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.
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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
58
Minocycline is a semisynthetic derivative of tetracycline and is indicated for the treatment of infections due to susceptible isolates of designated microorganisms.
Emory Decatur Hospital - Clinical Trials - Immunology/Infectious Disease
Decatur, Georgia, United States
Northwestern Memorial Hospital - ICU
Chicago, Illinois, United States
Northwestern Medicine - Department of Obstetrics and Gynecology - Division of Female Pelvic Medicine and Reconstructive Surgery
Chicago, Illinois, United States
University of Kentucky - UK Albert B Chandler Hospital
Lexington, Kentucky, United States
University of Louisville School of Medicine - Surgery
Louisville, Kentucky, United States
Henry Ford Health System - Henry Ford Hospital
Detroit, Michigan, United States
William Beaumont Hospital - Royal Oak Campus - Infectious Disease
Royal Oak, Michigan, United States
Washington University School of Medicine in St. Louis - Infectious Diseases
St Louis, Missouri, United States
Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit
Durham, North Carolina, United States
Duke University Hospital - Duke Medicine Pavilion - MICU
Durham, North Carolina, United States
...and 5 more locations
Calculated Exposure Measures for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24)
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.
Time frame: 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
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.
Time frame: 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
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.
Time frame: 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)
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).
Time frame: 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)
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.
Time frame: 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)
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.
Time frame: 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)
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.
Time frame: 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
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.
Time frame: 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
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.
Time frame: 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)
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).
Time frame: 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)
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.
Time frame: 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)
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.
Time frame: 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)
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).
Time frame: 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)
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%).
Time frame: 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)
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).
Time frame: 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)
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.
Time frame: 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)
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).
Time frame: 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)
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.
Time frame: 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)
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.
Time frame: 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)
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.
Time frame: 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)
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.
Time frame: 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)
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.
Time frame: Pre-dose, immediately after infusion termination (~1 hour) and at 4, 12, 24, 36, and 48 post dose
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