Author : Tuberculosis Branch of the Chinese Medical Association
Corresponding Author: Wu Guihui, Chengdu Public Health Clinical Medical Center; Gao Mengqiu , Beijing Chest Hospital Affiliated to Capital Medical University
Cited this article: Tuberculosis Branch of the Chinese Medical Association. Expert consensus on clinical application of Delamani [J]. Chinese Journal of Tuberculosis and Respiratory , 2022, 45(9): 872-880. DOI: 10.3760/cma.j.cn112147-20220422-00344.
Abstract
Multi-drug-resistant Tuberburial is the main problem in the global tuberculosis prevention and control, but the success rate of treatment at home and abroad is relatively low, and it is urgent to develop new anti-tuberculosis drugs and optimize anti-tuberculosis treatment plans. Delamani is a drug that has good activity against multidrug-resistant tuberculosis in recent years. At present, my country lacks its clinical drug guidance for the treatment of tuberculosis. In order to standardize the rational application of derramani in clinical practice, the Tuberculosis Branch of the Chinese Medical Association organized experts in relevant fields to formulate this consensus, explain its molecular structure, anti-tuberculosis mechanism, drug efficacy/pharmacokinetics, drug resistance mechanism and clinical research, and put forward recommended opinions on clinical application, and explain its adaptation population, contraindications, usage methods, adverse events and precautions, in order to provide reference for clinicians to use derramani.
Multidrug-resistant tuberculosis (MDR-TB) is the main issue in the treatment and control of tuberculosis worldwide. According to the Global Tuberculosis Report of the World Health Organization (MDR-TB) in 2021, the number of new cases of tuberculosis in 2020 was approximately 9.87 million, and about 1.28 million people died of tuberculosis; globally, the treatment success rate of MDR-TB/rifampicin-resistant tuberculosis (RR-TB) in 2018 was 59%, while only 54% of MDR/RR-TB patients in my country were successfully treated [1]. Therefore, there is an urgent need to develop new anti-tuberculosis drugs that are safe.
Delamanid (Dlm) is a new drug developed by Otsuka Pharmaceuticals Co., Ltd. in the treatment of multidrug-resistant tuberculosis. In 2014, Delamani was conditionally approved by the European Medicines Agency for and recommended for adult MDR-TB patients when they cannot form an effective regimen due to drug resistance or tolerance reasons [2] . In the same year, WHO recommended that Delamani be used conditionally for long-term treatment of MDR-TB in adults [3] . In 2016, WHO suggested that Delamani's applicable age be expanded to 6 to 17 years old [4] . In March 2018, Delamani was launched in China. In 2019, in WHO's "Integrated Treatment Guide for Drug-resistant Tuberculosis" [5] and my country's "Expert Consensus on the Treatment of Multidrug-resistant and Rifampin-resistant Tuberculosis in China (2019 Edition)" [6] , Delamani entered Group C recommended drugs. In 2020, WHO recommended that deramani be used for long-term treatment of patients with MDR/RR-TB aged ≥3 years old, and recommended that it be used for a full oral treatment plan [7]. In 2020, China conducted a phase IV clinical trial to evaluate the safety and effectiveness of the deramani regimen in the treatment of MDR-TB patients aged 18 to 65 years old. Some clinical experience has been accumulated during the implementation of the project, but my country has not yet formulated relevant consensus and guidelines. Therefore, the Tuberculosis Branch of the Chinese Medical Association organized experts to discuss issues related to the treatment of anti-tuberculosis in Delamani and formulated the "Dramani Clinical Application Expert Consensus" for reference by domestic colleagues.
1. Delamani molecular structure and anti-Mycobacterium tuberculositis, MTB) mechanism
Delamani, common name is Delamani, trade name Delba, also known as OPC-67683, chemical name: (2R)-2-methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]piperidine-1-yl}phenoxy)methyl]-2,3-dihydroimidazole [2,1-b]oxazole. Molecular formula: C25H25F3N4O6, the relative molecular mass of is 534.48, and the chemical structural formula is shown in Figure 1.
Figure 1 Dramani Chemical Structural Formula
Dramani is a nitrodihydroimidazole derivative. As a prodrug, deramani is activated by nitroreductase (Ddn), which is converted into the product with anti-MTB activity [8].Delamani mainly exerts bactericidal effect by inhibiting the synthesis of methoxymycinic acid and ketomycinic acid in MTB cell wall [9]. Since Gram-positive bacteria and Gram-negative bacteria cells do not have mycobic acid, Dramani has no bactericidal or antibacterial effect on these two types of bacteria, and has no cross-resistant properties with other antituberculosis drugs. It has a strong bactericidal effect on MTB-sensitive strain , multidrug-resistant strain, dormant strain and intracellular strain [9, 10].
2. Dramani drug effect kinetics and drug metabolic kinetics study
(I) Dramani drug effect kinetics
in vitro antibacterial activity research
in vitro showed that the minimum inhibitory concentration of Dramani for standard strain H37Rv in vitro (minimum inhibitory concentration, MIC) is 0.001~0.05 mg/L [11] , MIC50 is 0.004 mg/L, and MIC90 is 0.012 mg/L [9]. The critical concentration of the in vitro drug sensitivity test for the Dramani phenotype was 0.016 mg/L in agar medium and 0.06 mg/L in MGIT liquid medium was 0.06 mg/L [12] . Delamani is used in combination with rifampicin (RFP, R), isoniazid (isoniazid, INH, H), ethambutol (EMB, E), and streptomycin (streptomycin, Sm, S), and has synergistic or partial synergistic effects. Delamani is a dose-dependent drug. It can express effective intracellular anti-MTB activity at a concentration of 0.1 mg/L, which is comparable to rifampin (3 mg/L) titer and is better than isoniazid [9]. In guinea pigs infected with MTB, after 4 weeks of treatment with 100 mg·kg-1·d-1, the colony-forming unit (CFU) in lung tissue was significantly reduced, and all of them were cleared after 8 weeks.
(II) Drug metabolic kinetics of delamani
Animal studies show that delamani can highly bind plasma proteins, with a total protein binding rate of ≥99.5% [12] ; delamani is mainly metabolized through plasma albumin, and a small part is metabolized by multiple metabolic pathways involved in cytochrome P450 enzyme, and is less metabolized in liver microsomes, so delamani is less toxic to liver [9, 13] . The main metabolites of delamani such as DM-6705 are one of the main causes of QT interval prolongation, and they also bind widely to plasma albumin. Therefore, delamani is prohibited when plasma albumin is 28 g/L [12, 14]. Delamani and (or) metabolites are widely distributed, and can be distributed in various tissues such as lungs, liver, adrenal , pancreatic , kidneys, adipose tissue, central nervous system , embryos, etc., providing possibilities for extrapulmonary tuberculosis treatment [15, 16]. Delamani and (or) metabolites are excreted from the body with feces, and the urine clearance rate is low, about 6% [15] .
The complete metabolic characteristics of dramani in humans have not been fully elucidated. Studies on different dosage methods, doses and pharmacologics of Delamani showed that the maximum blood drug concentration (Cmax) can be achieved 4 to 8 hours after oral administration of Delamani, and the half-life of is 30 to 38 h [17] , and its metabolites half-life is 121 to 322 h. After continuous administration of 10 to 14 days, the blood drug concentration reaches a stable state [18] , and the blood drug concentration decreases by 94% after 4 half-lifes. When taken with standard meals, the oral bioavailability of Delamani increased by about 2.7 times compared with fasting conditions. Therefore, deramani should be taken at the same time as food to improve its bioavailability [19]. Animal studies have shown that Delamani and its metabolites are reproductive toxic and can be distributed in milk, but the impact of Delamani or its metabolites on humans is not yet clear. Therefore, it is not recommended that pregnant women, women who may be pregnant and lactating women take Delamani [14].
III. Delamani drug resistance mechanism
Delamani has no cross resistance with current anti-tuberculosis drugs, and natural resistance is rare (1%) [9, 20] , but drug resistance may be quickly obtained when the background treatment regimen of MDR/extensively drug-resistant tuberculosis (XDR-TB) is weak. It is currently reported that it is 3 months [21] . In vitro studies suggest that the mutation rate of natural resistance to the standard strain H37Rv is 6.44×10-6~4.19×10-5, which is similar to isoniazid and higher than rifampin [22]. Mutations in any gene of the following 5 coenzyme F420 genes can cause dramani resistance: ddn, fgd, fbiA, fbiB, fbiC [23, 24]. The phenotype resistance rates of deramani were detected in the clinical isolates of MDR-TB and XDR-TB, respectively, at 2.9% and 22.2%, respectively, but no mutation of the deramani gene was detected in these drug-resistant strains, suggesting that there may be a potential genetic mechanism [25].
is also a nitroimidazole. The currently known resistance genes are ddn, fgd1, fbiA, fbiB, fbiC and cofCh (Rv2983). In vitro activity studies found that fbiA non-synonymous mutation site Glu249Lys may lead to high levels of drug resistance to dramani and putomani [26]. The ddn mutation was detected from the strain of the highly virulent Beijing family, which is resistant to putomani, but is still effective against delamani [27] , indicating that delamani and putomani have partial cross resistance, but are less, and further research and discussion are needed.
4. Clinical study of Delamani
(I) Effectiveness evaluation of Delamani
In the Phase II A clinical trial studying early bacterial activity (EBA), it was found that during the 14-day trial period, different doses of Delamani group (100/200/300/400 mg, 1 time/d) could steadily reduce the CFU of patients with sputum positive smear [18]. Later, the Delamani Clinical Development and Development Project carried out two consecutive Phase IIb clinical trials and one observational study, namely, 204 trials (242-07-204 trials) [17] , 208 trials (242-07-208 trials) [28] and 116 studies (242-10-116 study) [29] , providing an important data source for the WHO to evaluate the effectiveness of Delamani. The 204 trial was a multi-center, randomized, double-blind, placebo-controlled Phase IIB clinical trial conducted in Japan, China, South Korea, the Philippines, Egyptian , Peru , the United States, Estonia and Latvia . A total of 481 MDR-TB patients in this trial were randomly assigned to Delamani 100 or 200 mg/time, 2 times/d or placebo combined with optimized background regimen (OBR). The difference in the sputum culture conversion (SCC) rate (SCC) in the three groups at the end of 2 months of treatment. The 208 trial was a voluntary extension of the Dramani treatment in 213 patients in the 204 trials. 116 studies completed an observational study of 24 months for 421 patients in the 204 and 208 trials (see Figure 2 [3] for details of the study design). The results of the 204 trial in my country (38 patients) showed that the SCC of the SCC when the treatment with Dramani and OBR reached the observation endpoint was 69.2% (18/26), and the placebo-controlled group was 5/12; the total treatment success rate of the 208 trial in my country was 78.9% (30/38), and the median SCC time was 74.5 d [30]. The global 204 and 208 trial results (Table 1) show that Delamani has achieved good results in the treatment of MDR-TB patients and was approved for launch in EU in 2014.
Figure 2Dramani 204 trial, 208 trial, 116 study design [3]
Subsequently conducted 213 trials (242-09-213 trial, multi-center, double-blind, randomized, placebo-controlled Phase III clinical trial), endTB observational studies, Japan's "Compassionate Drug" project (referred to as "Compassionate Drug" project, providing Deramani for patients with very limited treatment options) results showed that the SCC of Deramani combined with OBR at the end of 6 months was 87.6%, 80%, and 79% [31, 32, 33] (Table 1), suggesting that Delamani has good effectiveness and can be one of the choices for anti-tuberculosis combination regimens in patients with MDR-TB.
(II) Safety assessment of Delamani
WHO's safety assessment of Delamani's safety data mainly come from the Phase I, II and III clinical trials of Japan's Otsuka Pharmaceutical Co., Ltd. and the "Compassionate Drug Use" project (Table 2). Overall, the safety of the treatment of MDR-TB patients with Dramani combined with OBR is better, and the impact on the QT interval is controllable, but the safety evidence for the use of Dramani for more than 6 months is insufficient.
Summary of 12 Phase I trials conducted in healthy subjects showed that the treatment-related adverse events with higher incidence during the treatment period were headache (20.9%, 88/422 cases), nausea (11.6%, 49/422 cases), dizziness (8.8%, 37/422 cases) in subjects treated with deramani, followed by treatment-related adverse events such as headache (20.9%, 88/422 cases), nausea (11.6%, 49/422 cases), and dizziness (8.8%, 37/422 cases) in [3] .
In the Phase I and II clinical trials of Delamani conducted in drug-resistant tuberculosis patients, a total of 887 patients received Delamani treatment, of which 22.1% (196/887) of the patients received Delamani exposure for more than 6 months. The common adverse reactions are headache, abdominal pain and insomnia [3]. In the clinical trials of Delamani IIb and Phase III clinical trials and observational studies, the incidence of adverse events and serious adverse events in patients treated with Delamani combined with OBR was not significantly different from that of placebo; a total of 39 patients died, and the researchers believed that the deaths were not related to Delamani (Table 2). The results of adverse events distribution in phase IIb and phase III clinical trials showed (Table 3): Compared with the placebo group, the most common adverse events (10%) in patients treated with deramani combined with OBR include: nausea (32.9%), vomiting (29.9%), headache (27.3%), insomnia (27.2%), dizziness (22.4%), hypokalemia (17.1%), tinnitus (16.5%), gastritis (15.1%) and fatigue (11.3%) [17, 31] . The previous worrying incidence of QT interval prolongation was 6.5%. Although it was higher than that of the placebo control group, no correlation was found with clinical syncope or arrhythmia in , and no interruption of treatment was reported due to QT interval prolongation. It should be noted that among the patients participating in the 204 trial in my country, 7.7% (2/26) of patients stopped taking deramani due to mental disorders, which may be related to deramani's combination of high-dose isoniazid and levofloxacin [30] . The report of adverse events in the 204 trial showed that the QT interval prolongation (13.1%, 21/160), depression (8.1%, 13/160), and muscle spasm (2.5%, 4/160) was significantly higher than that of deramani's 100 mg/time and 1/d group [17] . The results of the "Compassionate Drug" project suggest that common adverse events using Delamani combined with OBR are nausea, vomiting and QTcF intervals (QT intervals corrected by heart rate using the Fridericia formula) prolong [33].
(III) Research on Delamani in special populations
Currently, the research data used by Delamani in special populations is limited. Phase II clinical trial 233 trial (242-12-233 trial) [34] evaluated the safety and effectiveness of Delamani in children with MDR-TB for 6 months. The trial was divided into 4 groups according to the age of the children and treated with different doses of deramani combined with OBR: 12-17 years old group (100 mg/time, 2 times/d), 6-11 years old group (50 mg/time, 2 times/d), 3-5 years old group (25 mg/time, 2 times/d), 0-2 years old group (suspension prepared with deramani dispersed tablets, the dose is calculated based on body weight).At the end of the 26th week of treatment, the success rates of treatment in the four groups were 6/7, 6/6, 10/12 and 11/12 respectively. Due to the limitations of sputum sampling in children, SCC-related data were not collected; the incidence of QTcF intervals in the 12-17-year-old group was 1/7, and the incidence of QTcF intervals in the 0-2-year-old group was 1/11, and the incidence of QTcF intervals in the 12-year-old group was 3/7, and the incidence of QTcF intervals in the 6-11-year-old group was 2/6, and the incidence of QTcF intervals in the 2-year-old group was 450 ms; no serious adverse events related to Delamani occurred. In the "Compassionate Drug" project, 34 children aged 6 to 17 years old had SCC of 80% (20/25), the most common adverse events were QTcF interval prolongation/abnormality, vomiting and hypoproteinemia, the incidence of serious adverse events was 15% (5/34), and one child died. The researchers considered that it had nothing to do with Delamani [33] . Based on the existing data, Dramani is safe and effective in children with MDR-TB.
HD data on using Deramani is very limited. In 213 trials, 12 HIV-positive patients were treated with deramani combined with OBR, and the median time for sputum culture to turn negative was 52 days; the incidence of adverse events was similar to that of the placebo group. In the "Compassionate Drug" program, the SCC of 44 HIV-positive patients received the deramani regimen for 24 weeks was 92% (44/48) [33] .
There are currently no data on the effectiveness and safety of using Delamani in pregnant and breastfeeding women. Multicenter clinical trials on patients with HIV infection and pregnancy-related tuberculosis IMPAACT 2026 and IMPAACT P1026s are in progress.
(IV) When the combined application of deramani and bedaquiline was first launched, the combined application of this drug with bedaquiline was not recommended because it was concerned about its impact on the QT interval. In March 2016, some scholars reported that combined use of deramani, bedaquiline and OBR in XDR-TB patients achieved good clinical outcomes, and no QT interval prolongation was observed during the treatment process. Apart from nausea, no other adverse events were found [35]. In 2017, WHO made a non-contraindicated/non-extra-instruction judgment on the combination of chemotherapy regimen containing dramani and bedaquiline, and encouraged more data and evidence to produce [36].
From 2014 to 2018, South Africa conducted a prospective study to evaluate the effectiveness and safety of bedaquiline, delamani combined with OBR in patients with MDR-TB [37] . The SCC at the end of 6 months of treatment of 40 bedaquiline combined with delamani and 82 bedaquiline combined with OBR group were 81.8% and 92.5%, respectively, and the rates of good outcomes at the end of 18 months of treatment were 67.5% and 63.4%, respectively, with no statistically significant difference; the incidence of psychiatric abnormalities in the combined drug group was higher than that in the single-use bedaquiline group (3.7% vs15.0%, P=0.02), which may be related to the higher simultaneous combination of terizidone and high-dose isoniazid. Increased age (HR=1.039) and use of deramani (HR=3.504) are independent risk factors for the occurrence of at least 1 450 ms during the QTcF interval. Nevertheless, all patients affected by the QTcF interval in this study did not reach 500 ms in the QTcF interval, and had no cardiac symptoms, and did not discontinue the use of Dramani. It is suggested that bedaquiline combined with deramani is relatively safe.
2021 AIDS Clinical Trials Group (AIDS Clinical Trials Group, ACTG) announced the results of Phase II clinical trial A5343 [38]. A total of 84 MDR/RR-TB patients were randomly assigned to bedaquiline combined with OBR group, deramani combined with OBR group and deramani combined with bedaquiline group, and deramani combined with bedaquiline group were compared with the differences in efficacy and safety of the three groups. The results showed that in the 24-week SCC, 95% of the group used in the combination of deramani and bedaquiline was 91%, and 92% of the group used in the single-use deramani group. In terms of safety, no adverse events of grade 3 or 4 QT interval prolongation occurred in the three groups. The combination of deramani and bedaquiline has no obvious superposition effect on the QTcF interval.
South Korea explored the effectiveness and safety of sequential use of deramani and bedaquiline. The sequential use of deramani and bedaquiline were used in different orders and the differences between the two groups were compared. [39]. After sequential use of the drug for 12 months, the overall SCC was 93.6% (44/47), and the overall good outcome rate was 91.9% (68/74).There was no difference in the SCC and good treatment outcome rates in different sequential groups; fluoroquinolones resistance and positive sputum culture during the interval between the use of two new drugs are risk factors for adverse outcomes.
Based on existing data, the WHO believes that the effectiveness data of the combination of deramani and bedaquiline is relatively limited, and has not yet made a formal recommendation for the combination of the two drugs, but it is proposed that the two drugs can be used in patients with limited treatment options. In terms of safety, WHO believes that the combination of the two drugs will not cause additional safety problems, but electrocardiogram and electrolyte monitoring should be strengthened during the treatment process, and other drugs in the regimen that can prolong the QT interval or cause potential adverse events [7].
V. Recommended clinical application of Delamani
(I) Adapting to population [1, 2, 3, 4, 5, 6, 7, 36, 40, 41, 42]
The data on evaluating the existing effectiveness and safety of Delamani based on the GRADE method is limited. It is recommended that when patients with tuberculosis cannot form an effective treatment plan due to drug resistance, contraindications or intolerance in group A or group B, delamani can be used as part of the combination treatment plan for the treatment of MDR/RR/XDR-TB patients (including HIV carriers), and the following two points are taken into account:
1. Applicable for ages 3 to 65 years;
2. The effectiveness in the treatment of patients with extrapulmonary tuberculosis has not been determined, but if there are no absolute contraindications, especially in central nervous system drug-resistant tuberculosis, delamani can be considered when the expected benefits exceed the potential risks.
Description: Group A and Group B drugs refer to WHO's 2020 "Module 4: Treatment of Drug-resistant Tuberculosis" recommended drug grouping for long-term MDR-TB regimen [4] , Group A drugs: levofloxacin/ moxifloxacin , bedaquiline, linezolid; Group B drugs: clofazimin, cycloserine /terizidone.
(Bi) Contraindications [1, 2, 3, 4, 5, 6, 7, 36, 40, 41, 42]
1. People who are allergic to nitroimidazoles and pyrrole drugs such as metronidazole , tinidazole ;
2. People who are serum albumin 28 g/L;
3. People who are taking CYP3A4 strong inducer drugs (such as carbamazepine);
4. People who are 500 ms during the QTcF interval (confirmed by repeated ECG);
5. Women who are pregnant or women who may be pregnant.
(III) Relative contraindications [1, 2, 3, 4, 5, 6, 7, 36, 40, 41, 42]
For patients with the following risk factors, the potential benefits exceed the potential risks and the expert group's discussion and approval can only be initiated. At the same time, the patients should undergo close monitoring throughout the entire Delamani treatment.
1. People with moderate and severe liver injury, severe renal function injury, alcohol or drug addict;
2. People with the following cardiac risk factors;
(1) Congenital QT interval prolongation syndrome or any disease that can prolong the QT interval;
(2) History of symptomatic arrhythmia or clinically related bradycardia;
(3) Any heart disease that can induce arrhythmia, such as high blood pressure grade 3 and poor blood pressure control , left ventricular hypertrophy (including hypertrophic cardiomyopathy ) or congestive heart failure accompanied by a decrease in the left ventricular ejaculation fraction ;
(4) electrolyte disorder , especially hypokalemia, hypocalcemia or hypomagnesemia ;
(5) are taking drugs known to prolong the QT interval, including (but not limited to):
① Antiarrhythmic drugs, such as amiodarone , disopylamide, dofelitide, ibriter, procaineamide, quinidine, hydrogenated quinidine, sotalol , etc.;
② Antipsychotic drugs, such as phenothiazine , serindole, suctopriligy, chlorpromazine , haloperidol, mesodazine, pimozide, thioridazine, and antidepressants;
③Certain antibiotics, Including: macrolides, such as erythromycin , clarithromycin, etc.; moxifloxacin, sparfloxacin; triazole antifungal drugs; pentamidine; saquinavir;
④Certain non-sedative antihistamines, such as terfenadine, astemidazole, imidazostin, etc.;
⑤ Other cardiac risk factors drugs: cisapride, fluperido, domperidone , benprodiil, dibenmani, probuco, levomethalol, methadone, vinblastine, arsenic trioxide.
3. People with moderate to severe sleep disorders, moderate to severe mental illnesses, and severe gastrointestinal disorders.
(IV) Dosage, usage and formulation of chemotherapy regimen
1. Dosage and usage: The recommended dosage for adults in Dramani is 100 mg/time, 2 times/d, regardless of weight, and it is taken continuously for 24 weeks. It is recommended to take medicine after meals. If you missed the dose, take the next dose immediately; if the dose is close to the time of taking the next dose, you do not need to take the dose, and take the next dose as planned. At present, the evidence of validity and safety in use for more than 6 months is insufficient. Use exceeding the restrictions should follow the WHO Best Practice Statement [39] . It is recommended to extend it at designated medical institutions for drug-resistant tuberculosis after collective discussion by experts.
2. Development of the Delamani-containing regimen: According to the results of reliable drug sensitivity tests, Delamani should combine with at least 3 drugs that are sensitive to the patient's isolate. After taking Delamani for 24 weeks, the remaining drugs need to be taken until the required course of treatment, and the drug can only be stopped after the efficacy is determined. In the absence of reliable drug sensitivity test results, Delamani should combine with at least 4 drugs that are sensitive to the patient's isolate. Drugs that may be sensitive are those that have never been used or have been used for less than 3 months, or are the primary drugs in treatment options that have been shown to be effective in previous treatments. Delamani cannot be added alone to chemotherapy regimens that have been proven to fail after clinical application.
(V) The use of delamani in special populations
Based on existing studies and WHO recommendations, it is recommended that children aged ≥3 years old can use delamani for restrictive use: 25 mg/time, 2 times/d for children aged 3 to 5 years old; the dose is 50 mg/time, 2 times/d for children aged 6 to 11 years old; the dose is 100 mg/time, 2 times/d for children aged 12 to 17 years old. Delamani can be used in HIV-infected patients, but interactions with antiviral drugs need to be taken into account and closely monitored.
(VI) Delamani and bedaquiline combined with
Although the WHO believes that there is currently no sufficient data to accurately evaluate the effectiveness of the combined use of delamani and bedaquiline, when drug-resistant patients have limited anti-tuberculosis drugs and cannot form an effective anti-tuberculosis regimen, when the potential benefits outweigh the potential risks, the use of delamani and bedaquiline can be considered at the same time or sequentially. Before and during the treatment, the electrocardiogram and blood electrolyte should be closely monitored, and adverse reactions should be detected early and early treatment should be handled.If sequential treatment is used, WHO recommends sequential medications with deramani first and bedaquiline, and gives 5 days of elution time of deramani. However, it should be noted that before adding the second new drug, the negative transformation of Mycobacterium sputum culture and the efficacy of intermediate treatment must be evaluated. Only when the new drug can be combined with 3 or more effective antituberculosis drugs can another new drug be added.
(VII) Adverse events and handling principles
In patients treated with Dramani combined with OBR, common adverse reactions are: nausea, vomiting, headache, insomnia, dizziness, tinnitus, hypokalemia, gastritis, loss of appetite, fatigue, palpitations and QT interval prolongation, mental abnormalities, sensory abnormalities, tremors , anxiety, etc. Before inclusion in treatment, contraindications and relative contraindications need to be strictly checked. During the medication process, liver and kidney function, electrolytes, blood, routine , and electrocardiogram are required to be checked every 2 to 4 weeks. When adverse drug events occur, they shall be treated in a timely manner in accordance with relevant Chinese standards and guidelines. To ensure the smooth progress of anti-tuberculosis treatment, if the adverse reaction symptoms are mild or moderate, active symptomatic treatment can be given first, and suspicious drugs are not necessary for the time being; if there is no improvement after treatment and the symptoms gradually worsen, suspicious drugs can be stopped and the symptoms can be observed to improve after the drug is stopped. If the electrocardiogram indicates that the QTcF interval is prolonged by more than 500 ms, the core electrogram should be re-extended first. If it is repeatedly confirmed that it is still prolonged, discontinue the use of Dramani and its related suspicious drugs to check the blood potassium, calcium and magnesium levels. It is recommended to keep the blood potassium level higher than 4 mmol/L and the blood magnesium level higher than 0.74 mmol/L. If the QTcF interval is between 450 and 500 ms and the patient has no obvious clinical cardiovascular symptoms, he or she may temporarily stop taking relevant suspicious drugs to increase the frequency of electrocardiogram reexamination.
(VIII) Precautions
1. All patients who need to use Delamani should submit to the expert group of designated medical institutions for drug-resistant tuberculosis for discussion, and the expert group will evaluate the indications and screening contraindications, and formulate corresponding chemotherapy plans.
2. All users of Delamani should have informed consent and sign an informed consent form. Informed consent includes the role of Delamani, efficacy and possible adverse reactions, the basis for adding Delamani to the treatment plan, possible benefits and potential risks.
3. Patients aged 65 years old currently have limited validity and safety data and should be used with caution.
4. Patients with respiratory failure with lung lesions should weigh the pros and cons of using Delamani and should be closely monitored throughout the treatment period.
5. Drug Interaction:
(1) Interaction with other anti-tuberculosis drugs: The interaction between Dramani and other anti-tuberculosis drugs in the human body has not been fully elucidated. Moxifloxacin is not currently recommended in patients with MDR-TB. If combined use of both drugs is inevitable, high-frequency electrocardiogram monitoring is recommended for patients throughout the Delamani treatment.
(2) Interaction with antiretroviral drugs: When delamanib was administered with the moderate CYP3A4 inducer efaviren, the blood concentration of the two drugs did not change significantly, but we should be wary of neuropsychiatric adverse events (such as euphoria and abnormal dreams) [43] ; when delamanib was combined with the strong CYP3A4 inhibitor lopinavir/ritonavir, the exposure of the metabolite DM-6705 of the delamanib increased, and there was a risk of QT prolongation. It is recommended to use [43, 44] with caution.
6. Strengthen treatment management, promptly detect and deal with adverse drug reactions. It is recommended to monitor 2 or 4 weeks after the first dose, and then monitor regularly every month. Monitoring items include: liver and kidney function, blood routine, urine routine, electrolytes, electrocardiogram, clinical symptoms and weight, etc. Plasma albumin levels should be paid attention to during the use of Delamani.
7. This product contains lactose. This product cannot be taken by patients with the following diseases: rare hereditary galactose intolerance, Lapp lactase deficiency, and glucose-galactose malabsorption.
8. Delamani needs to be combined with other anti-MTB drugs to form an effective anti-tuberculosis regimen, and adherence to the entire course of treatment is required. Missing or not completing the entire course of treatment may lead to a decrease in therapeutic effectiveness and increase the possibility of MTB resistance.
9. Strengthen health education, raise funds through multiple channels, ensure the supply of drugs, ensure patients' treatment compliance, complete the prescribed course of treatment, and avoid premature cessation of medication and irregular medication.
The good clinical efficacy and safety of dramani bring new hope to the treatment of MDR/RR-TB patients. Rational use of Delamani to reduce the occurrence of adverse drug reactions and drug resistance is an urgent problem that needs to be solved at present. In addition, more than 10 clinical trials are underway or are about to be carried out regarding the interaction between delamani and common drugs, the application of extrapulmonary tuberculosis, tuberculosis in special populations, and non-tuberculous mycobacteria. In the future, more clinical trials are needed to provide evidence-based medical evidence to facilitate the improvement and standardization of delamani's clinical application.
Personal: Wu Guihui, Gao Mengqiu
Member of the expert group (units are sorted by pinyin, experts are sorted by surname pinyin):
Anhui Provincial Chest Hospital (Liu Shengsheng, Wang Hua); Beijing Tsinghua Chang Geng Hospital (Lin Minggui); Changsha Central Hospital (Bai Chengli , Pei Yi); Chengdu Public Health Clinical Medical Center (Chen Qing, He Wei, Huang Tao, Shi Zhengyu, Wu Guihui); Chongqing Public Health Medical Treatment Center (Yan Xiaofeng, Yang Song); Chongqing Medical University First Affiliated Hospital (Wang Pu); Fujian Fuzhou Pulmonary Hospital (Chen Xiaohong); Guangzhou Chest Hospital (Tan Shouyong); Harbin Chest Hospital (Guo Chunhui, Wang Lianzhi); Hangzhou Normal University Affiliated Hospital (Xu Jintian); Hangzhou Red Cross Hospital ( Cai Qingshan); the Eighth Medical Center of the General Hospital of the People's Liberation Army (Liang Jianqin); Shandong Provincial Public Health Clinical Center (Xiong Yu); Beijing Chest Hospital Affiliated to Capital Medical University/Beijing Tuberculosis Chest Oncology Research Institute (Ding Weimin, Duan Jian, Duan Hongfei, Gao Jingtao, Gao Mengqiu, Li Liang, Liang Chen, Liu Yuhong, Ma Liping, Feng Yu, Qiao Min, Tang Shenjie, Wu Xiaoguang, Yu Jiajia); Taiyuan Fourth People's Hospital (Chang Yunqing, Wang Lihua); Tianjin Haihe Hospital ( Mei Zaoxian); Shanghai Pulmonary Hospital Affiliated to Tongji University (Fan Lin, Gu Jin, Hao Xiaohui, Liu Yidian, Sha Wei, Yao Lan); West China Hospital of Sichuan University (Chen Xuerong); Suzhou Fifth People's Hospital (Tang Peijun, Wu Meiying); Wuhan Pulmonary Hospital (Du Juan, Yuan Baodong); Institute of Microbiology, Chinese Academy of Sciences (Liu Cuihua)
References (omitted)
