Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects

Conte, John E.; Golden, Jeffrey A.; Krishna, Gopal; McIver, Marina; Little, Emily E.; Zurlinden, Elisabeth

doi:10.1128/aac.00663-08

Cited by 74 publications

(68 citation statements)

References 22 publications

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“…), 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.…”

Section: Lungmentioning

confidence: 99%

“…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.…”

Section: Limitations Of Current Understanding and Approachesmentioning

confidence: 99%

“…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.…”

Section: Beyond State Of the Artmentioning

confidence: 99%

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Tissue Penetration of Antifungal Agents

Troke²,

2014

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SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection.

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Section: Lungmentioning

confidence: 99%

Section: Limitations Of Current Understanding and Approachesmentioning

confidence: 99%

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Tissue Penetration of Antifungal Agents

Troke²,

2014

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“…Notably, the posaconazole-treated cells were found to resist infection by A. fumigatus 14,18 The protective effect of cell-associated posaconazole persisted for at least 48 h after removal of free drug. 18 Measurement of posaconazole kinetics in epithelial cells demonstrated that this prolonged post-antifungal effect was due to the persistence of high levels of drug within the epithelial cells, 18 thus providing an explanation for the prolonged post-antifungal effect reported in animal studies of posaconazole.…”

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Understanding antifungal prophylaxis with posaconazole in hematology patients: an evolving bedside to bench story

2014

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F e r r a t a S t o r t i F o u n d a t i o ntotal drug, as the majority of posaconazole is associated with cellular membranes. Indeed, the addition of serum to posaconazole-loaded cells does not impair their ability to inhibit the growth of A. fumigatus in vitro. 18 In addition, the highly hydrophobic nature of posaconazole would predict that, within the vascular compartment, this agent would easily flux between plasma proteins and the more hydrophobic cell membranes of fungi. This hypothesis is also supported by in vitro experimental data in which the observed antifungal effect of posaconazole in the presence of human serum is much greater than would have been predicted based on the free drug concentrations. 20Clarifying the importance of protein binding is critically important because achievable serum free drug concentrations of posaconazole have been used to guide the selection of breakpoints for the identification of resistance to this agent when performing antifungal susceptibility testing. 13 Implications for therapeutic drug monitoring and dosing strategiesThe results of these in vitro, animal, and clinical studies are beginning to shed new light on our understanding of the mechanisms of action and efficacy of posaconazole in primary antifungal prophylaxis, and suggest the need to rethink our strategies for use of serum therapeutic drug monitoring in this setting. Studies of human and animal pharmacokinetic data for posaconazole have focused on serum levels, and there are no data available on the pharmacokinetics of membrane posaconazole in either of these populations. The prolonged antifungal effect observed in animals and the posaconazole cellular pharmacokinetic studies in vitro suggest that membrane-associated posaconazole persists long after serum levels decline, and is able to confer protection against infection. Studies are needed in both animals and patients to confirm these findings and to guide the optimal use of this agent. By extension, the available data suggest that the ability of serum drug measurements to identify patients with inadequate posaconazole membrane concentrations is likely to be limited. The development of a therapeutic test for membraneassociated posaconazole will be invaluable for better monitoring of patients, and also for guiding dosing strategies for the new tablet and intravenous formulations of posaconazole that are currently in late stage clinical trials. © F e r r a t a S t o r t i F o u n d a t i o n Donald Sheppard is Director of the Division of Infectious Diseases and Associate Professor at the Departments of Medicine

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“…Posaconazole has a large apparent volume of distribution (1,774 liters), suggesting extensive extravascular distribution and penetration into body tissues, and a long mean half-life of 35 h (9,15). Pharmacokinetic data exist for the distribution of posaconazole within plasma, epithelial lining fluid, and alveolar cells (3,6,(10)(11)(12), but there are no clinical data on the bioavailability of posaconazole for skin or its effectiveness against fungal pathogens that affect skin.…”

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Skin Concentrations and Pharmacokinetics of Posaconazole after Oral Administration

Krishna

Beresford

et al. 2010

Antimicrob Agents Chemother

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A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concentration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high-fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC 90 value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC 90 in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC 90 . POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections.Posaconazole, an extended-spectrum triazole antifungal, is approved in Europe and the United States as prophylaxis for invasive fungal infection (IFI) in high-risk patients and for the treatment of oropharyngeal candidiasis (15, 16); in Europe, it is also approved for the treatment of refractory IFI (16). Posaconazole has a large apparent volume of distribution (1,774 liters), suggesting extensive extravascular distribution and penetration into body tissues, and a long mean half-life of 35 h (9, 15). Pharmacokinetic data exist for the distribution of posaconazole within plasma, epithelial lining fluid, and alveolar cells (3, 6, 10-12), but there are no clinical data on the bioavailability of posaconazole for skin or its effectiveness against fungal pathogens that affect skin.Newer azoles, such as itraconazole and fluconazole, have been used to treat superficial infections of the skin, hair, and nails that are caused by dermatophytes (20). Although topical and oral agents are available to treat these fungal infections, oral drugs such as terbinafine (an allylamine) and itraconazole (a triazole) (20) appear to be more efficacious. Posaconazole has potent in vitro activity against dermatophytes from the genera Trichophyton (T. rubrum and T. mentagrophytes), Epidermophyton, and Microsporum, which are primarily associated with dermatophytosis, and against yeast (Candida albicans) (7). Given the antidermatophyte and antiyeast activity of posaconazole in vitro and its characteristic tissue distribution and pharmacokinetic profiles in vivo, it is of clinical interest to determine the concentration of posaconazole in the skin after oral dosing.The objectives of this study were to compare skin and plasma concentr...

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Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects

Cited by 74 publications

References 22 publications

Tissue Penetration of Antifungal Agents

Tissue Penetration of Antifungal Agents

Understanding antifungal prophylaxis with posaconazole in hematology patients: an evolving bedside to bench story

Skin Concentrations and Pharmacokinetics of Posaconazole after Oral Administration

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