The Pharmacokinetics of Drugs Delivered to the Upper Nasal Space.

IF 3.1 Q2 PHARMACOLOGY & PHARMACY
Pharmaceutical Medicine Pub Date : 2023-11-01 Epub Date: 2023-08-03 DOI:10.1007/s40290-023-00495-7
Stephen B Shrewsbury
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Abstract

Pharmacokinetics (PK) includes how a drug is absorbed, distributed, metabolized and eliminated. The compartment providing this information is usually the plasma. This is as close to the tissue of interest that we can get, although biopsies may be obtained to give "tissue levels" of drugs. Ultimately, the goal of PK is to understand how long the drug is actually engaged with the target in the tissue of interest after a dose has been administered. Most drugs at some point in their development will have been administered intravenously (IV), which acts as the standard for 100% bioavailability. By comparing various routes of administration to IV, the percentage of drug delivered to the plasma, on a dose-normalized basis, can be calculated and is referred to as the "absolute bioavailability". As pharmacology has advanced and more drugs have become available, many older products have been reformulated to be given by routes other than those originally intended (often oral). As the drawbacks of oral (or IV) administration have become better appreciated, non-oral, non-IV formulations and methods of administration have become more popular. Nasal administration is one route that has historically been overlooked as an alternative to oral administration-particularly for products needing rapid and non-invasive access to the target tissue-mostly via the blood stream. But attention is now focused on nasal administration for direct access to the brain, as that has the potential to bypass the blood-brain-barrier (BBB), which not even IV administration can always achieve. Assessing PK for these drugs targeting the brain may require serial sampling of the cerebrospinal fluid (CSF), making PK assessments of CNS drugs more invasive and complex, but still possible in future product development. However, we are now seeing more drugs reformulated for nasal delivery to gain faster systemic levels than oral administration (especially in patients with known or suspected gastrointestinal dysmotility), while avoiding the use of needles. For example, in recent years several different formulations and delivery methods for an old drug, dihydroergotamine (DHE), have been developed and these show very different characteristics, suggesting that delivery to different parts of the nose may have very different PK profiles. This review summarizes the systemic PK of different nasal DHE options that have been, or are being, developed and suggests that delivery of drugs to the upper nasal space (UNS) may represent an optimal target. Further research is required to ascertain if this route could also be utilized for direct administration to the CNS (as an attractive alternative to intrathecal delivery) via the olfactory or trigeminal nerves-but already preclinical data (and some human data) suggest this is entirely possible.

Abstract Image

药物输送到上鼻空间的药代动力学。
药物动力学(PK)包括药物如何被吸收、分配、代谢和消除。提供这种信息的隔室通常是等离子体。这与我们所能得到的感兴趣的组织非常接近,尽管可以获得活检来给出药物的“组织水平”。最终,PK的目标是了解药物在给药后与感兴趣组织中的靶标实际接触的时间。大多数药物在开发过程中的某个阶段都会通过静脉注射(IV),这是100%生物利用度的标准。通过比较静脉注射的各种给药途径,可以计算出在剂量标准化的基础上输送到血浆中的药物百分比,并将其称为“绝对生物利用度”。随着药理学的发展和越来越多的药物的问世,许多较老的产品都经过了重新配方,可以通过最初计划之外的途径(通常是口服)给药。随着口服(或IV)给药的缺点得到更好的认识,非口服、非IV制剂和给药方法变得更加流行。鼻腔给药是一种历来被忽视的替代口服给药的途径,尤其是对于需要主要通过血流快速、无创地进入目标组织的产品。但现在人们的注意力集中在直接进入大脑的鼻腔给药上,因为这有可能绕过血脑屏障(BBB),即使是静脉给药也无法始终实现。评估这些针对大脑的药物的PK可能需要对脑脊液(CSF)进行连续采样,这使得中枢神经系统药物的PK评估更具侵入性和复杂性,但在未来的产品开发中仍然有可能。然而,我们现在看到更多的药物被重新配方用于鼻腔给药,以获得比口服更快的全身水平(尤其是在已知或疑似胃肠道运动障碍的患者中),同时避免使用针头。例如,近年来,已经开发出几种不同的老药二氢麦角胺(DHE)的配方和递送方法,这些配方和递送方式显示出非常不同的特征,这表明递送到鼻子的不同部位可能具有非常不同的PK特征。这篇综述总结了已经或正在开发的不同鼻腔DHE方案的系统PK,并表明向上鼻间隙(UNS)递送药物可能是一个最佳靶点。需要进一步的研究来确定这种途径是否也可以通过嗅觉或三叉神经直接给药到中枢神经系统(作为鞘内给药的一种有吸引力的替代方案),但临床前数据(和一些人类数据)表明这是完全可能的。
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来源期刊
Pharmaceutical Medicine
Pharmaceutical Medicine PHARMACOLOGY & PHARMACY-
CiteScore
5.10
自引率
4.00%
发文量
36
期刊介绍: Pharmaceutical Medicine is a specialist discipline concerned with medical aspects of the discovery, development, evaluation, registration, regulation, monitoring, marketing, distribution and pricing of medicines, drug-device and drug-diagnostic combinations. The Journal disseminates information to support the community of professionals working in these highly inter-related functions. Key areas include translational medicine, clinical trial design, pharmacovigilance, clinical toxicology, drug regulation, clinical pharmacology, biostatistics and pharmacoeconomics. The Journal includes:Overviews of contentious or emerging issues.Comprehensive narrative reviews that provide an authoritative source of information on topical issues.Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by PRISMA statement.Original research articles reporting the results of well-designed studies with a strong link to wider areas of clinical research.Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Pharmaceutical Medicine may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.All manuscripts are subject to peer review by international experts. Letters to the Editor are welcomed and will be considered for publication.
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