Dosing Obese With Noxafil® Under a Trial (DONUT) (DONUT)

Pharmacokinetics of Posaconazole Given as a Single Intravenous Dose to Obese Subjects: Dosing Obese With Noxafil® Under a Trial (DONUT)

Although posaconazole is approved for the prophylaxes and treatment of invasive fungal infections, specific dosing guidelines for posaconazole in (morbidly) obese patients are not specified. There is clear evidence indicating that heavier patients are receiving a sub-optimal dose if the current guidelines are used. Specifically in the setting of augmented prevalence of species with intermediate susceptible to posaconazole, adequate dosing is needed at start of treatment.

Therefore it seems prudent to conduct a trial in a cohort of obese patients who receive posaconazole (300mg or 400mg) and define the pharmacokinetics. These will then be compared to the pharmacokinetics in a normal-weight group receiving 300mg posaconazole.

Study Overview

• Status: Completed
• Conditions: Morbid Obesity
• Intervention / Treatment: Drug: Posaconazole Injection [Noxafil] 300mg; Drug: Posaconazole Injection [Noxafil] 400mg

Detailed Description

Obese patients with a BMI ≥ 35 kg/m2 undergoing endoscopic gastric bypass surgery will receive a 300 mg or 400mg dose of posaconazole. A PK curve will be determined after administration at t=0.45, 0.75, 1, 1.5, 2, 4, 8, 12, 24, and (if feasible) 48 hours post infusion. Blood samples (4 mL) on PK days will be taken to obtain at least 2.0 mL of plasma.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Nieuwegein, Netherlands
    • St. Antonius Hospital
  • Nijmegen, Netherlands
    • Radboudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects BMI:

   • obese groups: subject must have a BMI ≥35 kg/m2 at the time of inclusion,
   • non-obese group: subject must have a BMI ≥18.5 and < 25kg/m2 at the time of inclusion.
2. Subject is at least 18 of age on the day of screening and not older than 65 years of age on the day of dosing;
3. If a woman, is neither pregnant nor able to become pregnant and is not nursing an infant;

4. Subject is able and willing to sign the Informed Consent before screening evaluations.

   For the non-obese subjects the following additional inclusion criteria applies:

5. Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, hematology and urinalysis testing within 6 weeks prior to study drug administration. Results of biochemistry, hematology and urinalysis testing should be within the laboratory's reference ranges (see Appendix A). If laboratory results are not within the reference ranges, the subject is included based on the investigator's judgment that the observed deviations are not clinically relevant. This should be clearly recorded;

Exclusion Criteria:

1. Documented history of sensitivity to medicinal products or excipients similar to those found in the posaconazole preparation;
2. History of, or known abuse of drugs, alcohol or solvents (up until a maximum of three months before study drug administration);
3. Use of medication that has known relevant interaction with study drug as determined by the investigator up to 1 weeks prior to study drug administration.
4. Donation of blood or plasma to a blood bank or in a clinical study (except a screening visit) within 4 weeks prior to study drug administration;
5. Blood transfusion within 8 weeks prior to study drug administration;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Obese subjects; Subjects with a BMI>35 kg/m2	Drug: Posaconazole Injection [Noxafil] 300mg; Single dose by intravenous infusion 300mg; Drug: Posaconazole Injection [Noxafil] 400mg; Single dose by intravenous infusion 400mg
Active Comparator: Non-obese subjects; Subjects with a BMI>18.5 and <25 kg/m2	Drug: Posaconazole Injection [Noxafil] 300mg; Single dose by intravenous infusion 300mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Posaconazole exposure	The concentration-time curve of posaconazole in obese will be compared with that in non-obese subjects. Exposure is assessed by Area-Under-the-Curve from zero to 48 hours (AUC0-48h).	Through study completion (usually after 24 or 48 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exposure with augemented posaconazol dose	The concentration-time curve of posaconazole in obese receiving 400mg will be compared with that in non-obese subjects. Exposure is assessed by Area-Under-the-Curve from zero to 48 hours (AUC0-48h).	Through study completion (usually after 24 or 48 hours)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Merck Sharp & Dohme LLC; St. Antonius Hospital
• Investigators: Principal Investigator: Roger Brüggemann, PhD-PharmD, Radboud University Medical Center

Publications and helpful links

General Publications

• Wasmann RE, Smit C, van Donselaar MH, van Dongen EPA, Wiezer RMJ, Verweij PE, Burger DM, Knibbe CAJ, Bruggemann RJM. Implications for IV posaconazole dosing in the era of obesity. J Antimicrob Chemother. 2020 Apr 1;75(4):1006-1013. doi: 10.1093/jac/dkz546.

Helpful Links

• paper

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2017
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: August 2, 2017
• First Submitted That Met QC Criteria: August 7, 2017
• First Posted (Actual): August 11, 2017

Study Record Updates

• Last Update Posted (Actual): October 19, 2020
• Last Update Submitted That Met QC Criteria: October 16, 2020
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Obesity, Morbid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole
• Other Study ID Numbers: UMCN-AKF-17.08

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No