Minocycline Pharmacokinetics (ACUMIN)

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Bacterial Infection

Intervention / Treatment
-----------------
* Drug: Minocycline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female > / = 18 years of age. Subject is in the ICU, or is being admitted to the ICU. 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. 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. 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. The subject, or legally authorized representative (LAR), is able and willing to provide signed informed consent. Exclusion Criteria: History of significant hypersensitivity or allergic reaction to tetracycline antibiotics. Receipt of oral or intravenous tetracycline class drugs within 7 days of enrollment (e.g., minocycline, tetracycline, tigecycline, doxycycline). Use of isotretinoin within 2 weeks of enrollment into the study. 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. Pregnant or breastfeeding women. Patient is being treated for intracranial hypertension. 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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

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) | 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 | 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 | 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) | 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) | 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) | 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) | 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 | 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 | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ACUMIN, Infusion, Injection, Minocycline, Pharmacokinetic, PK