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雾化吸入阿米卡星溶液和阿米卡星脂质体，在临床上有什么优劣势？
雾化吸入阿米卡星溶液和阿米卡星脂质体（Amikacin Liposome Inhalation Suspension, ALIS）在临床应用中各有优劣势，主要体现在药代动力学、疗效、安全性以及适应症等方面。
阿米卡星脂质体（ALIS）的优势
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靶向肺部递送，降低全身毒性：
- ALIS是一种脂质体剂型，旨在通过吸入给药，实现药物在肺部的靶向和局部递送，同时最大限度地减少全身暴露 。这对于传统静脉注射阿米卡星来说是一个显著的改进，因为静脉注射阿米卡星常受限于严重的全身不良反应，如肾毒性和耳毒性 。
- 在健康大鼠的研究中，ALIS表现出在所有肺叶和区域的剂量依赖性沉积，并且脂质体和阿米卡星的标记物显示弥漫性细胞外共定位，随后被巨噬细胞摄取并逐渐消除 。这表明ALIS能够有效进入肺部感染部位并被局部细胞吸收，从而在感染部位达到高药物浓度。
- 群体药代动力学模型评估显示，在治疗难治性非结核分枝杆菌（NTM）肺病的患者中，每天一次ALIS给药后，血清和尿液中阿米卡星的全身暴露量显著低于静脉注射阿米卡星的报告值 。特别是在基线和大约6个月的每日给药后，血清中的中位最高浓度（Cmax）和曲线下面积（AUC）均较低（< 2 mg/L 和 < 20 mg·h/L），尿液中原型阿米卡星的排泄分数也低于吸入剂量的10% 。
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提高肺部药物浓度，增强疗效：
- ALIS能够使阿米卡星在痰液中的浓度远高于血清浓度，这表明它能够在感染部位实现更高的药物浓度 。在CONVERT研究中，服药后1-4小时内痰液中阿米卡星的中位浓度很高（242-426 μg/g），并在8小时内下降（中位7 μg/g）。这种局部高浓度有助于更有效地清除病原体。
- 在治疗难治性鸟分枝杆菌复合群（MAC）肺病的III期CONVERT临床试验中，ALIS联合标准指南治疗（GBT）相比单独GBT显著提高了培养转阴率 。具体而言，ALIS+GBT组有29.0%的患者在第6个月实现培养转阴，而单独GBT组仅为8.9% 。这意味着ALIS能够更有效地清除MAC感染。
- 对日本患者进行的亚组分析显示，ALIS+GBT组的痰培养转阴率（26.5%）也高于单独GBT组（0%），与总体研究结果一致 。
- 除了早期转阴率，ALIS还显示出持续和持久的培养转阴效果。在CONVERT研究中，ALIS+GBT组有16.1%的患者实现了持续和持久的培养转阴（治疗12个月内痰培养阴性，治疗结束后3个月痰培养阴性），而单独GBT组为0% 。在实现转阴的患者中，ALIS+GBT组有55.4%的患者达到了持续和持久转阴，而单独GBT组为0% 。
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减少复发率：
- 在CONVERT研究中，ALIS+GBT组的治疗结束后3个月的复发率为9.2%，而单独GBT组为30.0% 。这表明ALIS有助于维持治疗效果，降低疾病复发的风险。
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适用人群更广：
- ALIS尤其适用于对GBT治疗无效或无法耐受静脉注射阿米卡星的患者 。由于其较低的全身毒性，ALIS可能对老年患者具有吸引力，因为他们更容易出现肾毒性风险 。希腊的一项观察性研究也表明，ALIS对因严重不良反应而停用静脉注射氨基糖苷类药物的难治性或复发性NTM肺病患者是有效和安全的 。
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长期使用的安全性与疗效：
- 开放标签扩展研究（INS-312）评估了ALIS+GBT治疗12个月的安全性、耐受性和疗效。结果显示，呼吸道治疗相关不良事件（TEAE）常见，但肾毒性和听力下降不常见，并且培养转阴效果在治疗6个月后仍持续 。即使在长达20个月的ALIS使用中，呼吸道TEAEs仍然常见，但肾毒性和听力下降发生率低，且培养转阴持续超过6个月 。
阿米卡星脂质体（ALIS）的劣势
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呼吸道不良事件发生率高：
- ALIS联合GBT治疗与呼吸道不良事件的风险增加相关 。在CONVERT研究中，ALIS+GBT组有87.4%的患者报告了呼吸道不良事件（主要是发音困难、咳嗽和呼吸困难），而单独GBT组为50.0% 。这些不良事件主要发生在治疗的前8个月 。
- 在希腊的观察性研究中，最常见的ALIS相关不良反应是轻微且局限于呼吸道的，只有一名患者因过敏性肺炎停药 。
- 开放标签扩展研究也再次证实，呼吸道TEAEs在ALIS治疗患者中很常见 。
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临床益处尚待完全确立：
- 尽管ALIS在微生物学结果（如培养转阴率）方面显示出显著疗效，但其对临床益处（如症状改善、肺功能改善等）的证据仍有限，需要进一步研究来确立 。一些研究指出，目前ALIS的有效性证据主要局限于微生物学结果，其临床益处尚未完全确定 。
- PLoS One上的一篇系统性综述指出，ALIS可以提高痰培养转阴率并实现早期可持续和持久的阴性痰培养，但需要更多大规模研究来证实这些结果 。
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成本和可及性：
- 作为一种新型脂质体制剂，ALIS的成本可能高于传统的雾化阿米卡星溶液，并且其可及性可能受到地域和医保政策的限制。
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特定群体的数据有限：
- 目前的临床试验主要集中在MAC肺病患者，对于其他NTM种类引起的肺病，ALIS的疗效和安全性数据相对有限，需要进一步研究 。
传统雾化阿米卡星溶液的优势
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成本较低，可及性较高：
- 传统阿米卡星溶液作为一种广谱氨基糖苷类抗生素，价格相对较低，且在临床上广泛应用，可及性较好。
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已被用于多种肺部感染：
- 尽管在NTM感染中的应用受到限制，但传统雾化氨基糖苷类药物已被用于治疗多种肺部感染，包括囊性纤维化患者的铜绿假单胞菌感染 。
传统雾化阿米卡星溶液的劣势
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全身吸收与毒性风险：
- 传统雾化阿米卡星溶液虽然旨在局部作用，但仍存在一定程度的全身吸收，可能导致全身毒性，如肾毒性和耳毒性，尤其是在长期或大剂量使用时。这也是为何静脉注射阿米卡星常受限于这些不良反应，而ALIS试图通过脂质体技术解决此问题 。
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肺部药物浓度难以持久：
- 传统雾化剂型可能难以在肺部维持持久且足够高的药物浓度，这可能导致药物清除不彻底或需要更频繁的给药。
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对难治性MAC感染疗效有限：
- 对于ALIS的适应症——难治性MAC肺病，传统GBT（其中可能包含静脉或口服阿米卡星，但全身毒性限制了其长期应用）的培养转阴率远低于ALIS+GBT 。这意味着在难治性MAC感染中，传统治疗方案的疗效不佳。
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缺乏脂质体保护，易被清除：
- 非脂质体形式的阿米卡星在肺部可能更容易被巨噬细胞或其他机制清除或降解，导致局部作用时间缩短，不如脂质体包裹形式能够持续释放和作用 。
总结
综合来看，阿米卡星脂质体（ALIS）在治疗难治性MAC肺病方面具有显著优势，主要体现在其能够通过脂质体技术实现肺部的靶向递送，提高局部药物浓度，显著增加培养转阴率，并降低全身毒性风险，尤其适用于无法耐受静脉注射阿米卡星的患者。其优势在于疗效更佳、复发率更低、全身毒性更小。然而，其主要劣势是呼吸道不良事件发生率较高，且对其他NTM种类和临床益处的证据尚需进一步积累。
传统雾化阿米卡星溶液的优势在于成本较低、可及性高。然而，它在难治性MAC感染中的疗效有限，且仍存在一定的全身毒性风险，肺部药物浓度可能难以持久。
因此，在临床选择上，对于难治性MAC肺病患者，特别是那些对传统治疗无效或无法耐受静脉注射阿米卡星的患者，ALIS是更优的选择 。而对于其他肺部感染，或在成本和可及性受限的情况下，传统雾化阿米卡星溶液仍可能是一种选择，但需权衡其疗效和潜在的全身毒性。
References
1Amikacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Caused by Complex (CONVERT). A Prospective, Open-Label, Randomized Study.PubMed
David E Griffith, Gina Eagle, Rachel Thomson, et al.
Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by complex (MAC). To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Enrolled patients (ALIS + GBT, = 224; GBT-alone, = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57; < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).
2Amikacin Liposomal Inhalation Suspension for Non-Tuberculous Lung Infection: A Greek Observational Study.PubMed
Angeliki A Loukeri, Evgenia Papathanassiou, Aikaterini Kavvada, et al.
Intravenous amikacin, recommended for severe or recurrent (MAC) infections and as initial treatment for lung disease, is often limited by serious adverse effects such as renal and auditory toxicities. Inhaled Amikacin Liposome Inhalation Suspension (ALIS) enhances pulmonary drug deposition while minimizing systemic adverse effects, and it has recently been introduced as an add-on therapy for refractory MAC infections or when other standard treatments are inadequate. This study aims to retrospectively describe the outcomes of Greek patients with difficult-to-treat non-tuberculous mycobacterial (NTM) lung disease following the addition of ALIS to guideline-based therapy. Seventeen consecutive patients (median age: 66 years) treated with ALIS as an add-on therapy to a standard regimen at "Sotiria" General Hospital of Chest Diseases (Athens, Greece) from 2020 to 2023 were enrolled in this study. These patients had recurrent or refractory NTM lung disease and/or limited treatment options due to prior treatment-related adverse effects. Clinical, radiological, and microbiological data on treatment response and overall outcomes after ALIS initiation were recorded for each patient. By the end of 2023, 14 out of 17 patients had either successfully completed or were continuing their ALIS therapy. At 6 months, 85.7% (12/14) showed clinical, microbiological, and radiological improvement. However, 25% (3/12) of treated patients, primarily those with monomicrobial or combined lung disease, experienced disease relapse after therapy completion. The most frequent adverse effects related to ALIS were mild and localized to the respiratory tract, with only one patient discontinuing therapy due to hypersensitivity pneumonitis. Adding ALIS to standard regimens was effective and safe in a small group of Greek patients with refractory or recurrent NTM lung disease, particularly those who had discontinued intravenous aminoglycosides due to significant adverse effects, with notable responses observed in MAC lung disease. Further research is needed to validate these findings in clinical practice and to investigate ALIS's role in NTM lung disease caused by other species.
3Amikacin Liposome Inhalation Suspension for Complex Lung Disease.PubMed
Austin Golia, Brenden R Mahmood, Yaniset Fundora, et al.
To review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, administration, and role of amikacin liposome inhalation suspension (ALIS) in treatment of complex (MAC) lung disease.<br/> A PubMed search using the terms "amikacin inhaled," "nebulized," and "liposome suspension" was performed. Selected infectious diseaseconference posters were also examined for relevant information. In addition, pertinent guidelines were reviewed.<br/> Guidelines for the management of nontuberculous mycobacterial infections from the American Thoracic Society/ Infectious Diseases Society of America and the British Thoracic Society were used to summarize guidelinebased therapy (GBT). A phase II and a phase III clinical trial were reviewed to evaluate the role of ALIS in the treatment of MAC lung disease.<br/> ALIS is a new formulation of inhaled amikacin (AMK) indicated for the treatment of MAC lung disease refractory to GBT in adults who are not candidates for intravenous AMK. An ongoing clinical trial has demonstrated that once-daily ALIS plus GBT results in higher rates of culture conversion compared with GBT alone by month 6 among patients with a mean age of 65 years. The most common adverse reactions associated with ALIS were dysphonia, cough, bronchospasm, hemoptysis, and ototoxicity. Nephrotoxicity was uncommon.<br/> ALIS has been shown to increase culture conversion rates when added to GBT in adults with difficult-to-treat MAC lung disease. ALIS is associated with high rates of pulmonary and auditory adverse reactions and a low risk of renal adverse reactions. ALIS may be an attractive treatment option for older adults who are at high risk for nephrotoxicity.
4Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease: Sustainability and Durability of Culture Conversion and Safety of Long-term Exposure.PubMed
David E Griffith, Rachel Thomson, Patrick A Flume, et al.
BACKGROUND: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). RESEARCH QUESTION: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? STUDY DESIGN AND METHODS: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. RESULTS: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. INTERPRETATION: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov.
5Amikacin Liposome Inhalation Suspension: A Review in Mycobacterium avium Complex Lung Disease.PubMed
Matt Shirley
Amikacin liposome inhalation suspension (ALIS; Arikayce) [formerly known as liposomal amikacin for inhalation, or LAI] is a liposomal formulation of the aminoglycoside antibacterial drug amikacin. The ALIS formulation, administered via inhalation following nebulization, is designed to facilitate targeted and localized drug delivery to the lungs while minimizing systemic exposure. Based on the prespecified primary endpoint analysis of the ongoing phase III CONVERT trial, ALIS has been approved in the USA for use as part of a combination antibacterial drug regimen against Mycobacterium avium complex (MAC) lung disease that is treatment refractory (i.e. an active infection present despite ≥ 6 consecutive months of a multidrug regimen) in adult patients who have limited or no alternative treatment options. In the CONVERT trial, once-daily ALIS as an add-on to guidelines-based therapy (GBT) significantly increased the odds of achieving sputum culture conversion by month 6 compared with GBT alone in patients with treatment-refractory MAC lung disease. The addition of ALIS to GBT was associated with an increased risk of respiratory adverse events compared with GBT alone; however, serious adverse events were experienced by a similar proportion of patients in the two treatment groups. In conclusion, although current evidence for efficacy is limited to microbiological outcomes (with clinical benefit yet to be established), available data suggest that ALIS is a useful option for the treatment of patients with MAC lung disease who have not responded to conventional therapy and for whom there are limited or no alternative treatment options available.
6Amikacin Liposome Inhalation Suspension for Complex Lung Disease: A 12-Month Open-Label Extension Clinical Trial.PubMed
Kevin L Winthrop, Patrick A Flume, Rachel Thomson, et al.
Patients with refractory complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population. Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT. Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed. In the ALIS-naive cohort, 83.3% of patients ( = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% ( = 32) had serious TEAEs; 26.7% ( = 24) achieved culture conversion by Month 6 and 33.3% ( = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients ( = 34/73) experienced respiratory TEAEs, and 27.4% ( = 20) had serious TEAEs; 9.6% ( = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% ( = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts. In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).
7Amikacin liposome inhalation suspension for Mycobacterium avium complex pulmonary disease: A subgroup analysis of Japanese patients in the randomized, phase 3, CONVERT study.PubMed
Kozo Morimoto, Mizu Nonaka, Yoshitaka Yamazaki, et al.
BACKGROUND: CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease were more likely to achieve culture conversion with amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) versus those continuing on GBT alone. This subgroup analysis reports the efficacy and safety of ALIS in Japanese patients enrolled in CONVERT. METHODS: Japanese patients aged ≥20 years with treatment-refractory MAC pulmonary disease from Japanese sites were included. Patients were randomized to receive once-daily 590 mg ALIS + GBT or GBT alone; patients converting by Month 6 remained in the study to complete 12-month treatment followed by a 12-month off-treatment period. Nonconverters exited the study at Month 8. The primary endpoint was the proportion of patients achieving culture conversion by Month 6. RESULTS: Of the 59 Japanese patients screened, 48 were randomized to receive ALIS + GBT (n = 34) or GBT alone (n = 14), and 41/48 (85.4 %) were women. The mean (standard deviation) age of patients was 64.5 (8.6) years, and 83.3 % of patients had bronchiectasis at baseline. By Month 6, sputum culture conversion was cumulatively achieved in 9/34 (26.5 %) patients receiving ALIS + GBT versus none receiving GBT alone. Treatment-emergent adverse events were reported in 94.1 % and 100.0 % of patients receiving ALIS + GBT and GBT alone, respectively. No deaths were reported. CONCLUSIONS: The efficacy observed in the Japanese subpopulation was largely consistent with that in the overall CONVERT study population, with more patients achieving culture conversion with ALIS + GBT versus GBT alone. Safety profiles were similar between the overall population and the Japanese subpopulation. CLINICAL TRIAL REGISTRATION: NCT02344004.
8The Use of Amikacin Liposome Inhalation Suspension (Arikayce) in the Treatment of Refractory Nontuberculous Mycobacterial Lung Disease in Adults.PubMed
Omer Khan, Nauman Chaudary
Nontuberculous mycobacteria (NTM) can cause and perpetuate chronic inflammation and lung infection. Despite having the diagnostic criteria, as defined by the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA), clinicians find it challenging to diagnose and treat NTM-induced lung disease. Inhaled antibiotics are suitable for patients with lung infection caused by and other organisms, but until recently, their utility in NTM-induced infection was not established. The most common NTM pathogens identified are the slow-growing complex (MAC) and the rapid-growing complex (MABSC), both of which include several subspecies. Other less commonly isolated species include , and . NTM strains are frequently more resistant than what is found in bacterial sputum cultures. Until recently, there was no approved inhaled antibiotic therapy for patients who were culture positive for pulmonary NTM infection. Of late, inhaled amikacin has been under investigation for the treatment of NTM-induced pulmonary infection. The FDA approved Arikayce (amikacin liposome inhalation suspension or ALIS) based on results from the ongoing Phase 3 CONVERT trial. In this study, the use of Arikayce met its primary endpoint of sputum culture conversion by the sixth month of treatment. The addition of Arikayce to guideline-based therapy led to negative sputum cultures for NTM by month 6 in 29% of patients compared to 8.9% of patients treated with guideline-based therapy alone. The effectiveness of Arikayce holds promise. However, due to limited data on Arikayce's safety, it is currently useful only for a specific population, particularly patients with refractory NTM-induced lung disease. Future trials must verify the target group and endorse the clinical benefits of Arikayce.
9Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment-Refractory Nontuberculous Mycobacterial Lung Disease.PubMed
Christopher M Rubino, Nikolas J Onufrak, Jakko van Ingen, et al.
BACKGROUND AND OBJECTIVES: Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease. METHODS: In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg. RESULTS: Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (C) was < 2 mg/L and median area under the concentration-time curve (AUC) was < 20 mg·h/L, suggesting low systemic exposure at both time points. Exposure estimates were similar between Japanese and White patients. The median unchanged amikacin fraction excreted in urine was < 10% of inhaled dose throughout the TR02-112 study, indicating that relatively small amounts reached systemic circulation. Median t was 5.5 h. Amikacin concentrations were much higher in sputum than in serum, demonstrating the ability to achieve higher drug concentration at the site of infection. Median sputum amikacin concentrations in the CONVERT study were high at 1-4 h postdose (range 242-426 μg/g) and decreased by 8 h (median 7 μg/g). CONCLUSIONS: Systemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin. TRIAL REGISTRATION: ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015).
10Amikacin liposome and Mycobacterium avium complex: A systematic review.PubMed
Moein Zangiabadian, Donya Malekshahian, Erfan Arabpour, et al.
INTRODUCTION: The prevalence of Mycobacterium avium complex (MAC) is increasing globally. Macrolide-based multidrug regimens have been recommended as the first-line treatment for patients with MAC pulmonary disease. However, developing macrolide resistance was associated with poor treatment outcomes and increased mortality. In 2018, the U.S. Food and Drug Administration approved liposomal amikacin for inhalation (LAI) to treat refractory MAC pulmonary disease. The current systematic review aimed to evaluate LAI's outcomes and adverse events in MAC pulmonary disease. METHODS: The systematic search was performed in PubMed/Medline, EMBASE, and the Cochrane Controlled Register of Trials (CENTRAL) up to March 8, 2022. The search terms included Mycobacterium avium complex, MAC, amikacin, and liposomal amikacin. RESULTS: After reviewing 1284 records, four papers met the inclusion criteria, including three clinical trials and one prospective cohort study. These studies showed that adding LAI to guideline-based therapies can increase sputum culture conversion rate and achieve early sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for three months after treatment) negative sputum culture. In addition, extended LAI use was a potential benefit in patients considered refractory to initial treatment. The most prevalent treatment-emergent adverse events (TEAE) reported in the LAI group were the respiratory TEAE. CONCLUSIONS: LAI could increase the sputum culture conversion rate and achieve early sustainable, durable negative sputum culture. However, additional large-scale research is required to confirm the results.
11Pharmacokinetic and pharmacodynamic evaluation of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infection.PubMed
Olanrewaju O Okusanya, Sujata M Bhavnani, Jeffrey Hammel, et al.
The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. Serum, sputum, and 24-h urine samples were collected on days 1 and 14 of therapy; pulmonary function tests (PFT) and sputum for quantitative microbiology were assessed at baseline and serially for 14 days. Relationships between amikacin exposure in serum and sputum and absolute change in PFT endpoints and log10 CFU of Pseudomonas aeruginosa from baseline on days 7 and 14 of therapy were assessed. On days 7 and 14, absolute change from baseline in forced expiratory volume in 1 s (FEV1), percent predicted forced expiratory volume in 1 s (FEV1 % predicted), and forced expiratory flow between 25 and 75% of forced vital capacity (FEF(25-75%)) increased by 0.24 (P = 0.002) and 0.13 (P = 0.10) liters, 7.49 (P < 0.001) and 4.38 (P = 0.03), and 0.49 (P < 0.001) and 0.42 (P = 0.02) liters/s, respectively. In addition, relative change from baseline in FEV1 % predicted was 10.8% (P < 0.001) and 5.62% (P = 0.073) on days 7 and 14, respectively. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log10 CFU and serum AUC/MIC ratio and change in log10 CFU and absolute changes in all PFT endpoints were significant. Together, these findings likely represent drug effect and warrant the further development of liposomal amikacin for inhalation.
12Pulmonary Deposition and Elimination of Liposomal Amikacin for Inhalation and Effect on Macrophage Function after Administration in Rats.PubMed
Vladimir Malinin, Mary Neville, Gina Eagle, et al.
Pulmonary nontuberculous mycobacterial (PNTM) infections represent a treatment challenge. Liposomal amikacin for inhalation (LAI) is a novel formulation currently in development for the treatment of PNTM infections. The pulmonary deposition and elimination of LAI and its effect on macrophage function were evaluated in a series of preclinical studies in healthy rats. The pulmonary deposition of LAI was evaluated in female rats (n = 76) treated with LAI by nebulizer at 10 mg/kg of body weight per day or 90 mg/kg per day for 27 days, followed by dosing of dually labeled LAI (LAI with a lipid label plus an amikacin label) on day 28 with subsequent lung histological and amikacin analyses. In a separate study for assessment of alveolar macrophage function, rats (n = 180) received daily treatment with LAI at 90 mg/kg per day or 1.5% saline over three 30-day treatment periods followed by 30-day recovery periods; phagocytic and Saccharomyces cerevisiae (yeast) killing capabilities and inflammatory mediator release were assessed at the end of each period. LAI demonstrated equal dose-dependent deposition across all lung lobes and regions. Lipid and amikacin labels showed diffuse extracellular colocalization, followed by macrophage uptake and gradual amikacin elimination. Macrophages demonstrated accumulation of amikacin during treatment periods and nearly complete elimination during recovery periods. No evidence of an inflammatory response was seen. No differences in microsphere uptake or yeast killing were seen between LAI-treated and control macrophages. Neither LAI-treated nor control macrophages demonstrated constitutive inflammatory mediator release; however, both showed normal mediator release on lipopolysaccharide stimulation. LAI is readily taken up by macrophages in healthy rats without compromising macrophage function.
13Evaluation of the pharmacokinetics and pharmacodynamics of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infections using data from two phase 2 clinical studies.PubMed
Olanrewaju O Okusanya, Sujata M Bhavnani, Jeffrey P Hammel, et al.
The pharmacokinetic-pharmacodynamic (PK-PD) relationships between serum exposure measures of liposomal amikacin for inhalation (LAI) and the change in pulmonary function test (PFT) measures and number of CFU from baseline were evaluated in cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. A dose of 70, 140, 280, or 560 mg of LAI or placebo was administered to CF patients once daily for 28 days. PFTs and sputum samples for microbiology were assessed on days 7, 14, 21, 28, 35 (for log10 CFU), and 56 (for PFTs). Serum, urine, and sputum samples were collected for PK evaluation. The relationships between efficacy endpoints (relative change in forced expiratory volume in 1 s [FEV1 {expressed in liters}] and FEV1% predicted and the absolute change in log10 CFU of P. aeruginosa from baseline) and exposure measures (dose, day 1 area under the curve [AUC], dose/MIC ratio, and day 1 AUC/MIC ratio) and baseline MIC value were assessed. The serum and urine PK data were best fit by a 3-compartment model (lung, serum, and urine) with linear clearance and interoccasional variation on total and renal clearance. Significant univariable relationships between dose or day 1 AUC and the relative change in PFT measures (P≤0.017) or the absolute change in log10 CFU from baseline (P≤0.037) on the study days were identified. Repeated-measures mixed-effects models, which showed dose- and AUC-related improvements for each efficacy endpoint (P≤0.041), predicted the observed data well. The increases in the relative change in FEV1 and FEV1% predicted of 11% and 9.9%, respectively, and a 1.23-log10 CFU reduction per 560 mg of LAI estimated on day 7 were comparable to the observed increases of 10.7% and 10.3%, respectively, and a 1.24-log10 CFU reduction on the same day. The model-estimated PFT effects were predicted to be sustained to day 28. An additional 0.451-log10 CFU reduction (P=0.022) was estimated on day 14 relative to day 7, with a persistence of effect predicted to day 35.