Effect of Oral Posaconazole on the Pharmacokinetics of Cyclosporine and Tacrolimus

Sansone-Parsons, Angela; Krishna, Gopal; Martinho, Monika; Kantesaria, Bhavna; Gelone, Steven P; Mant, Tim

doi:10.1592/phco.27.6.825

Cited by 127 publications

(113 citation statements)

References 41 publications

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“…The observed increase in the serum creatinine over the course of the study was likely due to the fact that concomitant administration of azoles and tacrolimus results in a substantial increase in tacrolimus blood levels (20). This effect is usually countered by reducing the tacrolimus dose, but such reduction was originally felt not to be necessary because of the short duration of this study.…”

Section: Vol 54 2010 Posaconazole Pkpd In Lung Transplant Recipientmentioning

confidence: 95%

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

Conte

DeVoe²,

Little

et al. 2010

Antimicrob Agents Chemother

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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, ...

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Section: Vol 54 2010 Posaconazole Pkpd In Lung Transplant Recipientmentioning

confidence: 95%

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

Conte

DeVoe²,

Little

et al. 2010

Antimicrob Agents Chemother

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“…185 Inhibitor and substrate of P-gp. 86 Inhibition of CYP3A4 185 results in increased levels of ciclosporin, tacrolimus 186 and midazolam. 185 Genetic polymorphisms of P-gp did not affect posaconazole exposure in healthy individuals.…”

Section: Interaction Commentsmentioning

confidence: 99%

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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“…On the basis of its CYP3A4-inhibitory activity, posaconazole increases the exposure to CsA, warranting a recommendation for close monitoring of blood CsA levels and subsequent CsA dose adjustment, as required. It is noteworthy that the posaconazole prescribing information also includes a recommendation for upfront reduction of the dose of CsA upon initiation of combined treatment (17), which emerged from a very small study of cardiac transplantation (16) and has never been analyzed in allo-BMT recipients. In these patients, the potential occurrence of subtherapeutic blood CsA levels, even transiently, has a strong negative impact on GVHD and on the outcome of allo-BMT (5,6,11,12,14,19).…”

mentioning

confidence: 99%

“…However, very little is known about the impact of posaconazole on CsA. The original prescribing information recommendation to reduce the dose of CsA upon the initiation of combined treatment with posaconazole (17) results from a study of only four cardiac transplant recipients, three of whom required a CsA dose reduction because of important decreases in its clearance (16). The only report on the impact of posaconazole on CsA in allo-BMT comes in abstract format in a subset of 19 patients from the registration trial whose blood CsA level data were available, showing an increase in the CsA concentration-to-dose ratio after the start of posaconazole (10).…”

mentioning

confidence: 99%

Effect of Posaconazole on Cyclosporine Blood Levels and Dose Adjustment in Allogeneic Blood and Marrow Transplant Recipients

Sánchez-Ortega

Vázquez

Montes

et al. 2012

Antimicrob Agents Chemother

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eThe posaconazole prescribing information recommends an upfront cyclosporine dose reduction upon initiation of posaconazole prophylaxis. We examined this recommendation in the early phase of allogeneic transplantation, where cyclosporine levels potentially becoming subtherapeutic following upfront dose reduction would be deleterious to transplant outcome. Our data show that while posaconazole leads to an increase in cyclosporine levels, subsequent cyclosporine dose reduction can be safely guided by therapeutic drug monitoring and is not required upfront. Therefore, the current recommendation may be modified. Posaconazole is a novel triazole with broad-spectrum antifungal activity and a favorable toxicity profile (4, 7) that is currently approved for primary antifungal prophylaxis in allogeneic blood and marrow transplantation (allo-BMT) recipients with graft-versus-host disease (GVHD) (18). Posaconazole prophylaxis in allo-BMT recipients is normally administered in combination with immunosuppressive drugs for GVHD prophylaxis and/or treatment, most commonly cyclosporine (CsA). On the basis of its CYP3A4-inhibitory activity, posaconazole increases the exposure to CsA, warranting a recommendation for close monitoring of blood CsA levels and subsequent CsA dose adjustment, as required. It is noteworthy that the posaconazole prescribing information also includes a recommendation for upfront reduction of the dose of CsA upon initiation of combined treatment (17), which emerged from a very small study of cardiac transplantation (16) and has never been analyzed in allo-BMT recipients. In these patients, the potential occurrence of subtherapeutic blood CsA levels, even transiently, has a strong negative impact on GVHD and on the outcome of allo- BMT (5,6,11,12,14,19). The clinical need for such an upfront CsA dose reduction in patients starting posaconazole in this clinical setting ought to be studied.We have recently reported on the clinical efficacy and safety of primary antifungal prophylaxis with posaconazole during the early phase of allo-BMT (15). Here we present an analysis of the impact of posaconazole prophylaxis on CsA management in this clinical setting. Since potential subtherapeutic blood CsA levels pose the highest risk during the early posttransplant period, for this study we prospectively decided not to reduce the dose of CsA at the start of combined treatment with posaconazole. Instead, blood CsA levels were monitored at least three times weekly and the dose was adjusted as required to maintain trough CsA levels within the therapeutic range (125 to 300 ng/ml) or if CsA-related toxicity occurred. Other than this, all patients received posaconazole in keeping with the recommendations for administration in the product prescribing information. A total of 41 recipients of a first allo-BMT were included in this study (Table 1), with institutional approval by the clinical research ethics committee (CEIC Bellvitge; EPA 008/08). Patients were on steady-state CsA twice daily as a 2-h intravenous infusion for GVHD...

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Effect of Oral Posaconazole on the Pharmacokinetics of Cyclosporine and Tacrolimus

Cited by 127 publications

References 41 publications

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

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

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Effect of Posaconazole on Cyclosporine Blood Levels and Dose Adjustment in Allogeneic Blood and Marrow Transplant Recipients

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