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Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring.

ABSTRACT: Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

SUBMITTER: Dolton MJ

PROVIDER: S-EPMC3370770 | biostudies-other | 2012 Jun

REPOSITORIES: biostudies-other

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Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring.

Dolton Michael J MJ Ray John E JE Marriott Deborah D McLachlan Andrew J AJ

Antimicrobial agents and chemotherapy 20120305 6

Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely acc ...[more]

PMID: 22391534

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Project description:BACKGROUND:Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially because of inconsistencies in sirolimus exposure-response relationships. METHODS:The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary health care system from 2008 to 2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to simulate sirolimus concentrations, and (3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors determined relationships between sirolimus exposure and adverse events (AEs) (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal function) and the composite efficacy end point of graft loss or rejection. RESULTS:The developed 2-compartment population PK model showed appropriate goodness of fit. In a late-phase (>12 months), postrenal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (P = 0.018) and decline in renal function (P = 0.006), respectively. CONCLUSIONS:Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function. However, the method was limited in its assessment of other AEs. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly transplanted patients with a higher propensity toward AEs or efficacy failure.

Dataset Information

Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring.

Publications

Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring.

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