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Abstract
Clinical Pharmacokinetics Sixth Edition PDF Author Dr. William Spruill Pharm.D. FASHP FCCP Isbn File size 5.95 MB Year 2014 Pages 296 Language English File format PDF Category Free Medical Books,Pharmacology Download the Book Download Book Description: Concepts in Clinical Pharmacokinetics has helped thousands of students and practitioners through five editions by simplifying a.
Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its clinical efficacy. Since then, numerous clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preclinical and clinical setting. Nevertheless, insights into the pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound’s safety. In this article, we review the clinical pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further clinical research.
liposomal amphotericin B, clinical trial, fungal infection, pharmacokinetics, pharmacodynamics
The polyene class of antifungal agents remains an important option for the prevention and treatment of invasive fungal diseases, based on its broad spectrum; concentration-dependent fungicidal pharmacodynamics; potent, dose-dependent activity in a large number of animal models; and well-documented clinical efficacy. For decades, deoxycholate amphotericin B (DAmB) has been the cornerstone for the management of life-threatening fungal infections. However, its clinical utility is hampered by dose-dependent renal toxicity and infusion-associated reactions, thereby limiting therapeutic efficacy. The development of novel, less toxic, lipid-based polyene formulations in the late 1980s and early 1990s may be considered a breakthrough in antifungal chemotherapy, particularly for patients with invasive aspergillosis and mucormycosis.
This document reviews the clinical pharmacology of liposomal amphotericin B (LAmB; AmBisome®), a small, unilamellar, liposomal formulation of amphotericin B (AmB). For the purpose of this paper, the term LAmB refers exclusively to AmBisome. Emphasis is placed on the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of this compound relative to those of DAmB, providing scientific evidence for improved safety and tolerability and assessing efficacy in the management of invasive fungal diseases.
CLINICAL PHARMACOKINETICS
LAmB, in the form of AmBisome, consists of small, unilamellar vesicles of 60–80 nm in size, which are composed of hydrogenated soy phosphatidylcholine and distearoyl phosphatidylglycerol, stabilized by cholesterol and combined with AmB in a 2:0.8:1:0.4 molar ratio (Table 1) [1-6]. After intravenous administration, the liposomal carrier stays physicochemically intact for prolonged periods of time, providing an extended residence time of AmB in the central blood compartment (Figure 1) [7]. In preclinical studies, throughout all animal species, much higher peak plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) values were achieved relative to equal doses of DAmB [8]. Distribution studies in rats with 4-[(14)C]cholesterol-LAmB demonstrate that the dominant route of elimination is fecal, presumably via biliary excretion; the liver, spleen, and lungs presented with the highest levels of radioactivity, and levels in the kidney were 15% of those in the liver and lungs [9].
Pharmacokinetic and Pharmacodynamic Properties of Liposomal Amphotericin B