A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis

Chandrasekaran, Padmapriyadarsini and Szumowski, John D. and Akbar, Nabila and Shanmugasundaram, Prema and Jain, Anilkumar and Bathragiri, Marasamy and Pattnaik, Manoranjan and Turuk, Jyotirmayee and Karunaianantham, Ramesh and Balakrishnan, Senthilkumar and Pati, Sanghamitra and Hemanth Kumar, AK and Rathore, Manoj Kumar and Raja, Jegadeesh and Raghu Naidu, K and Horn, John and Whitworth, Laura and Sewell, Roger and Ramakrishnan, Lalita and Swaminathan, Soumya and Edelstein, Paul H (2024) A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis. A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis, 115 (2). pp. 324-332.

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Abstract

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil’s mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Affiliation:	ICMR-National Institute for Research in Tuberculosis
Item Type:	Article
Uncontrolled Keywords:	R-verapamil; drug tolerance; efflux; norverapamil; rifampin; tuberculosis; verapamil
Subjects:	Tuberculosis > Clinical Research
Divisions:	Clinical Research
Depositing User:	Mrs. N Lakshmi
Date Deposited:	09 Feb 2024 11:53
Last Modified:	02 Aug 2024 17:15
URI:	http://eprints.nirt.res.in/id/eprint/1991

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