Posaconazole plasma exposure correlated to intestinal mucositis in allogeneic stem cell transplant patients

Vanstraelen, Kim; Prattes, Juergen; Maertens, Johan; Lagrou, Katrien; Schoemans, Hélène; Peersman, Nele; Vermeersch, Pieter; Theunissen, Koen; Mols, Raf; Augustijns, Patrick; Annaert, Pieter; Hoenigl, Martin; Spriet, Isabel

doi:10.1007/s00228-016-2057-6

Cited by 23 publications

(15 citation statements)

References 39 publications

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“…Similar findings were documented in another group of haematological patients , in lung transplanted patients and in healthy volunteers receiving a 400 mg daily dose . The presence of gastro‐intestinal mucositis is not associated with the risk of posaconazole underexposure during the use of delayed‐release tablets in two previous studies .…”

Section: Discussionsupporting

confidence: 85%

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Co‐administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed‐released tablets in adult patients with haematological malignancies

Cojutti

Candoni

Lazzarotto

et al. 2018

Brit J Clinical Pharma

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Section: Discussionsupporting

confidence: 85%

“…Marked variability in posaconazole exposure is still observed in PK studies of the delayed‐released tablet formulation . Patients receiving 300 mg daily have a median posaconazole C min concentration of 1.08–1.89 mg l −1 at steady state with a concentration range of <0.1–7.89 mg l −1 .…”

Section: Discussionmentioning

confidence: 99%

Co‐administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed‐released tablets in adult patients with haematological malignancies

Cojutti

Candoni

Lazzarotto

et al. 2018

Brit J Clinical Pharma

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“…However, this association did not reach significance in multivariate analyses, suggesting that the influence of age on POS C min was dependent on another variable in our cohort. Conversely, we found no effect of BMI, mucositis, or PPI cotreatment on the POS C min , whereas several studies did (3,11,19). However, these studies were not all comparable in terms of sample size and patient inclusion criteria, which could explain, at least in part, these discrepancies.…”

Section: Discussioncontrasting

confidence: 72%

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations

Gautier-Veyret

Bolcato

Roustit

et al. 2019

Antimicrob Agents Chemother

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The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (C min ) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS C min for the two formulations and identify determinants of the POS-tab C min and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 C min ) treated with POS-tab (n ϭ 41), POS-susp (n ϭ 29), or both (n ϭ 7) from January 2015 to December 2016 were collected retrospectively. Interpatient and within-subject coefficients of variation (CVs) of the C min adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS C min was higher for the tablet than for the suspension (median [25th-75th percentile]: 1.8 [1.2-2.4] mg/liter versus 1.2 [0.7-1.6] mg/liter, P Ͻ 0.0001). Interpatient CVs for the tablet and suspension were 60.8 versus 63.5% (P ϭ 0.7), whereas within-subject CVs were 39.7 and 44.9%, respectively (P ϭ 0.3). Univariate analysis showed that age and treatment by POS-tab were significantly and positively associated with the POS C min , whereas diarrhea was associated with a diminished POS C min . Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS C min , with a trend toward a lower impact of diarrhea during treatment with POS-tab (P ϭ 0.07). Despite increased POS exposure with the tablet formulation, the variability of the POS C min was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy.

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“…In addition, identification of mucositis patients for this study relied on the reporting of the events by the treating investigator, which could be underrepresenting the incidence in the study. We did not utilize a validated mucositis score or a biomarker, such as citrulline, to capture severity as has been done in other studies (27). Finally, we assumed that compliance was 100%, which may be overly optimistic.…”

Section: Discussionmentioning

confidence: 99%

Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole

Kovanda

Marty

Maertens

et al. 2017

Antimicrob Agents Chemother

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Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUCave]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.

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Posaconazole plasma exposure correlated to intestinal mucositis in allogeneic stem cell transplant patients

Abstract: Posaconazole tablets should be preferred to suspension in HSCT patients immediately after transplantation to prevent insufficient plasma exposure due to intestinal mucositis.

Cited by 23 publications

References 39 publications

Co‐administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed‐released tablets in adult patients with haematological malignancies

Co‐administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed‐released tablets in adult patients with haematological malignancies

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations

Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole

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