Bedaquiline: a review of human pharmacokinetics and drug-drug interactions

Abstract

Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…199 In human beings, bedaquiline is highly proteinbound (99·9%), is metabolised by cytochrome P450 isoenzyme 3A (CYP3A) to a less active metabolite (M2), and has a very long terminal half-life (about 5 months). 364 Clearance of the drug is 52% higher in black people, suggesting an undiscovered pharmacogenomic determinant of exposure. Several important drug-drug interactions exist between bedaquiline and antiretroviral drugs: bedaquiline concentrations are estimated to be reduced by about 50% with concurrent efavirenz treatment, and increased two-times with concurrent lopinavir and ritonavir.…”

Current therapies for the treatment of multidrug-resistant tuberculosis in children in India

“…If a HIV-positive child receiving efavirenz is started on bedaquiline, efavirenz should be replaced with nevirapine as efavirenz reduces the serum concentration of bedaquiline [68]. …”

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children

“…The recommended adult dose is 400 mg daily for 2 weeks, then 200 mg thrice weekly for 22 weeks. In adults, the time to maximum bedaquiline serum concentrations is 4–6 h, with 2.0–2.4‐fold increased absorption when administered together with food 3. Absolute bioavailability, i.e.…”

“…the fraction of the total dose administered which is absorbed to the systemic blood circulation, for bedaquiline is not known 4. Bedaquiline is primarily metabolized by CYP3A4 to M2 3. This leads to drug–drug interactions with several antiretroviral and anti‐TB compounds which induces or inhibits CYP3A4 5, 6, 7.…”

“…Both bedaquiline and its M2 metabolite have cationic amphiphilic properties. They bind to phospholipids and accumulate in cells and tissues, resulting in long terminal elimination half‐lives (bedaquiline 164 days; M2 159 days) due to the slow release from tissues 3.…”