Steady-State Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole in Lung Transplant Recipients

Abstract

This prospective study evaluated the plasma and intrapulmonary pharmacokinetics and pharmacodynamics (PKPD) of posaconazole (POS) in lung transplant recipients. Twenty adult lung transplant patients were instructed to take a 400-mg POS oral suspension twice daily (BID) with a high-fat meal for a total of 14 doses. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected at the approximate time of bronchoscopy. POS concentrations were assayed using liquid chromatography with tandem mass spectrometry. The maximum concentrations (C max ) (mean ؎ standard deviation [SD]) in plasma, ELF, and AC were 1.3 ؎ 0.4, 1.3 ؎ 1.7, and 55.4 ؎ 44.0 g/ml. POS concentrations in plasma, ELF, and AC did not decrease significantly, indicating slow elimination after multiple dosing. Mean concentrations of POS in plasma, ELF, and AC were above the MIC 90 (0.5 g/ml) for Aspergillus species over the 12-h dosing interval and for 24 h following the last dose. Area under the concentration-time curve from 0 to 12 h (AUC 0-12 )/MIC 90 ratios in plasma, ELF, and AC were 21.98, 22.42, and 1,060. We concluded that a dose of 400 mg BID resulted in sustained plasma, ELF, and AC concentrations above the MIC 90 for Aspergillus spp. during the dosing interval. Confirmation of the therapeutic value of these observations requires further investigation. The intrapulmonary PKPD of POS may be favorable for treatment or prevention of aspergillosis, although further research on the relevant PKPD parameters and the effect of POS protein binding is required.Posaconazole (POS) is a new antifungal agent with activity against Aspergillus, Cryptococcus, Candida, Histoplasma, and Blastomyces spp. and others (9,15,17,19,27). POS is approved for prophylaxis of invasive aspergillosis and candidiasis in immunocompromised patients and for the treatment of refractory oropharyngeal candidiasis. Recent reports suggest that it may also be effective in the treatment of refractory invasive aspergillosis (16, 26), zygomycosis (23), and other fungal infections (3,18).The oral bioavailability of POS is increased by ingestion of a high-fat meal and by the use of divided dosing (8, 10). There are no clinically or kinetically important metabolites of POS. POS has a high apparent volume of distribution, 1,774 liters, and a prolonged half-life, 35 h, at steady state (G. Krishna and A. Sansone-Parsons, presented at the 41st American Society of Health System Pharmacists Midyear Clinical Meeting and Exhibition, Anaheim, CA, 3 to 7 December 2006). Its pharmacokinetics (PK) are unaffected by age, gender, or race/ethnicity (21), and dose correction is not required for patients with impaired renal function (7); 66.3% of an oral POS dose is excreted unchanged in feces (12). Protein binding in human plasma is Ͼ98%. We recently reported on the intrapulmonary pharmacokinetics and pharmacodynamics (PKPD) of POS in healthy subjects (5). Maximum concentration of drug in serum (C max ) values were 2.08, 1.86, ...

Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation

“…Similar findings were presented in a case report in which posaconazole accumulation was seen in the lung, liver, spleen, and kidney tissues of a renal transplant patient (8). Our finding was also in accordance with the findings that posaconazole was accumulated in alveolar macrophages and white blood cells in humans (9)(10)(11). A recently published study using an in vitro model of pulmonary epithelial cells found accumulation of posaconazole in cell membranes, especially in the endoplasmic reticulum, which persisted for at least 48 h after the removal of extracellular posaconazole (12,13).…”

Intrapulmonary Distribution and Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Inhaled Administration of Its Prodrug, Laninamivir Octanoate, in Healthy Volunteers

“…The calculated values of AUC last for LO and laninamivir in AM were 77 to 364 times higher than those for the drugs in ELF (Table 2). High-level accumulation in AM was also observed in several human BAL studies after the oral administration of antibiotics (3,5,8,18,22). The uptake mechanism of clarithromycin and azithromycin to AM was explored using cultured AM cells (NR8383 cells), and it was found that the uptake was partly reduced by ATP depletors (21).…”

“…Drug concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from BAL fluid have been evaluated in healthy volunteers (1,5,8,18) as well as lung transplant recipients (3,22) and critically ill patients (9) to consider the efficacy of drugs against respiratory pathogens and the appropriate dosage regimens for antiinfective drugs. Among the neuraminidase inhibitors, the concentration of zanamivir in ELF after intravenous (i.v.)…”

Tissue Penetration of Antifungal Agents

“…), the ELF/plasma concentration ratio was 11 (142) (57) and lung transplant patients (143). It has been suggested that high intracellular posaconazole concentrations may explain its effectiveness for prophylaxis ( Fig.…”