AUCTORES
Globalize your Research
Research Article | DOI: https://doi.org/10.31579/2688-7517/014
Employees of Adamis Pharmaceuticals, San Diego, California.
*Corresponding Author: Ronald B. Moss, Employees of Adamis Pharmaceuticals, San Diego, California.
Citation: Ronald B. Moss, Fiona Carleton, Charles P. Lollo , Dennis J. Carlo. (2019) Comparative Pharmacokinetic Analysis of Community Use Naloxone formulations for Acute Treatment of Opioid Overdose.Addiction Research and Adolescent Behaviour 2(3); Doi: 10.31579/2688-7517/014
Copyright: © 2019 Ronald B. Moss, This is an open-access article distributed under the terms of The Creative Commons. Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 25 October 2019 | Accepted: 05 November 2021 | Published: 07 November 2019
Keywords: narcan; evzio; zimhi, naloxone; opioid; pharmacokinetics; overdose; fentanyl
Recent increases in mortality from overdoses in the US have been primarily driven by deaths due to the more potent synthetic opioids. Naloxone is an effective countermeasure to treat opioid overdose. We compared the pharmacokinetics of the three available doses of naloxone used to treat prehospital opioid overdoses. Overall, the systemic exposures of 2 mg intramuscular and 4 mg intranasal of naloxone appear to be similar. By comparison, the exposure levels of the 5 mg dose intramuscular naloxone (ZIMHI) appears to be greater and more rapid. These results support the notion that higher doses of naloxone result in greater bioavailability which may be required for reversal due to the more potent synthetic opioids, such as fentanyl.
The rapid rise of deaths in the current opioid epidemic has resulted in significant efforts by federal and local public health officials to develop countermeasures to effectively treat drug overdoses and to facilitate treatment programs for the problem of addiction [1].
Naloxone is an effective countermeasure to treat opioid overdoses and widespread use of naloxone is encouraged by public health experts, including the Surgeon General [2]. Naloxone is an opioid antagonist that competes for the mu receptors resulting in reversal of opioid toxicity. However, in spite of increased access to current formulations of naloxone, deaths due to the more potent synthetic opioids continue to increase [3]. One possible explanation for the increased mortality due to the synthetic opioids is the increased potency and rapid toxicity compared to other opioids [4]. Overdose deaths due to respiratory failure and brain hypoxia can occur within minutes of fentanyl exposure. Therefore, reaching adequate levels of naloxone in the CNS to antagonize the opioids may be a critical factor for successful reversal and survival.
ZIMHI is an investigational 5 mg intramuscular (IM) injection of naloxone hydrochloride utilizing a previously approved device [5]. Current doses for community and prehospital use of naloxone to treat opioid overdose are 2 mg IM (Evzio) or 4 mg intranasal (IN) (Narcan) [6]. Previously, we reported a pharmacokinetic study in healthy subjects comparing ZIMHI 5 mg IM dose to Evzio 2mg IM autoinjector dose. The results suggested higher Cmax and Area Under the Curve (AUC) exposures for ZIMHI compared to Evzio [7].
The purpose of this study was to compare the pharmacokinetics of the three available dose formulations of naloxone used to treat prehospital opioid overdoses. Overall, the systemic exposures of 2mg IM and 4 mg IN were comparable. By comparison, the exposure levels of the 5 mg dose IM naloxone (ZIMHI) was observed to be significantly greater and more rapid.
Data for comparison of the different formulations utilized two pharmacokinetics studies of naloxone that both enrolled healthy adults. APC 6000-03 was a Phase I, open-label, randomized, single-dose, 2- period, 2-treatment crossover bioavailability study comparing 5 mg/0.5 mL of IM naloxone HCl to 2 mg/2 mL IM naloxone HCl injection (1 mg/1 mL, International Medical Systems) in healthy subjects. Fourteen male and female subjects 18 to 55 years of age (inclusive) were enrolled in the study. APC 6000-03 was conducted in accordance with the United States (US) Code of Federal Regulations (CFR) governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug Application (21 CFR 312), and Bioavailability and Bioequivalence Requirements (21 CFR 320), as appropriate. Informed consent and Institutional Review Board (IRB) approval was obtain prior to study initiation.
The primary Pharmacokinetic (PK) endpoints for APC 6000-03 were the area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC0-inf) and the maximum observed plasma concentration (Cmax). This study consisted of a screening visit (up to 28 days before the first dosing period) and 2 study periods (each separated by a minimum of 48 hours). Subjects reported to the Clinical Research Unit (CRU) on Day -1 (Check-in) and remained at the CRU for 5 days (approximately 12 hours after Period 2, Day 4). Subjects were randomized to 1 of 2 treatment sequences on Day 1 of each study period which consisted of either ZIMIHI (5 mg/0.5 ml naloxone hydrochloride) in a prefilled syringe device, or 2mg/2 ml of naloxone hydrochloride (1 mg/1 mL, International Medical Systems) in a prefilled syringe. Subjects then crossed-over to the alternative formulation. All subjects received a single intramuscular dose of naloxone hydrochloride in the anterolateral aspect of the thigh administered on Day 1 of each period (Study Days 1 and 3).
The second study was previously published and examined different doses of Narcan [8]. The details of this study can also be found in the Narcan label [9]. The data from this study was kindly provided by Dr. Phillip Krieter, NIDA, NIH. We utilized data from the 4 mg IN group in our comparison as it is the approved dose.
A comparison of the pharmacokinetic parameters is shown in Table 1 for 2mg IM, ZIMHI and Narcan.
Figure 1a shows a comparison of the mean plasma concentration of all three different formulations of naloxone over 1 hour (a) and 12 hours (b). These data suggest the 4 mg IN (Narcan) and 2 mg IM doses have similar pharmacokinetics in terms of Cmax and AUC. In contrast, higher Cmax and AUC is observed for ZIMHI compared to the other two formulations. It is also demonstrated from figure 1a that there is a more rapid systemic exposure for ZIMHI compared to 2 mg IM and Narcan. Although not measured in the Narcan study, as noted in Table 1, the AUC’s for the first 2.5 and 5 minutes are significantly higher for ZIMHI compared to 2 mg IM dose of naloxone.
The purpose of this analysis was to compare the pharmacokinetics of three different dose formulations of naloxone approved for community and prehospital use. Naloxone can be administered in different forms including sublingual, buccal, subcutaneous, intranasal, intravenous and intramuscular. This study examined a comparison of two different doses of intramuscular naloxone with an approved nasal formulation. Results of this comparison suggest that the exposure levels of 2 mg IM and 4 mg IN are very similar. However, others have raised issues regarding factors that could affect absorption of nasal administration of naloxone in real life situations. For example, nasal absorption of naloxone could be impacted by nasally administered illicit drugs such as cocaine and nasal allergies [10]. However, in healthy normal subjects this comparison suggests the systemic levels of 2 mg IM and 4 mg IN are similar with the nasal product having about 45% bioavailability compared to IM administration [11]. Other factors involving the formulation of IN naloxone may be relevant to permeability and stability including preservatives, stabilizers, and the pH [12].
In comparison, the 5 mg IM naloxone (ZIMHI) was superior to both 4 mg IM and 2 mg IM in terms of PK exposure parameters. In addition, it is apparent that the 5 mg dose also resulted in a more rapid systemic exposure of naloxone. Because of the potency and rapid onset of the synthetic opioids, this characteristic may be critical in order to achieve a successful reversal. This notion agrees with a greater AUC during the first 2.5 and 5 minutes observed with the 5 mg naloxone dose (ZIMHI) compared to 2 mg IM.
This pharmacokinetic comparison study between three different formulations of naloxone for community use suggest that the 2mg IM and 4 mg IN formulations of naloxone provide similar systemic exposure levels in healthy subjects. In contrast, the 5 mg dose of naloxone provides higher and more rapid exposure.
Fentanyl can result in rapid respiratory failure with resulting brain hypoxia and ultimately, death. Rapid naloxone systemic exposure and egress to the mu receptors in CNS may mean the difference between life and death. The risks of underdosing with naloxone outweighs any risks particularly because of the more potent synthetic opioids that drive the current epidemic [13],
This pharmacokinetic comparison suggests that the 5 mg naloxone (ZIMHI) should result in more rapid and higher systemic levels of naloxone which may be needed to counter the more potent synthetic opioids such as fentanyl and its analogues.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
