Pharmacokinetics Of Antifungal Agents Research Articles

Pharmacokinetics of Antifungal Agents in Neonates and Young Infants

The prevention and treatment of pediatric fungal infections are limited by the fact that not all antifungal drugs are approved for the pediatric age and appropriate dosages have not been established for each age group. The management of neonates and infants with invasive fungal infection is becoming more complex with an increasing number of antifungal agents available. Dosing information, is not available for newer antifungals and is limited with older antifungal agents. Insufficient neonatal studies have been performed with newer agents and there are numerous differences between neonates, children and adults with invasive fungal infection. Kinetic parameters such as the half-life [t(½)], clearance [CL], and volume of distribution [Vd] change with development, therefore the kinetics of antifungals need to be studied in order to optimize therapy with these drugs. A reasonable aim of pediatric dosing is to ensure levels of drug exposure which are comparable to those achievable in adults and which approximate those for which antifungal efficacy has been established. Therefore it will be of clinical relevance to ascertain the dosages of antifungals which produce an equivalent magnitude of exposure to that observed in adults. Drug therapy, studies on prescription and dosing should consider differences between neonates, infants and toddlers, children and adolescents in terms of drug disposition: absorption, metabolism and elimination/excretion. Determining the safety and pharmacokinetics of antifungals in neonates addresses an unfulfilled medical need given that data are sparse in neonates; at present, reports of antifungal pharmacokinetics in the treatment of neonatal fungal infections are limited to case series. The aim of this article is to review the pharmacokinetics of old and new antifungal drugs in neonates and young infants in a single article in order to provide a critical analysis of the literature. It will be important to evaluate all newly developed antifungals in neonates and infants to assure their maximum efficacy and safety. More pharmacokinetic data are required to ensure that the dose recommended for the treatment of fungal infections in the neonate achieves evidence based medicine.

Invasive Aspergillosis in Children With Acquired Immunodeficiencies

Invasive aspergillosis has emerged as an important cause of morbidity and mortality in immunocompromised children. It remains difficult to diagnose, and outcome depends on early diagnosis, appropriate treatment, and restoration of host defenses. Pediatric patients represent a unique population in their clinical presentation and epidemiology, particularly in respect to the utility of newer diagnostic tools and the pharmacokinetics of antifungal agents. This article reviews the presentation and epidemiology of invasive aspergillosis in children and adolescents with acquired immunodeficiencies and discusses the value of current diagnostic tools and the options for treatment and prevention in this population.

Pharmacokinetics of antifungal agents in children

Invasive fungal infections in immunocompromised children are common and often fatal. The first antifungal agents such as amphotericin B and fluconazole offered effective treatment, but their use was often limited by toxicity and resistance. Numerous new antifungal agents have since been developed and appear to be as effective. Most dosing and safety trials have been done in adults, and extrapolation of this data to children has proven inadequate. We reviewed the literature regarding the pharmacokinetics/pharmacodynamics (PK/PD) and safety of antifungal agents with an emphasis on the newer azoles and echinocandins. From a small but growing number of PK/PD trials, better dosing guidelines have been developed.

Antifungal Therapy in Pregnancy and Breastfeeding

Antifungal therapy during pregnancy and lactation is challenging because of a lack of data on efficacy and safety, coupled with reports of teratogenicity. Although the Food and Drug Administration pregnancy category provides guidance regarding a drug’s potential fetal risks, limitations such as lack of a specific toxic dose or predisposing pregnancy trimester thwart its application. Central to the selection of optimal antifungal therapy are exploration of the literature and assessment of patient-specific factors, including awareness of effects on the pharmacokinetics of antifungal agents that result from physiologic changes during pregnancy. Topical azoles are favored for superficial fungal infections during pregnancy and lactation, whereas amphotericin B is preferred for invasive fungal infections. Data regarding the use of antifungal agents by breastfeeding women are lacking. More studies are needed, particularly with newer antifungals, to better guide clinicians in selecting optimal antifungal therapy that will provide benefit to the mother without harm to the fetus.

Invasive fungal infections in pediatric patients: a review focusing on antifungal therapy

Invasive fungal infections in children appear to have increased over the past few decades. Substantial differences compared with adult patients in risk factors, pathogen epidemiology, pathophysiology and, most notably, pharmacokinetics of antifungal agents require age-adapted management and treatment approaches. The present article reviews these aspects for invasive aspergillosis and invasive candidiasis, the two most common life-threatening fungal infections.

Pharmacokinetics of an Elevated Dosage of Micafungin in Premature Neonates

Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/d) dose of micafungin. A repeated dose, open-label pharmacokinetic, and safety trial of intravenous micafungin in 12 preterm neonates >48 hours of life with suspected systemic infections. Neonates received 15 mg/kg/d of micafungin for 5 days. Blood samples were drawn relative to either the fourth or fifth dose. Systemic exposure was assessed by examination of the plasma area under the curve. The median birth weight and gestational age of the neonates were 775 g and 27 weeks, respectively. No adverse events related to micafungin were detected. The mean area under the curve and clearance for the cohort was 437.5 microg'h/mL and 0.575 mL/min/kg, respectively. The calculated clearance and volume of distribution for neonates was greater than that observed in older children and adults. These data suggest that 15 mg/kg dosing in premature neonates corresponds to an exposure of approximately 5 mg/kg in adults. No adverse events related to micafungin were observed.

Pharmacokinetics of antifungal agents in onychomycoses.

Onychomycosis is caused by infection by fungi, mainly dermatophytes and nondermatophyte yeasts or moulds; it affects the fingernails and, more frequently, the toenails. Dermatophytes are responsible for about 90 to 95% of fungal infections. Trichophyton rubrum is the most common dermatophyte; Candida albicans is the major nondermatophyte yeast. Although topical therapy of onchomycosis does not lead to systemic adverse effects or interactions with concomitantly taken drugs, it does not provide high cure rates and requires complete compliance from the patient. At present there are 3 oral antifungal medications that are generally used for the short term treatment of onychomycosis: itraconazole, terbinafine and fluconazole. The persistence of these active drugs in nails allows weekly administration, reduced treatment or a pulse regimen. Good clinical and mycological efficacies are obtained with itraconazole 100 to 200 mg daily, terbinafine 250mg daily for 3 months, or fluconazole 150 mg weekly for at least 6 months. Itraconazole is a synthetic triazole with a broad spectrum of action. It is well absorbed when administered orally and can be detected in nails 1 to 2 weeks after the start of therapy. The nail : plasma ratio stabilises at around 1 by week 18 of treatment. Itraconazole is still detectable in nails 27 weeks after stopping administration. Nail concentrations are higher than the minimum inhibitory concentration (MIC) for most dermatophytes and Candida species from the first month of treatment. The elimination half-life of itraconazole from nails is long, ranging from 32 to 147 days. Terbinafine is a synthetic allylamine that is effective against dermatophytes. Terbinafine is well absorbed from the gastrointestinal tract, and the time to reach effective concentrations in nail is 1 to 2 weeks. The half-life is from 24 to 156 days, explaining the observed persistence of terbinafine in nails for longer than 252 days. Fluconazole is a bis-triazole broad spectrum antifungal with high oral bioavailability. The uptake of fluconazole by nail increases with the length of treatment, and nail : plasma ratios are generally 1.5 to 2 at steady state. Fluconazole concentrations exceed the MIC for Candida species soon after the start of treatment. Fluconazole concentrations fall slowly after the drug is stopped, with a half-life of 50 to 87 days, and fluconazole is still detectable in nails 5 months after the end of treatment. All these drugs are potent inhibitors of cytochrome P450 (CYP) enzymes and may increase the plasma concentrations of concomitantly used drugs. Itraconazole inhibits CYP3A4. Fluconazole inhibits CYP3A4, but to a lesser degree than itraconazole, CYP2C9 and CYP2C19. Terbinafine inhibits CYP2D6.

Pharmacokinetics of Antifungal Agents

The authors have evaluated the pharmacokinetics of four antifungal agents used in the therapy of fungal peritonitis. Amphotericin B (Amph B) poorly diffuses from blood into peritoneal fluid, which intraperitoneal administration induces severe abdominal pain. 5-Fluorocytosine (5FC) easily crosses peritoneum, but resistance may appear when the drug is used alone. Ketoconazole (K) poorly penetrates into peritoneal fluid, while Fluconazole (F), used per os or intraperitoneally, shows a good antifungal activity both in serum and in the peritoneal fluid. In conclusion, from a pharmacokinetic point of view, all the antifungal agents examined, perhaps with the exception of F, do not offer, when used alone, sufficient guarantees in curing peritonitis. Therefore, for treating fungal infections in CAPD, drug combinations such as AmphB + 5FC, K + 5FC or 5FC+F have to be used.