Minocycline Pharmacokinetics (ACUMIN)

A Phase IV Open-Label Pharmacokinetic Study of Minocycline for Injection Following a Single Infusion in Critically-Ill Adults (ACUMIN)

This is a Phase IV, multi-center open-label pharmacokinetic trial studying the pharmacokinetics and pharmacodynamics of a single dose of Minocin IV. Up to 67 subjects will be enrolled to obtain 50 evaluable, ICU patients who are already receiving antimicrobial therapy for a known or suspected Gram-negative infection. The entire study duration will be approximately 16 months and each subject participation duration will be approximately 2 days. The study will be conducted at approximately 13 clinical sites. Each subject will receive a single 200 mg dose of Minocin IV infused over approximately 60 minutes. Each subject will have 7 PK samples collected (1 pre-dose, 6 post-dose) at designated time points over a ~48 hour period following the start of the Minocin IV infusion. The primary objectives are: 1) To characterize minocycline PK at the population level in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria and 2) To assess patient-level and clinical covariates associated with minocycline pharmacokinetic properties in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a Phase IV, multi-center open-label pharmacokinetic trial studying the pharmacokinetics and pharmacodynamics of a single dose of Minocin IV. Up to 67 subjects will be enrolled to obtain 50 evaluable, ICU patients who are already receiving antimicrobial therapy for a known or suspected Gram-negative infection. The entire study duration will be approximately 16 months and each subject participation duration will be approximately 2 days. The study will be conducted at approximately 13 clinical sites. Each subject will receive a single 200 mg dose of Minocin IV infused over approximately 60 minutes. Each subject will have 7 PK samples collected (1 pre-dose, 6 post-dose) at designated time points over a ~48 hour period following the start of the Minocin IV infusion. The primary objectives are: 1) To characterize minocycline PK at the population level in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria and 2) To assess patient-level and clinical covariates associated with minocycline pharmacokinetic properties in critically-ill adults, with illness known or suspected to be caused by infection with Gram-negative bacteria. Up to 67 subjects will be enrolled in order to obtain 50 PK evaluable subjects in the study. To be considered PK evaluable, a subject must receive the full infusion of study drug, and is required to have at least 3 PK samples collected in the first 12 hours post dose and at least 1 PK sample collected 24-48 hours post dose. Subjects who are dosed with minocycline but do not meet this PK sampling requirement will still be included in the population PK analysis, but an additional subject will be enrolled as a replacement to meet the goal of having 50 PK evaluable subjects with intensive PK sampling.

Study Type

Interventional

Enrollment (Actual)

58

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Georgia
      • Decatur, Georgia, United States, 30033
        • Emory Decatur Hospital - Clinical Trials - Immunology/Infectious Disease
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern Medicine - Department of Obstetrics and Gynecology - Division of Female Pelvic Medicine and Reconstructive Surgery
      • Chicago, Illinois, United States, 60611-2908
        • Northwestern Memorial Hospital - ICU
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • University of Kentucky - UK Albert B Chandler Hospital
      • Louisville, Kentucky, United States, 40202-1622
        • University of Louisville School of Medicine - Surgery
    • Michigan
      • Detroit, Michigan, United States, 48202-2608
        • Henry Ford Health System - Henry Ford Hospital
      • Royal Oak, Michigan, United States, 48073-6700
        • William Beaumont Hospital - Royal Oak Campus - Infectious Disease
    • Missouri
      • Saint Louis, Missouri, United States, 63110-1010
        • Washington University School of Medicine in St. Louis - Infectious Diseases
    • North Carolina
      • Durham, North Carolina, United States, 27701
        • Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit
      • Durham, North Carolina, United States, 27710
        • Duke University Hospital - Duke Medicine Pavilion - MICU
      • Greenville, North Carolina, United States, 27834-9997
        • East Carolina University - Infectious Diseases and Tropical/Travel Medicine Clinic
    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • University of Cincinnati College of Medicine - Division of Infectious Diseases
      • Cleveland, Ohio, United States, 44106-1716
        • Case Western Reserve University School of Medicine - Medicine - Infectious Diseases and HIV Medicine
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health and Science University - Division of Pulmonary and Critical Care Medicine
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213-3403
        • University of Pittsburgh - Medicine - Infectious Diseases

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 99 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Male or female > / = 18 years of age.
  2. Subject is in the ICU, or is being admitted to the ICU.
  3. Known or suspected Gram-negative infection for which the subject is receiving systemic antibiotics, and which was the reason for admission to the ICU, or reason for persistent need for ICU care.
  4. Expectation, in the judgment of the investigator, that the subject will remain admitted in the hospital for at least 48 hours following enrollment and that all study procedures will be completed.
  5. Expectation that intravenous access will be sufficient for drug infusion and either intravenous or arterial access will be sufficient to allow for all protocol required blood sampling to occur.
  6. The subject, or legally authorized representative (LAR), is able and willing to provide signed informed consent.

Exclusion Criteria:

  1. History of significant hypersensitivity or allergic reaction to tetracycline antibiotics.
  2. Receipt of oral or intravenous tetracycline class drugs within 7 days of enrollment (e.g., minocycline, tetracycline, tigecycline, doxycycline).
  3. Use of isotretinoin within 2 weeks of enrollment into the study.
  4. Major surgery* within 48 hours prior to enrollment.

    *Major surgery is defined as "the opening of either a body cavity or the mesenchymal barrier, using general anesthesia".

  5. Pregnant or breastfeeding women.
  6. Patient is being treated for intracranial hypertension.
  7. Any condition that, in the judgment of the investigator, precludes participation because it could affect subject safety.*

    *Subjects on, or who may be considered for Renal Replacement Therapy (RRT) during the study period are not excluded from participating in the study.

  8. Receipt of an investigational study product within 7 days prior to enrollment. Investigator discretion should be used when longer acting agents have been used in the previous 30 days.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Minocin® IV
200 mg minocycline hydrochloride IV infusion over approximately 60 minutes, n=50
Minocycline is a semisynthetic derivative of tetracycline and is indicated for the treatment of infections due to susceptible isolates of designated microorganisms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Calculated Exposure Measures for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Total AUC0-24 is defined as area under the plasma minocycline concentration-time curve from 0 to 24 hours after a dose (milligrams x hours per liter (mg•hr/L)). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-24 was calculated using numerical integration using the data from 0 to 24 hours post-dose.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Free-drug (unbound) AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate unbound concentration-time profiles. The AUC0-inf was calculated as Dose/CL.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Total AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-inf was calculated as Dose/CL.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Calculated Exposure Measures for Area Under the Curve to the Last Quantifiable Sample (AUC0-last)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
AUC0-last is defined as the area under the plasma minocycline concentration-time curve from 0 to the time of the last quantifiable sample after a dose (mg•hr/L). This was not calculated for the primary outcome measure using the individual post-hoc PK parameters, however was calculated as part of the Non-compartmental analysis using the linear trapezoidal rule (linear up, log down calculation method).
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Calculated Exposure Measures for Maximum Plasma Concentration (Cmax)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Total-drug Cmax is defined as the maximum plasma total minocycline concentration (mg/L) Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. Total Cmax was calculated for each simulated patient as the maximum simulated concentration.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Calculated Exposure Measures for Plasma Concentration at 24 Hours After Dose (C24)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Total-drug C24 is defined as total plasma minocycline concentration at 24 hours after a dose (mg/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The total C24 were calculated for each simulated patient as the simulated concentration at 24 hours after dose.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Individual Post-hoc PK Parameter Estimates for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Total AUC0-24 is defined as area under the plasma minocycline concentration-time curve from 0 to 24 hours after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-24 was calculated for each individual using numerical integration using the data from 0 to 24 hours post-dose. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Free-drug (unbound) AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate unbound concentration-time profiles. The AUC0-inf was calculated for each individual as Dose/CL. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Individual Post-hoc PK Parameter Estimates for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Total AUC0-inf is defined as area under the plasma minocycline concentration-time curve from 0 to infinity after a dose (mg•hr/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The AUC0-inf was calculated for each individual as Dose/CL. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Individual Post-hoc PK Parameter Estimates for Area Under the Curve to the Last Quantifiable Sample (AUC0-last)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
AUC0-last is defined as the area under the plasma minocycline concentration-time curve from 0 to the time of the last quantifiable sample after a dose (mg•hr/L). This was not calculated of the primary outcome measure for the population PK model, however was calculated as part of the Non-compartmental analysis using the linear trapezoidal rule (linear up, log down calculation method).
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Individual Post-hoc PK Parameter Estimates for Maximum Plasma Concentration (Cmax)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Total-drug Cmax is defined as the maximum plasma total minocycline concentration (mg/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The Individual post-hoc PK parameter estimate for total Cmax was calculated for each simulated patient as the maximum simulated concentration. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Individual Post-hoc PK Parameter Estimates for Plasma Concentration at 24 Hours After Dose (C24)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Total-drug C24 is defined as total Plasma minocycline concentration at 24 hours after a dose (mg/L). Patient dosing histories along with the individual post-hoc PK parameters were used to generate total concentration-time profiles. The Individual post-hoc PK parameter estimates for the total C24 were calculated for each simulated patient as the simulated concentration at 24 hours after dose. Summary statistics were calculated using the individual post-hoc parameters and reported as calculated exposure measures.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, and 24 hours post dose
Magnitude of the Inter-individual Variability for Central Volume of Distribution (Vc)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Vc was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (%CV).
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Magnitude of the Inter-individual Variability for Distribution Clearance (CLd)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
CLd was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1. The standard error of the mean as fixed. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (CV%).
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Magnitude of the Inter-individual Variability for Free-drug Clearance (CL)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Unbound minocycline concentration is determined as the product of total minocycline concentrations and fub. Total minocycline concentrations and fub were estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (%CV).
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Magnitude of the Inter-individual Variability for Peripheral Volume of Distribution (Vp)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Vp was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Magnitude of the Inter-individual Variability for Total-drug Clearance (CL)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
CL was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1. Magnitude of the inter-individual variability is expressed as percent coefficient of variation (%CV).
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Population Mean PK Parameter Estimates for Central Volume of Distribution (Vc)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Vc was estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Population Mean PK Parameter Estimates for Distribution Clearance (CLd)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
CLd was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Population Mean PK Parameter Estimates for Free-drug Clearance (CL)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Unbound minocycline concentration is determined as the product of total minocycline concentrations and fub. Total minocycline concentrations and fub were estimated from the structural two-compartment population PK model with constant fraction unbound (fub) which was used to characterize the total and unbound minocycline concentration-time data from ICU patients.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Population Mean PK Parameter Estimates for Peripheral Volume of Distribution (Vp)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Vp was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Population Mean PK Parameter Estimates for Total-drug Clearance (CL)
Time Frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
Total-drug clearance (CL) was estimated from the structural two-compartment population PK model with constant fraction unbound (fub), which was used to characterize the total and unbound minocycline concentration-time data from ICU patients. The model was developed on using nonlinear mixed effects modeling on PK time points collected up to 48 hours after a single-dose on Day 1.
Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 28, 2018

Primary Completion (ACTUAL)

July 20, 2019

Study Completion (ACTUAL)

July 20, 2019

Study Registration Dates

First Submitted

December 7, 2017

First Submitted That Met QC Criteria

December 7, 2017

First Posted (ACTUAL)

December 12, 2017

Study Record Updates

Last Update Posted (ACTUAL)

December 3, 2020

Last Update Submitted That Met QC Criteria

November 10, 2020

Last Verified

December 4, 2017

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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