Medical Research: What is the background for this study? What are the main findings?
Dr. Gupta: Verapamil is an efflux pump inhibitor drug that has been used to treat hypertension and other cardiac conditions in patients. Adding verapamil to standard tuberculosis (TB) treatment accelerates both the killing activity of the regimen in mouse model. We have recently shown in vitro that supplementing bedaquiline with verapamil profoundly decreases the MIC of bedaquiline in the wild type strain M. tuberculosis H37Rv, and also in drug-susceptible and drug-resistant clinical isolates. The MIC of another anti-mycobacterial drug clofazimine against M. tuberculosis H37Rv also decreased significantly in the presence of verapamil.
Bedaquiline is the first drug to be approved by the USFDA in last forty years for the treatment of multidrug-resistant tuberculosis (MDR-TB). Bedaquiline usage in patients presents several safety concerns including increased mortality and hepatic-related adverse drug reactions. Bedaquiline also prolongs the QT interval in patients, which is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. In a phase 2 trial involving patients with advanced MDR-TB, a significantly higher number of participants receiving bedaquiline died than those receiving placebo although the causes of mortality were not directly attributable to the drug. Thus strategies to reduce the human dose of bedaquiline while retaining antibacterial activity may be valuable. We hypothesized verapamil may potentiate the killing of M. tuberculosis by bedaquiline and accelerate clearance of mycobacteria that in an in vivo infection model. Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of bedaquiline-related adverse effects and thereby improve MDR-TB treatment outcomes.
In this study, we investigated the effect of verapamil on the activity of bedaquiline against M. tuberculosis in a mouse model of TB infection. In addition to investigating the effects of verapamil on the full human bioequivalent dose of bedaquiline (25 mg/kg), we also used a sub-optimal dose of bedaquiline (12.5 mg/kg) daily, with or without verapamil to test if verapamil may potentiate the activity of bedaquiline. We have also determined if verapamil can protect bedaquiline monotherapy from the development of resistance.
Using mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same antibacterial effect as the higher toxic doses. A lower dose of bedaquiline will cause no or less severe side effects. Verapamil also protected bedaquiline against the development of resistant mutants of the bacteria in the animals.
Medical Research: What should clinicians and patients take away from your report?
Dr. Gupta: Our finding that verapamil potentiates bedaquiline raises the possibility of extending these findings to TB patients where the daily doses of bedaquiline may be reduced when co-administered with verapamil. A lower human dose of bedaquiline is likely to reduce the frequency of bedaquiline-related adverse effects such as QTc prolongation and hepatic toxicity.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Gupta: In the study, we have used a single dose of verapamil with bedaquiline in the mouse infection experiment. It is interesting to determine if there is a dose effect of verapamil on potentiating the bedaquiline activity. Also, it is pertinent to take the results and test in other tuberculosis animal models that might more closely resemble human TB. The results of this study can be used in designing a clinical trial in humans where the lower doses of bedaquiline with verapamil can be used to treat patients successfully with fewer side effects.