Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Abstract

Early initiation of antiretroviral therapy (ART) during TB therapy substantially reduces TB-related morbidity and mortality rates for coinfected patients (2, 3), and the World Health Organization recommends that ART be started as soon as possible but within 8 weeks after the initiation of TB therapy (4). Simultaneously, the global emergence and increased dissemination of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have increased the need for novel anti-TB drugs with new mechanisms of action. Data from Eastern Europe indicate that multidrug resistance is approximately twice as common among patients with TB who have HIV, compared with patients without HIV (5), and a South African study found that 100% of patients with XDR-TB who were tested had HIV infections (6). Ensuring access to novel anti-TB compounds and determining safe and efficacious doses for coinfected patients must be priorities (7).The diarylquinoline bedaquiline (BDQ) (previously called TMC207) was recently approved for the treatment of MDR-TB and XDR-TB by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. The mechanism of action is novel and involves the inhibition of mycobacterial ATP synthase, leading to disrupted energy metabolism (8, 9). Phase II trials showed that BDQ significantly decreased the time to sputum culture conversion and increased the proportion of patients with negative culture results after 6 months of treatment, when added to a regimen of other anti-TB drugs (10,11). This treatment benefit was sustained at the end of the 120-week trial (12). The exposure-response relationship for BDQ is poorly characterized, but a recent study of early bactericidal activity detected a linear increase in bactericidal activity with increasing doses over 14 days of treatment (13). The main safety issue for BDQ is moderate QT prolongation; in addition, an unexplained increase in late deaths, compared to the placebo group, was observed in one phase II study in which all patients also received standard MDR-TB treatment, which resulted in a black-box warning in the U.S. label (12,14). In general, however, BDQ is better tolerated than other second-line TB drugs, the majority of which produce clinically significant and often treatment-limiting side effects (15). The current standard dosing regimen for BDQ is 2 weeks of 400 mg given daily, followed by 22 weeks of 200 mg administered three times per week. BDQ is extensively distributed to the tissues and has a multiphasic elimination pattern with a long terminal half-life (4 to 5 months) (16,17). It is mainly metabolized by the cytochrome P450 (CYP) enzyme CYP3A4 to a N-monodesmethyl metabolite, M2 (38). The activity of M2 against Mycobacterium tuberculosis is 3-to 6-fold weaker than the activity of BDQ, and there is concern that the metabolite may have a higher risk of toxicity (39). M2, though, circulates at much lower concentrations than the parent drug in humans. M2 is further primarily demethylated to the M3 metabolite, likely also by CYP3A4 (11,18).Ne...

Outcomes of HIV-infected versus HIV-non-infected patients treated for drug-resistance tuberculosis: Multicenter cohort study

“…More data are needed on the safety and interaction of the bedaquiline and delamanid new anti-TB drugs with the antiretroviral drugs [37][38][39][40][41]. The study also confirms the importance of ART to improve treatment outcomes of DRTB HIV co-infected patients [14].…”

Current research toward optimizing dosing of first-line antituberculosis treatment

“…Bedaquiline and its M2 metabolite are substrates of cytochrome p450 3A4. As bedaquiline has a very long terminal halflife, the extent of the efavirenz and lopinavir/ritonavir interactions with chronic administration were only appreciated when pharmacokinetic modeling was used to account the cumulative effects [99][100][101]. The 5-fold increase in bedaquiline's clearance mediated by rifampin precludes their combined use [101].…”

State‐of‐the‐Art Review of HIV‐TB Coinfection in Special Populations

“…Bedaquiline, which is metabolized by CYP 3A4, can be used with nevirapine (and presumably with raltegravir or dolutegravir). Efavirenz reduces and ritonavir‐boosted lopinavir increases bedaquiline concentrations, yet the clinical relevance of these interactions and the effectiveness of potential dose modifications in mitigating the DDIs has not been explored in patients . Dosing for bedaquiline in children is still being established; the magnitude of DDIs with this drug and efavirenz or ritonavir‐boosted lopinavir for children cannot be extrapolated directly from adult studies, particularly for children aged <5 years, in whom expression of CYP3A isoforms is different from adults and varies by age.…”

“…Efavirenz reduces and ritonavir-boosted lopinavir increases bedaquiline concentrations, yet the clinical relevance of these interactions and the effectiveness of potential dose modifications in mitigating the DDIs has not been explored in patients. [59][60][61] Dosing for bedaquiline in children is still being established; the magnitude of DDIs with this drug and efavirenz or ritonavir-boosted lopinavir for children cannot be extrapolated directly from adult studies, particularly for children aged <5 years, in whom expression of CYP3A isoforms is different from adults and varies by age. Mechanistic models or models that consider CYP3A maturation function are available to predict drug PKs in children but not to predict the effects of inducers or inhibitors of CYP3A on substrates of that enzyme.…”