Single Dose PK of IV Tedizolid Phosphate in Morbidly Obese and Non-Obese Adults

Single Dose Pharmacokinetics of Intravenous Tedizolid Phosphate in Morbidly Obese and Age-, Sex-, and Ideal Body Weight-Matched Non-Obese Adults

This is an open label, single-dose, pharmacokinetic study in 9 obese and 9 age-, sex-, ideal body weight- matched non-obese subjects. Qualifying subjects who have completed an informed consent will receive a single intravenous dose of tedizolid with the collection of 11 blood samples over 72 hours post dose.

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Drug: Tedizolid phosphate

Detailed Description

Subjects will present to the clinical research unit in the morning (approximately 6:30 a.m.) of the dosing day. A urine pregnancy test will be performed to rule out pregnancy prior to administration of the tedizolid phosphate dose to female subjects. The subject's height, total body weight, and vital signs (heart rate, blood pressure, temperature, and respiratory rate) will be recorded. Subjects judged (by study physician) to be healthy enough to participate will proceed with the study procedures.

An 18-20 gauge intravenous peripheral catheter will be inserted into the antecubital vein or a vein in the fore-arm of the non-dominant arm for sequential blood sampling, and an initial predose blood sample (5 mL) will be collected. A minimum of 3-5 mL of blood is required per pharmacokinetic sampling time-point. Each blood collection tube will be pre-labeled with: 1.) study protocol number; 2.) subject study number; 3.) date of collection; 4.) time-point. A 0.9% Sodium Chloride infusion may be run through the peripheral line at 30 to 40 mL per hour to maintain catheter patency for the 12 hour sampling phase. Alternatively, a heparin lock technique will be utilized to maintain intravascular catheter patency.

A single-dose of tedizolid phosphate will be administered as an intravenous infusion (250 mL normal saline) over 1 hour (~8:00 a.m.). The intravenous administration tubing will be flushed with 0.9% Sodium Chloride infusion at 250 mL per hour (to match the tedizolid phosphate rate of infusion) for 10 minutes to ensure complete dose delivery. Blood samples (5 mL) will be collected 0.5 (middle of infusion), 1 (end of infusion), 2, 4, 6, 8, 12, 24, 48, and 72 hours post dose in blood collection tubes. The plasma will be harvested (centrifugation at 4°C) within 60 minutes of collection and stored at -70°C as two aliquots until analysis. The intravascular catheter "dead-space" volume will be discarded prior to blood sample collection by withdrawing 1.5-2 mL from the catheter to ensure no unintentional sample dilution. The intravascular catheter will be removed after the 12 hour sample and the subject will be discharged from the research unit. The subject will return to the research unit for blood sample collection on a daily basis at the following points: 24 (Visit 3), 48 (Visit 4), and 72 hours (Visit 5) after the dose via a peripheral vein needle stick. The exact date and time of blood sample collection will be recorded on case report forms. Each blood sample tube will be inverted and made up-right 5 times to afford mixing of blood with the anticoagulant. Blood samples will be maintained on wet ice and centrifuged at 1200 g for 10 minutes at 4°C within 60 minutes of collection to yield approximately 2 mL of plasma per 5 mL blood collection. The plasma samples will be transferred from the -20°C freezer for storage at -70°C at the end of the sample collection period until analysis.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Non-smoking or light-smoking (≤ 5 cigarettes per day) volunteers
• Estimated CLcr (Cockcroft-Gault equation) ≥ 90 mL/min
• Female subjects of childbearing potential (CBP) either surgically sterilized, using hormonal contraceptives or an effective barrier method of contraception (diaphragm, cervical cap, condom) or agree to abstain from sex from the time of pre-study screening, during the entire study period and 4 weeks following the study period
• Platelets count ≥ 140,000/mL
• Absolute neutrophil count (ANC) ≥ 1800/mL

Exclusion Criteria:

• History of hypersensitivity reaction to any oxazolidinone
• BMI < 18.5 kg/m2
• Any chronic medical condition requiring pharmacologic therapy
• Transaminases (AST or ALT) > 2.5 x upper limit of normal
• Total bilirubin > 1.5 x upper limit of normal
• Positive urine pregnancy test (if female)
• Abnormal electrocardiogram (ECG) as judged by the study physician
• Unable to tolerate venipuncture and multiple blood draws
• Clinically significant abnormal physical examination defined as a physical finding requiring further clinical work-up
• Unable to independently provide a written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Morbidly obese; The morbidly obese (BMI ≥ 40 kg/m2) arm will be recruited first. Each morbidly obese subject will be matched to a non-obese subject (BMI 18.5-29.9 kg/m2) based on age (± 5 years), sex, and ideal body weight (± 4.6 kg, i.e. ± 5 cm in height). Each group will receive a single dose of tedizolid phosphate 200 mg through a peripheral intravenous catheter.	Drug: Tedizolid phosphate; Each group will receive a single dose of tedizolid phosphate 200 mg through a peripheral intravenous catheter.; Other Names: Sivextro
Active Comparator: Non-obese; Each non-obese subject will be matched to a morbidly obese subject (BMI 18.5-29.9 kg/m2) based on age (± 5 years), sex, and ideal body weight (± 4.6 kg, i.e. ± 5 cm in height). Each group will receive a single dose of tedizolid phosphate 200 mg through a peripheral intravenous catheter.	Drug: Tedizolid phosphate; Each group will receive a single dose of tedizolid phosphate 200 mg through a peripheral intravenous catheter.; Other Names: Sivextro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
This Outcome Measure is the Tedizolid Area Under the Concentration Time-curve From Time 0 to 72 Hours in Morbidly Obese Subjects and Matched Non-obese Subjects.	The area under the concentration-time curve is measured in units of mg of tedizolid per liter of plasma multiplied by time in hours (hour*mg/L) from time 0 to 72 hours. This comparison was made between the two groups of subjects that included morbidly obese subjects to matched non-obese subjects.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
This Outcome Measure is the Maximum Plasma Concentration of Tedizolid in Morbidly Obese Subjects Compared to Nonobese Subjects	The maximum concentration or Cmax value is measured in units of milligrams of tedizolid per liter of plasma.This comparison was made between the two groups of subjects that included morbidly obese subjects to matched non-obese subjects.	12 months

Collaborators and Investigators

• Sponsor: Amit.Pai
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Manjunath Pai, PharmD, University of Michigan

Publications and helpful links

General Publications

• Pai MP. Pharmacokinetics of Tedizolid in Morbidly Obese and Covariate-Matched Nonobese Adults. Antimicrob Agents Chemother. 2016 Jul 22;60(8):4585-9. doi: 10.1128/AAC.00682-16. Print 2016 Aug.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: January 9, 2015
• First Submitted That Met QC Criteria: January 14, 2015
• First Posted (Estimate): January 21, 2015

Study Record Updates

• Last Update Posted (Actual): March 15, 2017
• Last Update Submitted That Met QC Criteria: January 25, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Tedizolid; Tedizolid phosphate
• Other Study ID Numbers: 14-019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Summative data have been published