scholarly journals Phase 1B Study of the Pharmacokinetics and Safety of Posaconazole Intravenous Solution in Patients at Risk for Invasive Fungal Disease

2014 ◽  
Vol 58 (7) ◽  
pp. 3610-3617 ◽  
Author(s):  
Johan Maertens ◽  
Oliver A. Cornely ◽  
Andrew J. Ullmann ◽  
Werner J. Heinz ◽  
Gopal Krishna ◽  
...  
Keyword(s):  
Steady State ◽  
Invasive Fungal Disease ◽  
Central Line ◽  
Fungal Disease ◽  
Average Concentration ◽  
Study Phase ◽  
Time Curve ◽  
Exposure Target ◽  
Patients At Risk ◽  
Phase 1B

ABSTRACTThis was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (n= 10) were compared with those of a placebo (n= 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (n= 21) and 300 mg q.d. (n= 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {Cavgs}], of ≥500 to ≤2,500 ng/ml in ≥90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-stateCavg, ∼1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01075984.)

scholarly journals Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease

2015 ◽  
Vol 71 (3) ◽  
pp. 718-726 ◽  
Author(s):  
Oliver A. Cornely ◽  
Rafael F. Duarte ◽  
Shariq Haider ◽  
Pranatharthi Chandrasekar ◽  
David Helfgott ◽  
...  
Keyword(s):  
At Risk ◽  
Steady State ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Oral Suspension ◽  
Safety Study ◽  
Phase 3 ◽  
Once Daily ◽  
Patients At Risk ◽  
Phase 1B

This Phase 1B study showed that a single tablet of 300 mg of posaconazole, given once daily as prophylaxis to 210 patients at risk for invasive fungal disease, was as safe as that reported for posaconazole oral suspension and achieved steady-state >500 ng/mL for all but one patient.

scholarly journals Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease

2017 ◽  
Vol 72 (12) ◽  
pp. 3501-3501 ◽  
Author(s):  
Oliver A Cornely ◽  
Michael N Robertson ◽  
Shariq Haider ◽  
Andrew Grigg ◽  
Michelle Geddes ◽  
...  
Keyword(s):  
At Risk ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Study ◽  
Label Study ◽  
Patients At Risk

scholarly journals Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease

2017 ◽  
Vol 72 (12) ◽  
pp. 3406-3413 ◽  
Author(s):  
Oliver A Cornely ◽  
Michael N Robertson ◽  
Shariq Haider ◽  
Andrew Grigg ◽  
Michelle Geddes ◽  
...  
Keyword(s):  
At Risk ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Study ◽  
Label Study ◽  
Patients At Risk

scholarly journals Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)

2016 ◽  
Vol 60 (8) ◽  
pp. 4568-4576 ◽  
Author(s):  
Laura L. Kovanda ◽  
Amit V. Desai ◽  
Qiaoyang Lu ◽  
Robert W. Townsend ◽  
Shahzad Akhtar ◽  
...  
Keyword(s):  
Nonparametric Estimation ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Water Soluble ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Open Label ◽  
Time Curve ◽  
Content Type

ABSTRACTIsavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n= 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 forAspergillusspp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 forCandida albicans(up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candidaspp. (up to a MIC of 0.125 mg/liter). The estimations forCandidaspp. were exploratory considering that no patients withCandidainfections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.)

scholarly journals Phase 1b Study of New Posaconazole Tablet for Prevention of Invasive Fungal Infections in High-Risk Patients with Neutropenia

2014 ◽  
Vol 58 (10) ◽  
pp. 5758-5765 ◽  
Author(s):  
Rafael F. Duarte ◽  
Javier López-Jiménez ◽  
Oliver A. Cornely ◽  
Michel Laverdiere ◽  
David Helfgott ◽  
...  
Keyword(s):  
High Risk ◽  
Fungal Infections ◽  
Average Concentration ◽  
Myelogenous Leukemia ◽  
Time Curve ◽  
Once Daily ◽  
High Risk Patients ◽  
Exposure Target ◽  
Risk Patients ◽  
Neutropenic Patients

ABSTRACTPosaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n= 20) and 300 mg posaconazole once daily (n= 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered atClinicalTrials.govunder registration no. NCT01777763.)

scholarly journals A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers

2020 ◽  
Vol 16 ◽  
pp. 174550652095719
Author(s):  
Dace Melka ◽  
Kalev Kask ◽  
Enrico Colli ◽  
Pedro-Antonio Regidor
Keyword(s):  
Steady State ◽  
Breast Milk ◽  
Area Under The Curve ◽  
Average Concentration ◽  
Primary Objective ◽  
Repeated Dose ◽  
Open Label ◽  
Time Curve ◽  
Dose Administration ◽  
Concentration Time

Objective: The primary objective of this trial was to assess the transfer of drospirenone to breast milk after daily administration of an oral test preparation containing 4 mg of drospirenone at the steady state. The secondary objective of the trial was to assess safety based on clinical and laboratory measurements and reporting of adverse events and/or adverse drug reactions. Patients and Methods: This was an open label, non-comparative single-center study. Drospirenone 4 mg per day was the first postpartum contraceptive for the study participants who were no longer breastfeeding yet were still lactating. It was administered for 7 days to achieve steady-state concentration. All participants were volunteers who planned to use oral contraceptives as their family planning method in the future. Results: Twelve volunteers completed the trial according to the protocol, and the samples of all 12 study completers were analyzed. The average concentration–time curve of drospirenone in plasma 24 h after the administration of the last dose (area under the curve (0–24 h)) was 635.33 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0–120 h)) was 1180.57 ng h/mL, respectively. The average Cmax was 48.64 ng/mL. The average concentration–time curve of drospirenone in milk 24 h after the administration of the last dose (area under the curve (0–24 h)) was 134.35 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0–120 h)) was 227.17 ng h/mL, respectively. The average Cmax was 10.34 ng/mL. Conclusion: On average, 18.13% of plasma drospirenone made it to breast milk and the highest concentration of drospirenone in breast milk was 17.55% of that in plasma. The total quantity of drospirenone passing to breast milk is on average 4478 ng during a 24-h period representing 0.11% of the maternal daily dose. Thus, at the recommended doses, no effects on breastfed newborns/infants are anticipated with drospirenone 4 mg.

scholarly journals Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease

2016 ◽  
Vol 71 (6) ◽  
pp. 1747-1747 ◽  
Author(s):  
Oliver A. Cornely ◽  
Rafael F. Duarte ◽  
Shariq Haider ◽  
Pranatharthi Chandrasekar ◽  
David Helfgott ◽  
...  
Keyword(s):  
At Risk ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Tablet Formulation ◽  
Safety Study ◽  
Phase 3 ◽  
Patients At Risk

scholarly journals A Single Arm Study to Evaluate the Transfer of Drospirenone to Breast Milk after Reaching Steady State after Oral Administration of 4 MG Drospirenone Only Pill in Healthy Lactating Female Volunteers

2020 ◽  
Author(s):  
Dace Melka ◽  
Kalev Kask ◽  
Enrico Colli ◽  
Pedro-Antonio Regidor
Keyword(s):  
Steady State ◽  
Breast Milk ◽  
Average Concentration ◽  
Primary Objective ◽  
Repeat Dose ◽  
Open Label ◽  
Time Curve ◽  
Dose Administration ◽  
Concentration Time ◽  
Study Participants

Objective: The primary objective of this trial was to assess the transfer of drospirenone to breast milk after daily administration of an oral test preparation containing 4 mg of drospirenone at the steady state. The secondary objective of the trial was to assess the safety of the preparation based on safety clinical and laboratory measurements (at the beginning and at the end of the trial) and reporting of adverse events and/or adverse drug reactions. Patients and Methods: This was an open label, non-comparative single center study. Drospirenone 4mg per day was the first postpartum contraceptive for the study participants who were no longer breastfeeding yet were still lactating. It was administered for 7 (seven) days to achieve steady-state concentration. All participants were volunteers who planned to use oral contraceptives as their family planning method in the future. Results: A total number of 12 volunteers completed the trial according to the protocol and the samples of all the 12 study completers were analyzed. The average concentration-time curve of drospirenone in plasma 24 h after the administration of the last dose (AUC(0-24h)) was 635.33 ng*h/mL and 120 h after the single repeat dose administration (AUC(0-120h) was 1180.57 ng*h/mL, respectively. The average Cmax was 48.64 ng/mL. The average concentration-time curve of drospirenone in milk 24 h after the administration of the last dose (AUC(0-24h)) was 134.35 ng*h/mL and 120 h after the single repeat dose administration (AUC(0-120h) was 227.17 ng*h/mL respectively. The average Cmax was 10.34 ng/mL. Conclusion: On average 18.13% of plasma drospirenone made it to breast milk and the highest concentration of drospirenone in breast milk was 17.55% of that in plasma. The total quantity of drospirenone passing to breast milk is on average 4478 ng during a 24 h period representing 0.11% of the maternal daily dose. Thus, at the recommended doses, no effects on breastfed newborns/infants are anticipated with drospirenone 4 mg.

scholarly journals Lessons from an Educational Invasive Fungal Disease Conference on Hospital Antifungal Stewardship Practices across the UK and Ireland

2021 ◽  
Vol 7 (10) ◽  
pp. 801
Author(s):  
Alida Fe Talento ◽  
Malcolm Qualie ◽  
Laura Cottom ◽  
Matthijs Backx ◽  
P. Lewis White
Keyword(s):  
At Risk ◽  
Treatment Strategies ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Diagnostic Tools ◽  
Optimal Time ◽  
Rapid Diagnostics ◽  
Antifungal Stewardship ◽  
Patients At Risk ◽  
The Uk

Invasive fungal disease (IFD) is a growing health burden. High mortality rates, increasing numbers of at-risk hosts, and a limited availability of rapid diagnostics and therapeutic options mean that patients are increasingly exposed to unnecessary antifungals. High rates of prescriptions promote patient exposure to undue toxicity and drive the emergence of resistance. Antifungal stewardship (AFS) aims to guide antifungal usage and reduce unnecessary exposure and antifungal consumption whilst maintaining or improving outcomes. Here, we examine several AFS approaches from hospitals across the UK and Ireland to demonstrate the benefits of AFS practices and support the broader implementation of AFS as both a necessary and achievable strategy. Since the accuracy and turnaround times (TATs) of diagnostic tools can impact treatment decisions, several AFS strategies have included the development and implementation of diagnostic-driven care pathways. AFS informed treatment strategies can help stratify patients on a risk basis ensuring the right patients receive antifungals at the optimal time. Using a multidisciplinary approach is also key due to the complexity of managing and treating patients at risk of IFD. Through knowledge sharing, such as The Gilead Antifungal Information Network (GAIN), we hope to drive practices that improve patient management and support the preservation of antifungals for future use.

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