CYP3A4 Inducers/Inhibitors: Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Avoid coadministration of strong CYP3A4 inducers such as rifamycins (., rifampin, rifapentine, and rifabutin) or moderate CYP3A4 inducers such as efavirenz. Co-administration of SIRTURO ® with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, avoid the use of strong CYP3A4 inhibitors used for more than 14 consecutive days while on SIRTURO ® , unless the benefit of treatment with the drug combination outweighs the risk. Appropriate clinical monitoring for SIRTURO ® -related adverse reactions is recommended.
Tolerance and dependence
Tolerance and dependence are induced by chronic exposure to morphine and other opioids more than any other group of drugs. Tolerance means that higher doses of opioids are required to produce an effect. When the degree of tolerance is very marked, the maximum response attainable with the opioid is also reduced. Tolerance is mainly due to receptor desensitisation induced by functional uncoupling of opioid receptors from G-proteins, thus uncoupling the receptors from their effector systems. However, the mechanism of this desensitisation is still not fully understood.
When mice were orally administered ER-464195-01 as a prophylactic treatment, in addition to exhibiting remarkable anti-inflammatory effects in dextran sodium sulfate (DSS)-induced colitis, from a comprehensive analysis of gene expression using RNA sequencing found that inflammatory cytokines and expression of inflammatory response signaling factors were significantly suppressed. Furthermore, when ER-464195-01 was therapeutically administered to mice with DSS-induced colitis, it was interesting that mucosal barrier injury as well as infiltration of inflamed cells was remarkably improved. This novel mechanism of action revealed through this joint research is expected to lead to the provision of a new IBD treatment option.