulmonary TB for 12 weeks.[9] Rifampicin 40 mg/kg was recently identified as the highest tolerated dose with dose-limiting factors reported as gastrointestinal disorders, pruritus, hyperbilirubinemia, and jaundice.[10] However, the safety of simultaneously administered high-dose pyrazinamide and rifampicin remains to be explored.[11] CONCLUSION The TB community’s focus on a once daily, 600 mg dose of rifampicin is being questioned. This dose is at the low end of the dose-response curve and was selected in the past mainly for financial reasons. Comparing the strength of evidence for the efficacy and safety of bedaquiline and delamanid, it is ideal to opt for higher dosing of rifampicin, when multiple studies have shown already that it is safe and more efficacious. It is time for the rapid programmatic introduction of a high dose of rifampicin (30–35 mg/kg) for at least four high-risk groups that are not well treated by the standard dose, i.e., patients with TB meningitis, HIV, diabetes, and severe illness characterized by a low body mass index (<18 kg/m2).