scholarly journals Isavuconazole Treatment in a Mixed Patient Cohort with Invasive Fungal Infections: Outcome, Tolerability and Clinical Implications of Isavuconazole Plasma Concentrations

2020 ◽  
Vol 6 (2) ◽  
pp. 90 ◽  
Author(s):  
Christoph Zurl ◽  
Maximilian Waller ◽  
Franz Schwameis ◽  
Tina Muhr ◽  
Norbert Bauer ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Plasma Concentrations ◽  
Clinical Implications ◽  
Malignant Diseases ◽  
Efficacy And Safety ◽  
Response Side ◽  
Patient Cohort ◽  
Real World Setting ◽  
Underlying Diseases ◽  
Trough Plasma

Isavuconazole (ISA) is a triazole antifungal agent recommended for treatment of invasive aspergillosis or mucormycosis. The objective of this study was to evaluate ISA levels in a real world setting in a mixed patient cohort including patients with non-malignant diseases and extracorporeal treatments, and to correlate findings with efficacy and safety outcomes. We investigated 33 ISA treatment courses in 32 adult patients with hematological and other underlying diseases and assessed the clinical response, side effects and ISA trough plasma concentrations. ISA treatment led to complete and partial response in 87% of patients and was well tolerated. The median ISA plasma concentration was 3.05 µg/mL (range 1.38–9.1, IQR 1.93–4.35) in patients without renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) and significantly lower in patients with RRT including cases with additional ECMO or Cytosorb® adsorber therapy (0.88 µg/mL, range 0.57–2.44, IQR 0.71–1.21). After exclusion of values obtained from four patients with ECMO or Cytosorb® adsorber the median concentration was 0.91 µg/mL (range 0.75–2.44, IQR 0.90–1.36) in the RRT group. In addition to previous recommendations we propose to monitor ISA trough plasma concentrations in certain circumstances including RRT, other extracorporeal treatments and obesity.

scholarly journals Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

2013 ◽  
Vol 57 (4) ◽  
pp. 1888-1894 ◽  
Author(s):  
William W. Hope ◽  
Michael VanGuilder ◽  
J. Peter Donnelly ◽  
Nicole M. A. Blijlevens ◽  
Roger J. M. Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Multiple Model ◽  
Pharmacokinetic Variability ◽  
Hematopoietic Stem ◽  
Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

scholarly journals Influence of CYP3A Metabolizer Status on the Pharmacokinetics and Pharmacodynamics of Amiodarone

2000 ◽  
Vol 43 (3) ◽  
pp. 95-101
Author(s):  
Stanislav Mičuda ◽  
Martin Hodač ◽  
Petr Pařízek ◽  
Miloslav Pleskot ◽  
Luděk Šišpera ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Inverse Correlation ◽  
Urinary Free Cortisol ◽  
Information Value ◽  
Therapeutic Drug ◽  
Amiodarone Therapy ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Electrophysiologic Study ◽  
Free Cortisol ◽  
Trough Plasma

The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status. Methods: 12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6β-hydroxycortisol (6β-OHC and the ratio of 6β-hydroxycortisol to urinary free cortisol (6β-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 ± 11 days (2nd period) and after 182 ± 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 ± 11 days (during the second period). Results: Both the 6β-OHC excretion and 6β-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6β-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6β-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics. Conclusion: This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.

scholarly journals The tablet formulation of posaconazole: clinical pharmacology and the use in patients with hematologic malignancies

2020 ◽  
Vol 22 (2) ◽  
pp. 96-117
Author(s):  
Alexander V. Veselov
Keyword(s):  
Clinical Studies ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Hematologic Malignancies ◽  
Tablet Formulation ◽  
Oral Suspension ◽  
Tolerability Profile ◽  
Hematopoietic Stem ◽  
Release Tablet

Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various fungi, including yeast and molds, including Mucorales, what makes a key difference with itraconazole and voriconazole. Clinical studies have demonstrated his efficacy for prophylaxis against invasive fungal infections in hematological patients at high risk (with acute myeloid leukemia, myelodysplastic syndrome, aplastic anemia, and in patients after hematopoietic stem cell transplantation, especially with graft versus host disease). Posaconazole also use as salvage therapy against invasive aspergillosis, mucormycosis and some other systemic mycoses. For today there are 3 posaconazole formulations – oral suspension, modify release tablet and intravenous solution (not registered in Russia at the time of writing this paper). As far as bioavailability of posaconazole following administration by oral suspension is highly variable with low unstable plasma concentrations and there are number of factors with negatively influence to the pharmacokinetic profile of suspension a delayed-release tablet was developed using hot-melt extrusion technology with a pH-sensitive polymer. The tablet formulation releases the drug in the intestine, and this leads to the enhanced bioavailability and increased posaconazole exposure parameters and, as a result, to a higher efficacy. This was demonstrated in pre-clinical, early phase clinical studies and confirmed with data from real practice. The tablet formulation has well tolerability profile with a low incidence of clinically significant adverse events. For today posaconazole included in all relevant clinical recommendations with high levels of evidence, including prophylaxis of invasive mycoses and therapy of their refractory forms, while the authors agree that for the oral therapy a preference should be given to the tablet formulation of posaconazole.

scholarly journals Is It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
François Danion ◽  
Vincent Jullien ◽  
Claire Rouzaud ◽  
Manal Abdel Fattah ◽  
Simona Lapusan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Drug Monitoring ◽  
Invasive Aspergillosis ◽  
Drug Monitoring ◽  
Standard Treatment ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Life Threatening ◽  
Trough Plasma

ABSTRACT Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring to optimize therapy. We report two cases of central nervous system aspergillosis treated with voriconazole. Because of low trough plasma concentrations, we identified gain-of-function mutations in CYP2C19 that were partially responsible for the therapeutic failure of voriconazole. We suggest that systematic voriconazole pharmacogenomic investigation of cerebral aspergillosis be performed to avoid effective therapy delay in this life-threatening disease.

Prospective, multicenter study of apatinib combine with TACE in treating intermediate to advanced stage HCC patients: A real-world study from China.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 282-282
Author(s):  
Hailiang Li ◽  
Hongtao Hu ◽  
Guangshao Cao ◽  
Gang Wu ◽  
Pengxu Ding ◽  
...  
Keyword(s):  
Real World ◽  
Safety Profile ◽  
Objective Response ◽  
Intermediate Stage ◽  
Advanced Stage ◽  
Efficacy And Safety ◽  
First Line ◽  
Multicenter Observational Study ◽  
Real World Setting ◽  
Tace Treatment

282 Background: Combination of transcatheter arterial chemoembolization (TACE) with apatinib are emerging as an effective treatment for patients with intermediate to advanced stage HCC. However, the data of HCC treated by apatinib in the real-world setting are not reported. In this real-world study, we aimed to explore the efficacy and safety of HCC pts which underwent TACE combine with apatinib. Methods: This was a prospective, multicenter observational study in a real-world setting and this study was approved by our Ethics Committee. Pts aged ≥18 years with well diagnosed intermediate or advanced stage HCC were included. The pts received apatinib plus TACE treatment as the first-line therapy. TACE treatment was performed on demand, the dose of apatinib was selected by the investigator. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival rate (OS), objective response rate (ORR), disease control rate (DCR) and safety profile. All of the objective response was assessed by independent central review per mRECIST criteria. Results: From Jun 2019 to Feb 2020, a total of 98 well diagnosed HCC pts with age from 31 to 86 were enrolled in this study. As of August 2020, the median follow-up was 9.5 months. The mPFS of 98 pts was 7 months. The ORR, DCR and 6 months OS rate was 35.7%, 76.5% and 82.6%, respectively.The PFS was 7.5 months in intermediate stage and 6.4 months in advanced stage. The ORR was 46.3% in intermediate stage (41 cases) and 28% in advanced stage (57 cases) HCC. And the 6 months OS rate was 90.2% in intermediate stage and 77.1% in advanced stage HCC. Overall, 17 (17.3%) pts had grade≥3 treatment-related AEs. All of the safety adverse effects can be tolerated or reduced after symptomatic treatment and no unexpected adverse events were observed. Conclusions: In this real-world study, apatinib showed a favorable efficacy and safety profile in pts with intermediate and advanced stage cancer. Apatinib combination TACE therapy might lead to better survival benefit in first-line treatment for HCC pts. Clinical trial information: ChiCTR1900024030.

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