Chemical formula: C₂₅H₂₅F₃N₄O₆ Molecular mass: 534.492 g/mol
The pharmacological mode of action of delamanid involves inhibition of the synthesis of the mycobacterial cell wall components, methoxy-mycolic and keto-mycolic acid. The identified metabolites of delamanid do not show anti-mycobacterial activity.
Delamanid has no in vitro activity against bacterial species other than mycobacteria.
Mutation in one of the 5 coenzyme F420 genes is suggested as the mechanism for resistance against delamanid in mycobacteria. In mycobacteria, the in vitro frequencies of spontaneous resistance to delamanid were similar to those for isoniazid, and were higher than those for rifampicin. Resistance to delamanid has been documented to occur during treatment. Delamanid does not show cross-resistance with any of the currently used anti-tuberculosis medicinal products except pretomanid. In vitro studies have shown cross-resistance with pretomanid. This is likely to be due to delamanid and pretomanid being activated via the same pathway.
When 7H11 agar medium is used for drug susceptibility testing, the recommended epidemiological cut-off (ECOFF) and susceptibility testing interpretive criteria for delamanid are:
ECOFF: 0.016 mg/L
Clinical breakpoint: S ≤ 0.016 mg/L; R > 0.016 mg/L
S = susceptible; R = resistant
Oral bioavailability of delamanid improves when administered with a standard meal, by about 2.7 fold compared to fasting conditions. The peak plasma concentrations are reached in approximately 4 hours post-dose, regardless of food intake.
Delamanid plasma exposure increases less than proportionally with increasing dose.
Delamanid highly binds to all plasma proteins with a binding to total proteins of ≥99.5%. Delamanid has a large apparent volume of distribution (Vz/F of 2,100 L).
Delamanid is primarily metabolised in plasma by albumin and to a lesser extent by CYP3A4. The complete metabolic profile of delamanid has not yet been elucidated, and there is a potential for drug interactions with other co-administered medicinal products, if significant unknown metabolites are discovered. The identified metabolites do not show anti-mycobacterial activity but some contribute to QTc prolongation, mainly DM-6705. Concentrations of the identified metabolites progressively increase to steady state after 6 to 10 weeks.
Delamanid disappears from plasma with a t1/2 of 30 to 38 hours. Delamanid is not excreted in urine.
During treatment with the recommended delamanid doses to adolescents and children with a body weight of at least 10 kg, similar plasma exposure were obtained as in adults.
Less than 5% of an oral dose of delamanid is recovered from urine. Mild renal impairment (50 mL/min < CrCLN < 80 mL/min) does not appear to affect delamanid exposure. Therefore no dose adjustment is needed for patients with mild or moderate renal impairment. It is not known whether delamanid and metabolites will be significantly removed by haemodialysis or peritoneal dialysis.
No dose adjustment is considered necessary for patients with mild hepatic impairment. Delamanid is not recommended in patients with moderate to severe hepatic impairment.
No patients of ≥65 years of age were included in clinical trials.
Non-clinical data reveal no specific hazard for humans based on conventional studies for genotoxicity and carcinogenic potential. Delamanid and/or its metabolites have the potential to affect cardiac repolarisation via blockade of hERG potassium channels. In the dog, foamy macrophages were observed in lymphoid tissue of various organs during repeat-dose toxicity studies. The finding was shown to be partially reversible; the clinical relevance of this finding is unknown. Repeat-dose toxicity studies in rabbits revealed an inhibitory effect of delamanid and/or its metabolites on vitamin Kdependent blood clotting. In rabbits reproductive studies, embryo-fetal toxicity was observed at maternally toxic dosages. Pharmacokinetic data in animals have shown excretion of delamanid/metabolites into breast milk. In lactating rats, the Cmax for delamanid in breast milk was 4-fold higher than that of the blood. In juvenile toxicity studies in rats, all delamanid treatment-related findings were consistent with those noted in adult animals.
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