Intrapulmonary Pharmacokinetics and Pharmacodynamics of Itraconazole and 14-Hydroxyitraconazole at Steady State

Abstract

Itraconazole (ITRA) is a triazole antifungal agent that has been used successfully for the treatment of aspergillosis, candidiasis, coccidioidomycosis, blastomycosis, cryptococcosis, and histoplasmosis (7,10,13,25,32,35,39,40). The recommended oral and intravenous dose in adults is 200 mg once or twice daily. Bioavailability is approximately 55% after administration of the oral solution. At steady state, the maximum concentration of drug in serum (C max ), time to C max , minimum concentration of drug in serum (C min ), and half-life in humans receiving 200 mg twice daily are approximately 2.3 g/ml, 4.6 h, 1.9 g/ml, and 65 h (8,21,22,33). The main metabolite, 14-hydroxyitraconazole (OH-IT), is present in plasma at concentrations that are approximately twice those of the parent drug, and OH-IT is approximately as active, on a weight basis, as ITRA (23, 28). Although ITRA is approved for the treatment of fungal respiratory infection, the in vivo concentrations of ITRA and OH-IT in pulmonary alveolar cells (AC) and pulmonary epithelial lining fluid (ELF) in humans have not been reported. The purpose of this study was to determine the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered ITRA in healthy volunteers. MATERIALS AND METHODSStudy design and subjects. This was a prospective, nonblinded study of the plasma and intrapulmonary concentrations of ITRA at steady state. All subjects gave written informed consent and were required to be 21 to 55 years of age and have a body mass index from 18 to 29 (5). Subjects agreed to abstain from alcohol for 48 h prior to and during the study period. The evaluation included a medical history, physical examination, and baseline laboratory testing, including complete blood count with differential, platelet count, and blood urea nitrogen, serum creatinine, aspartate aminotransferase, alanine aminotransferase, gamma glutaryl transferase, alkaline phosphatase, and total bilirubin urinalysis with microscopy. The evaluation was repeated following bronchoscopy. The serum human chorionic gonadotropin hormone was performed on female subjects at baseline and immediately prior to the first dose. Subjects were excluded if they had a history of clinically significant disease, clinically significant abnormal findings at the screening physical examination (including laboratory tests), intolerance to ITRA, ketoconazole, or lidocaine; if they were pregnant and/or lactating, had a history of drug abuse within 1 year of the start of the study, a positive drug screen, history of smoking within the previous year, or were required to take prescription medications (including oral contraceptives) or nonprescription drugs (including protein pump inhibitors and H-2 antagonists) within 7 days of the study; and if they had known problems with malabsorption or other conditions affecting drug absorption or had received an investigational drug within 30 days prior to the study. Twenty-six subjects were assigned to one of five groups of five subjects, each accordi...

Determination of Antifungal Activities in Serum Samples from Mice Treated with Different Antifungal Drugs Allows Detection of an Active Metabolite of Itraconazole

“…The conversion of itraconazole to an active metabolite, hydroxy-itraconazole, has also been confirmed in humans (8,9). The antifungal titer obtained in our results suggested that the pharmacodynamic activity of the metabolite was comparable to that of itraconazole in mice as well as humans (4,13,23,31). The parent compound and its active metabolite would shared in vivo activities against C. albicans and A. fumigatus in mice.…”

Tissue Penetration of Antifungal Agents

“…Fluconazole also readily penetrates the extracellular space of the rat lung (fluid/plasma concentration ratio of 1.38), and this is unaffected by inflammation (138). Itraconazole exhibits ELF exposures that are one-third of the plasma AUC in human volunteers, while the AUC in alveolar cells is more than double that of the plasma (56). In postmortem samples from four hematology patients, the mean lung tissue/plasma concentration ratio of itraconazole was 7 (139), while Heykants and colleagues (73) reported concentrations 0.9 to 2.4 times higher than those in the plasmas of four patients.…”

“…For this reason, it may be more useful to present the tissue area under the concentrationtime curve (AUC) for comparison. There are few studies that do this for humans (56,57,58,59,60,61,62), and with one exception (59), all deal with pulmonary distribution. Most of the antifungal agents considered in this review do exhibit hysteresis.…”

“…Estimating concentration-time profiles (and thereby calculating the AUC in tissues) is possible using population pharmacokinetic modeling techniques. Relatively few studies have done this for humans to date (56)(57)(58)(59)(60)(61)(62), and all but one (59) deal with pulmonary distribution.…”

Farmacología de los azoles

“…Con itraconazol y tras la administración oral de 200 mg cada 12 h en dosis múl-tiple, se observaron resultados similares que incluyen concentraciones elevadas dentro de las células alveolares [7].…”