Use of bedaquiline and delamanid in diabetes patients: clinical and pharmacological considerations

Abstract

Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo® (bedaquiline) and Deltyba® (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients. Possible alterations in the pharmacokinetics of these novel drugs induced by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy in diabetes patients, and possible drug–drug interactions with hypoglycemic agents, are of special interest, since the efficacy of bedaquiline and delamanid is concentration dependent. Moreover, it is of fundamental importance to avoid possible additive or synergistic effects of adverse drug reactions in this already vulnerable patient group. We reviewed clinical particularities related to the use of bedaquiline and delamanid in patients with type 1 and 2 diabetes mellitus (DM), as well as pharmacological aspects of the concurrent use of these agents with oral and injectable hypoglycemic agents. Bedaquiline shares liver metabolic pathways with several oral hypoglycemic agents, whereas delamanid may compete with several oral hypoglycemic agents and insulin analogs at protein-binding sites. Special concern exists regarding the use of bedaquiline and delamanid in diabetes patients aged >65 years and patients with severe renal or hepatic impairment or electrolyte disturbances. Concurrent use of bedaquiline and delamanid with insulin analogs, and other hypoglycemic agents that prolong the heart rate-corrected QT interval, such as sulfonylureas and glinides, may enhance this adverse reaction. Hepatic-related adverse reactions may develop more frequently when these drugs are combined with thiazolidinediones and acarbose. Data from Phase III and postmarketing studies are needed to elucidate the effect of DM and hypoglycemic agents on bedaquiline and delamanid effects in MDR-TB patients.

Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study

“…It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [ 17 ]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM.…”

“…BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [ 17 ]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) ( P < 0.001).…”

Effect of Disease State on the Pharmacokinetics of Bedaquiline in Renal-Impaired and Diabetic Rats

“… 33 Moreover, there may be enhanced risk of QT prolongation by bedaquiline if a CYP3A4 inhibitor like bromocriptine (recommended adjunct therapy for glycemic control) is used for diabetic patients under antidiabetic drugs like sulfonylureas therapy. 34 Dosage adjustment may be required for anti-TB oral therapy with bedaquiline in diabetic conditions. The present findings are based on the pharmacokinetic study after single dose oral administration.…”

Diabetes mellitus comorbidity in patients enrolled in tuberculosis drug efficacy trials around the world: A systematic review

“…Regarding the effect of DM comorbidity to unfavourable treatment of TB, none of the TB trials that included DM comorbidity reported specific outcomes related to the TB‐DM subpopulation. A systematic review suggested a phase III clinical trial to ensure the safe use of new TB drugs in diabetes patients . Indeed, there is still a lack of sufficient data regarding pharmacokinetic and clinical data of TB drugs in DM patients, despite the continuous growth of DM patients in the future that will cause a further threat to TB control.…”