Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis

Zhang, Hongfei; Nguyen, M.H.; Clancy, Cornelius J.; Joshi, Rujuta; Zhao, Wenchen; Ensor, Chris; Venkataramanan, Raman; Shields, Ryan K.

doi:10.1128/aac.00424-16

Cited by 14 publications

(11 citation statements)

References 20 publications

(23 reference statements)

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“…Zhang and colleagues found that LTR with CF had average steady state concentrations 61% lower than non-CF LTR using posaconazole suspension. 30 In reviewing subjects that had concentrations below goal in our study, 36.4% had cystic fibrosis. In the 11 patients with CF, the mean daily dose was 200 mg and mean serum concentration was 1.5 mcg/mL.…”

Section: Discussionmentioning

confidence: 78%

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Low dose posaconazole delayed release tablets for fungal prophylaxis in lung transplant recipients

Kozuch

Feist

Yung

et al. 2018

Clinical Transplantation

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In November 2013, posaconazole delayed release (DR) tablets were approved by the FDA with the labeled dose of 300 mg daily for fungal prophylaxis. There are no studies demonstrating the appropriate dose in lung transplant recipients (LTR). We performed a 2-center retrospective cohort study of LTR taking posaconazole DR tablets for prophylaxis between January 2014 and January 2017. Mean serum trough concentrations and percentage of measurements ≥0.7 mcg/mL were compared by daily dose. Forty-nine subjects with 156 steady state serum posaconazole concentrations were included. There was a significant difference in percentage of first measured concentration ≥0.7 mcg/mL by initial daily dose (P = .04). The mean serum posaconazole concentration by dose was 0.9 (±0.42) mcg/mL for 100 mg daily, 1.66 (±0.91) mcg/mL for 200 mg daily, 2.39 (±1.49) mcg/mL for 300 mg daily, and 1.75 (±0.21) mcg/mL for 400 mg daily (P < .001). Mean concentrations were at goal in 63.3%, 96.9%, 94.9%, and 100% of subjects taking 100 mg, 200 mg, 300 mg, and 400 mg daily respectively (P = .04). Our results suggest that doses less than 300 mg daily of posaconazole DR tablets may be adequate to achieve target serum concentrations in LTR. Larger studies are needed to confirm these findings.

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Section: Discussionmentioning

confidence: 78%

“…Fishers exact test was used to compare the proportion of measured serum concentrations reaching a target of ≥0.7 mcg/mL. 30 In reviewing subjects that had concentrations below goal in our study, 36.4% had cystic fibrosis. R version 2.15.3 software was used to analyze data.…”

Section: Discussionmentioning

confidence: 99%

Low dose posaconazole delayed release tablets for fungal prophylaxis in lung transplant recipients

Kozuch

Feist

Yung

et al. 2018

Clinical Transplantation

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“…As one example, we did not find a significant difference in AUC 0 -24 h or C trough among 7 patients with cystic fibrosis (CF) and 19 patients without CF. In general, patients with CF have increased V and fast clearance (26), and low voriconazole and posaconazole exposures have been documented in this population (27,28). It is also important to recognize that all of our patients were non-Hispanic whites, and all received i.v.…”

Section: Discussionmentioning

confidence: 93%

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Clancy

Rivosecchi

et al. 2018

Antimicrob Agents Chemother

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Isavuconazole may be useful in treating and preventing fungal infections in solid-organ transplant (SOT) recipients due to its safety profile and activity against Aspergillus and some Mucorales. Isavuconazole has favorable pharmacokinetics based on clinical trials in various patient populations, but data are limited in SOT recipients. We evaluated the steady-state pharmacokinetics of isavuconazole in 26 SOT recipients receiving the drug intravenously for prophylaxis. There was moderate interpatient variability in isavuconazole pharmacokinetic parameters (coefficients of variation of 51% for the area under the plasma concentration-versus-time curve [AUC] and 59% for the trough plasma concentration [C trough ]). AUC and steady-state C trough were significantly lower in women, patients with a body mass index of Ն18.5 kg/m 2 , and those receiving hemodialysis. Trough plasma concentrations were highly correlated with AUCs (R 2 ϭ 0.94) and can serve as a suitable measure of isavuconazole exposure in patients. In conclusion, moderate interpatient variability in isavuconazole exposure, the identification of factors associated with lower exposure, the recognition that C trough is a surrogate marker for AUC, and the availability of a simple analytical method suggest that therapeutic drug monitoring (TDM) may be useful for guiding treatment in at least some SOT recipients. Future studies are needed to correlate isavuconazole exposure with patients' clinical outcomes and to determine the clinical role of TDM.

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“…The apparent CL/F observed upon administration of the posaconazole suspension in patients is significantly higher than in healthy volunteers and differs among different patient populations. Patients with persistent febrile neutropenia or refractory IFD, patients from ICU, and cystic fibrosis patients after lung transplantation appear to have high CL/F values (283.0, 195.0 and 143.2 L/h, respectively) [27,36,69], compared with those suffering from AML/MDS/HSCT (42.5-67.0 L/h) [35,37,38]. In general, the difference in F plays an important role in the substantial differences of posaconazole reported absolute clearance with the intravenous formulation and apparent clearance with the oral suspension.…”

Section: Biotransformation and Eliminationmentioning

confidence: 99%

“…As the steady-state trough concentration for posaconazole delayed-release tablet is significantly higher than for the suspension both in cystic fibrosis (CF) (1.1 mg/L vs. 0.19 mg/L) and in non-CF lung transplant patients (1.9 mg/L vs. 0.47 mg/L) [69,148], the delayed-release tablet form is considered a promising alternative to the suspension with satisfactory drug exposure and good tolerance. In lung transplant patients, patients with CF showed significantly lower posaconazole concentrations compared to non-CF patients with both oral formulations [69,148,149], which can increase the risk of subtherapeutic concentration in this subgroup, especially for the suspension.…”

Section: Patients With Cystic Fibrosismentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Posaconazole

Chen

Krekels

Verweij

et al. 2020

Drugs

109

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Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.

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Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis

Cited by 14 publications

References 20 publications

Low dose posaconazole delayed release tablets for fungal prophylaxis in lung transplant recipients

Low dose posaconazole delayed release tablets for fungal prophylaxis in lung transplant recipients

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Pharmacokinetics and Pharmacodynamics of Posaconazole

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