Exploratory pharmacokinetic-pharmacodynamic analysis of 3736 plasma samples from 1053 patients enrolled in voriconazole therapeutic studies found that the rate of treatment success appeared proportionately lower in patients with mean plasma concentrations less than 0.5 g/mL than in patients with concentrations between 0.5 and 5 g/mL.99 The difference in clinical outcome was not statistically significant, however, because of the heterogeneous response rates in each quartile of drug exposurea reflection of the varied response rate among different patient groups included in the analysis (ie, those receiving transplants, those with lymphoma, those with leukemia). sharing sensitive information, make sure youre on a federal The metric used to determine appropriate dosing in hepatic disease is the Child-Pugh scoring system, which is appropriate for patients with chronic liver dysfunction but not for patients who have acute hepatic injury. Rogers PD, Jenkins JK, Chapman SW, et al. From the University of Houston College of Pharmacy and The University of Texas M. D. Anderson Cancer Center, Houston. Global Epidemiology of Mucormycosis. Blocks with dotted lines indicate fungal genera/species in which resistance is common. Antifungals: From Pharmacokinetics to Clinical Practice. Unlike posaconazole, genetic variability in metabolism plays a more important role in the patient-to-patient pharmacokinetic variability of voriconazole.46 Polymorphisms in the CYP2C19-encoding gene result in 3 populations of patients with markedly different rates of nonlinear voriconazole clearance despite the administration of the same fixed daily dose: (1) homozygous patients who extensively metabolize voriconazole, (2) heterozygous patients with moderate clearance rates of voriconazole, and (3) homozygous patients who metabolize drug poorly through this pathway and have slow rates of voriconazole clearance.47 The poor metabolism genotype is more common in some ethnic groups, such as patients of Asian or Pan-Pacific origin (14%-19%), than in patients of African origin or whites (2%).47 In contrast, pediatric patients often exhibit more rapid linear clearance of voriconazole, which may result in low or undetectable serum drug concentrations at standard adult doses.48,49 Therefore, higher weight-based doses are recommended in children (7 mg/kg every 12 hours, sometimes increased up to 12 mg/kg every 12 hours without a loading dose) (Table 1). 2004;48:35433551. Therefore, it is important to have an appreciation of the differences among these drugs with regard to their pharmacokinetic properties, including absorption, distribution, metabolism, and excretion. sharing sensitive information, make sure youre on a federal In addition, antacid therapy does not have a negative effect on absorption [41, 75]. Neuroprotective effect of lansoprazole against cisplatin-induced brain toxicity: Role of Nrf2/ARE and Akt/P53 signaling pathways. 3. Oral itraconazole solution is also relatively safe but can be associated with nausea and diarrhea severe enough to force discontinuation. Am J Respir Crit Care Med. Curr Clin Pharmacol. Epub 2010 Oct 15. Absorption is not affected by food consumption, gastric pH, or disease state [38, 39]. Tissue penetration of antifungal agents. Newer broad-spectrum triazoles, in particular voriconazole and posaconazole, display significant variability in bloodstream concentrations from one patient to the next that may necessitate TDM in select situations to guide drug therapy and dosing. Satish S, Jimnez-Ortigosa C, Zhao Y, Lee MH, Dolgov E, Krger T, Park S, Denning DW, Kniemeyer O, Brakhage AA, Perlin DS. In general, the cyclodextrin solution is more efficiently absorbed (i.e., the area under the concentration curve [AUC] is increased by 30%) than is the capsule formulation [40]. Until the early 1990s, the lack of oral treatment options left intravenous therapy as the only alternative for the treatment of invasive fungal infections. [New systemic antifungal drugs: mechanisms of action, drug interactions and side effects]. Clinicians now have access to an expanded number of antifungal agents; however, the panacea of antifungal therapy remains to be found. Itraconazole, voriconazole, posaconazole and isavuconazole are metabolised in the liver. Unlike amphotericin B and the earlier imidazole antifungal agents (miconazole, ketoconazole), fluconazole possessed excellent oral bioavailability; predictable linear pharmacokinetics with wide distribution into many tissues, including the cerebral spinal fluid and vitreous chamber of the eye; and a much lower risk of drug interactions and toxicity in critically ill patients compared with earlier azoles.2 Fluconazole was also effective for the treatment of oropharyngeal candidiasis in patients with AIDS; however, resistance could be problematic in patients receiving prolonged treatment who had declining CD4+ cell counts.3 Fluconazole quickly became one of the most widely prescribed antifungal agents for mucosal and systemic yeast infections. However, with these new therapies comes a need for increased awareness of the limitations in their spectrum of activity, pharmacokinetics, and risk for pharmacokinetic drug interactions. Azole and polyene antifungal agents exert their antifungal effects by targeting ergosterolthe principal cell membrane sterol of many pathogenic fungi. This article was supported by an educational grant from Schering-Plough. Accessibility Suggested dose modifications for antifungal agents, by type of organ dysfunction. 2023 Jun 2. doi: 10.1007/s12098-023-04592-y. Table 6 reviews the major comparative toxicities of the systemic antifungal agents available for management of invasive fungal disease. Substitutions at methionine 220 in the 14alpha-sterol demethylase (Cyp51A) of, Candida krusei, a multidrug-resistant opportunistic fungal pathogen: geographic and temporal trends from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005, Variation in susceptibility of bloodstream isolates of, Systemic antifungal agents: drug interactions of clinical significance, Activity of terbinafine against serious fungal pathogens. government site. Thus, this agent should be administered on an empty stomach. Toxicity profiles also play a major role in the treatment of fungal disease, and differences among the antifungal classes, as well as agents within a given class, must be understood. Similarly, patients with possible or proven invasive aspergillosis who have random voriconazole serum concentrations less than 2.05 g/mL were shown to have poorer treatment responses.100 Subsequent studies in adults101 and pediatric patients48 have also demonstrated that the probability of successful outcome while receiving voriconazole therapy declines when trough serum concentrations in patients are less than 1 g/mL. -, Felton T, Troke PF, Hope WW. The effect of this on protein binding of drugs may result in higher concentrations of available or active drug; however, this concept has not been sufficiently studied with regard to a potential effect on antifungal drug dosing or efficacy [79, 8486]. More recent data, however, suggest that this effect is not reproducible in infected patients receiving the drug [99, 100]. [(accessed on 3 March 2020)]; Available online: Bongomin F., Gago S., Oladele R.O., Denning D.W. Ophthalmologic fungal infections are also difficult to treat. Another mechanism involved in drug-drug interactions relates to the role of P-glycoprotein (P-gp). Table 5 outlines the appropriate conditions for monitoring, target concentrations, and the association between this information and clinical outcomes, either therapeutic or toxic. Unable to load your collection due to an error, Unable to load your delegates due to an error. This problem has been solved with the introduction of triazole antifungal agents; however, the degree of absorption varies considerably from one drug to the next (Table 1). eCollection 2023. Variable gastrointestinal absorption does occur with the other members of this class, however, and, for one compound (itraconazole), it varies according to the specific formulation. Med. Its concentrations in lung and kidney are intermediate and relatively low myocardium and brain. Your comment will be reviewed and published at the journal's discretion. Optimization of therapies through targeted application of various kinetic and dynamic principles may be one strategy to maximize the cost-effectiveness of treatment of invasive fungal infections. Serum drug concentration monitoring for antifungal agents. In contrast, posaconazole absorption is optimized when administered with a high-fat meal or a similar composition nutritional supplement, such as Boost Plus (Novartis Nutrition) [46]. As with antibacterial therapy, the routes of administration and elimination are often important considerations in selecting a drug. 2023 Apr 12;16:2167-2178. doi: 10.2147/IDR.S372546. Flucytosine and fluconazole display low protein binding and are eliminated by the kidney. Many systemic antifungal agents undergo some degree of hepatic metabolism before elimination. Micafungin does have weak inhibitory properties against CYP3A4 and has been shown to increase serum concentrations of substrates of this enzyme. An official website of the United States government. Posaconazole has been well tolerated in clinical trials to date. 2023 May 9;12(5):884. doi: 10.3390/antibiotics12050884. A comprehensive knowledge and understanding of the pharmacodynamics of antifungal drugs elucidates dose-response relationships and is expected to lead to optimized dosage regimens in various circumstances. Cureus. Sci. According to studies by Glasmacher et al90,91 in patients with hematologic malignancy receiving itraconazole prophylaxis, patients who did not achieve trough concentrations of greater than 0.5 g/mL (determined by high-performance liquid chromatography) by the first week were at significantly higher risk of subsequent breakthrough aspergillosis. AMB = amphotericin; ANID = anidulafungin; CAS = caspofungin; 5-FC = flucytosine; FLU = fluconazole; ITRA = itraconazole; MICA = micafungin; POSA = posaconazole; VORI = voriconazole. New Horizons in Antifungal Therapy. Bone marrow suppression and hepatotoxicity are the most common dose-limiting toxicities of 5-FC and have been strongly linked to serum peak concentrations greater than 100 g/mL. This review summarizes published pharmacokinetic data on four classes of antifungal agents used in the neonatal population. The frequency and timing of serum sampling for triazole TDM is not well established. After intravenous administration, AMB dissociates from deoxycholate, binds to plasma lipoproteins, and accumulates in the spleen and liver. Therapeutic drug monitoring has long played an important role in improving the safety of 5-FC because the drug is frequently administered with nephrotoxic agents such as amphotericin B that cause wide fluctuations in drug clearance. Yet, many of these newer antifungal agents have important limitations in their spectrum of activity, pharmacokinetics, and unique predisposition for pharmacokinetic drug-drug interactions and unusual toxicities associated with long-term use. Additionally, these targets can be amplified or changed due to several types of mutations, such as amino acid substitution. 2019;5:26. doi: 10.3390/jof5010026. Oxford University Press is a department of the University of Oxford. Therefore, the use of these formulations in patients with creatinine clearance <50 mL/min, in the case of voriconazole, and 30 mL/min, in the case of itraconazole, is cautioned for these formulations [41, 45]. Fluconazole and voriconazole both have oral bioavailability exceeding 90% and can be administered without regard to food (fluconazole) or preferably on an empty stomach (voriconazole).40 Itraconazole capsules and posaconazole suspension require food to prolong gastric residence time to enhance drug dissolution, which is not an issue with the oral cyclodextrin formulation of itraconazole that is administered on an empty stomach. The purpose of this review is to discuss the studies on treatment with antifungal agents with relevance to their pharmacokinetic interaction. Therefore, although considerable progress has been achieved since the dawn of systemic antifungal therapy in the 1950s, the current antifungal armamentarium is far from perfect. With judicious use of the available agents, we are able to successfully and safely treat a growing number of life-threatening infections. Protein binding with the echinocandin class varies from 85% to 99% for anidulafungin, caspofungin, and micafungin [4, 46, 47, 5153, 80, 81]. Azoles are substrates and inhibitors of cytochrome P450 (CYP) isoenzymes and are therefore involved in numerous drug-drug interactions. No single antifungal agent is appropriate for all patients for a given mycosis because of patient-specific comorbid conditions, hypersensitivities, risk of drug interactions, immunosuppression, site of infection, and risk of infection with more intrinsically antifungal-resistant pathogens. See this image and copyright information in PMC. Each agent has been shown to decrease nephrotoxicity in comparison with the conventional preparation of amphotericin B [28]. D.A. Epub 2023 May 19. Key pharmacokinetic characteristics of systemic antifungal agents are summarized in Table 1. Absorption. Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Reprints or correspondence: Dr. Elizabeth S. Dodds Ashley, Div. Although a detailed discussion of drug interactions is beyond the scope of this review, several recent reviews have been published on this topic.50,57-59, Cytochrome P450 (CYP) Inhibition Profile of Triazole Antifungal Agents, Finally, the site of infection is an important consideration in the selection of antifungal therapy because some antifungal agents have limited distribution to anatomically privileged sites, such as the central nervous system and vitreous fluid, or, in the case of oral itraconazole and posaconazole, may not achieve sufficient concentrations in the bloodstream to treat hematogenous infection (Table 1). The paper analyses the in-teractions with other drugs, and the impact of the fed state on the representatives of the second generation of antifungal drugs, i.e., itraconazole, voriconazole, posaconazole, and Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA. Effect of organ dysfunction on drug dosing. J. Along with new options, however, comes the need to understand the uniqueness of each agent, including its role in therapy, toxicity profile, and interactions with concomitant medications. Fungi. has received grants and research support from Ortho-McNeil; has received consultation fees from Wyeth Pharmaceuticals, Ortho-McNeil, and Elan Pharmaceuticals; has received honoraria from Pfizer and Ortho-McNeil; and is on the paid speakers' bureaus of Ortho-McNeil, Wyeth Pharmaceuticals, and Elan Pharmaceuticals. These toxicities seem to occur less frequently than with other members of the triazole class [113]. Another example is the cyclodextrins, which are present in the intravenous preparations of itraconazole and voriconazole and can accumulate in renal disease. 8600 Rockville Pike The .gov means its official. To aid clinicians in implementing these principles, serum drug concentration monitoring is now available for several of the available antifungal agents. Introduction: [Antifungals cellular targets and mechanisms of resistance]. This was based on data obtained in studies of healthy volunteers who received these drugs in combination as part of phase 1 development of caspofungin. Caspofungin concentrations are decreased when administered with CYP450 inducers, such as rifampin and phenytoin [98]. Itraconazole (1992) was a partial solution to the limitations of fluconazole because the drug had improved activity against endemic fungi and Aspergillus species, but the oral dosing formulations were plagued by erratic absorption (capsules)4 or adverse gastrointestinal (GI) effects (solution formulation)5 that limited its effectiveness in cancer patients with mucositis or nausea and vomiting.6. Newer triazoles currently under investigation (ie, isavuconazole) appear to have a spectrum of activity similar to voriconazole and posaconazole, with less pharmacokinetic variability and drug interactions.14 Efforts under way to reformulate the posaconazole suspension into better oral and intravenous dosage forms could address many of the drug's pharmacokinetic shortcomings. Disclaimer. Similar to azole antifungal agents, the allylamine terbinafine inhibits ergosterol biosynthesis by inhibiting squalene monoxygenasean enzyme in fungi responsible for conversion of squalene to squalene epoxide, which is a precursor to lanosterol in the ergosterol synthesis pathway.20 Although allylamines do not seem to have the same collateral effects on human CYP enzymes as azole antifungal agents, drugs such as rifampin that strongly induce CYP metabolism in mammals will increase the metabolism of terbinafine.25 Once taken orally, terbinafine concentrates in the skin and nail beds and has relatively low bloodstream concentrations.26 Consequently, its use as a systemic antifungal agent is primarily restricted to the treatment of onychomycosis and cutaneous fungal infections.26. Traditionally, topical therapies have been used for these infections, especially when the disease is limited to superficial infection. Colored dots refer to specific antifungal drug classpolyenes (blue), pyrimidine analogues (purple), triazoles (green), and echinocandins (orange). Bethesda, MD 20894, Web Policies The oral bioavailability of voriconazole is >90% when the stomach is empty, but it decreases when food is present [44, 45]. Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Comparative Pharmacokinetic and Pharmacodynamic Properties of Systemic Antifungal Agentsa, Several classes of antifungal agents must be administered intravenously, including amphotericin B and the echinocandins, because these agents are not sufficiently absorbed from the GI tract. Although it is a weak substrate for cytochrome P450 (CYP450), the metabolism of micafungin does not appear to be affected by inhibitors or substrates of this enzyme system. 2012;8:512. However, patients may prefer to take itraconazole solution with food because of GI intolerance and the unpalatable aftertaste of the solution.41. official website and that any information you provide is encrypted The echinocandins exhibit fungicidal activity against many Candida species, making this drug class a desirable alternative to the azole agents, which exhibit only static activity against yeasts [35, 36]. Yet, many of these newer antifungal agents have important limitations in their spectrum of activity, pharmacokinetics, and unique predisposition for . Unable to load your collection due to an error, Unable to load your delegates due to an error, Sixty-five years of antifungal therapy. 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