Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Otsuka Novel Products GmbH, Erika-Mann-Straße 21, 80636 München, Germany
Pharmacotherapeutic group: Antimycobacterials, antibiotics
ATC code: J04AK06
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 (see section 4.4). 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
Delamanid has been evaluated in two, double-blind, placebo controlled trials for the treatment of MDR TB. The analyses of SCC were conducted on the modified intent to treat population which included patients who had positive cultures at baseline and the isolate was resistant to both isoniazid and rifampicin, i.e., had MDR TB.
In the first trial (Trial 204), 64/141 (45.4%) patients randomised to receive delamanid 100 mg BID + OBR and 37/125 (29.6%) of patients randomised to receive placebo (PLC) + OBR achieved two-month sputum culture conversion (SCC) (i.e. growth of Mycobacterium tuberculosis to no growth over the first 2 months and maintained for 1 more month) (p=0.0083). The time to SCC for the group randomised to 100 mg BID was also found to be faster than for the group randomised to receive placebo + OBR (p=0.0056).
In the second trial (Trial 213), delamanid was administered orally at 100 mg BID as an add-on therapy to an OBR for 2 months followed by 200 mg once daily for 4 months. The median time to SCC was 51 days in the delamanid + OBR group compared with 57 days in the PLC + OBR group (p=0.0562 using the stratified modified Peto-Peto modification of Gehan’s Wilcoxon rank sum test). The proportion of patients achieving SCC (sputum culture conversion) after the 6-month treatment period was 87.6% (198/226) in the delamanid + OBR treatment group compared to 86.1% (87/101) in the placebo + OBR treatment group (p=0.7131).
All missing cultures up to the time of SCC were assumed to be positive cultures in the primary analysis. Two sensitivity analyses were conducted – a last-observation-carried-forward (LOCF) analysis and an analysis using “bookending” methodology (which required that the previous and subsequent cultures were both observed negative cultures to impute a negative result, otherwise a positive result was imputed). Both showed a 13-day shorter median time to SCC in the delamanid + OBR group (p=0.0281 for LOCF and p=0.0052 for “bookending”).
Delamanid resistance (defined as MIC ≥0.2 µg/ml) has been observed at baseline in 2 of 316 patients in Trial 204 and 2 of 511 patients in Trial 213 (4 of 827 patients [0.48%]). Delamanid resistance emerged in 4 of 341 patients (1.2%) randomised to receive delamanid for 6 months in Trial 213. These four patients were only receiving two other medicinal products in addition to delamanid.
The pharmacokinetics, safety and efficacy of delamanid in combination with a background regimen (BR) were evaluated in trial 242-12 -232 (10 days pharmacokinetics) followed by trial -233 (pharmacokinetics, efficacy and safety), both single-arm, open-label trials, which included 37 patients who had a median age of 4.55 years (range 0.78 to 17.60 years), 25 (67.6%) were Asian and 19 (51.4%) were female.
Paediatric patients were enrolled in four groups: Group 1: 12 to 17 years (7 patients), group 2: 6 to 11 years (6 patients), group 3: 3 to 5 years (12 patients) and group 4: 0 to 2 years (12 patients). The overall mean baseline body weight of subjects was 19.5 kg and in groups 1, 2, 3, and 4 the mean body weights were 38.4, 25.1, 14.8, and 10.3 kg, respectively.
The patients had confirmed or probable MDR-TB infection and were to complete 26 weeks of treatment with delamanid + OBR, followed by OBR only in accordance with the WHO recommendation. Patients in groups 1 and 2 received film-coated tablets. The delamanid dose in group 1 was 100 mg twice daily and 50 mg twice daily in group 2. The doses administered were higher than the currently recommended weight-based dosage in the paediatric population. Patients in groups 3 and 4 received dispersible tablets. This paediatric formulation is not bio-equivalent with the film-coated tablets. Patients in group 3 were administered 25 mg twice daily and patients in group 4 were administered doses between 10 mg twice daily and 5 mg once daily based on body weight. The doses administered in group 4 were below the currently recommended weight-based dosage in the paediatric population.
A population PK analysis was performed on data from the 2 paediatric trials to determine the doses in paediatric subjects which would provide delamanid exposures similar to those observed in adult subjects with MDR-TB. Data in children with a body weight of less than 10 kg were too limited to determine doses for that patient population.
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
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 (see section 4.2), 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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