Minocycline Pharmacokinetics (ACUMIN)

NCT03369951 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: 16-00112UM1AI104681-08
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 15

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.

Conditions

Bacterial Infection

Keywords

ACUMIN; Infusion; Injection; Minocycline; Pharmacokinetic; PK

Outcome Measures

Primary Outcomes (22)

• 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

Study Arms (1)

Minocin® IV

EXPERIMENTAL

200 mg minocycline hydrochloride IV infusion over approximately 60 minutes, n=50

Drug: Minocycline

Interventions

Minocycline DRUG

Minocycline is a semisynthetic derivative of tetracycline and is indicated for the treatment of infections due to susceptible isolates of designated microorganisms.

Minocin® IV

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (15)

Emory Decatur Hospital - Clinical Trials - Immunology/Infectious Disease

Decatur, Georgia, 30033, United States

Location

Northwestern Memorial Hospital - ICU

Chicago, Illinois, 60611-2908, United States

Location

Northwestern Medicine - Department of Obstetrics and Gynecology - Division of Female Pelvic Medicine and Reconstructive Surgery

Chicago, Illinois, 60611, United States

Location

University of Kentucky - UK Albert B Chandler Hospital

Lexington, Kentucky, 40536, United States

Location

University of Louisville School of Medicine - Surgery

Louisville, Kentucky, 40202-1622, United States

Location

Henry Ford Health System - Henry Ford Hospital

Detroit, Michigan, 48202-2608, United States

Location

William Beaumont Hospital - Royal Oak Campus - Infectious Disease

Royal Oak, Michigan, 48073-6700, United States

Location

Washington University School of Medicine in St. Louis - Infectious Diseases

St Louis, Missouri, 63110-1010, United States

Location

Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit

Durham, North Carolina, 27701, United States

Location

Duke University Hospital - Duke Medicine Pavilion - MICU

Durham, North Carolina, 27710, United States

Location

East Carolina University - Infectious Diseases and Tropical/Travel Medicine Clinic

Greenville, North Carolina, 27834-9997, United States

Location

University of Cincinnati College of Medicine - Division of Infectious Diseases

Cincinnati, Ohio, 45267, United States

Location

Case Western Reserve University School of Medicine - Medicine - Infectious Diseases and HIV Medicine

Cleveland, Ohio, 44106-1716, United States

Location

Oregon Health and Science University - Division of Pulmonary and Critical Care Medicine

Portland, Oregon, 97239, United States

Location

University of Pittsburgh - Medicine - Infectious Diseases

Pittsburgh, Pennsylvania, 15213-3403, United States

Location

MeSH Terms

Conditions

Bacterial Infections; cyclopia sequence

Interventions

Minocycline

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Richard G. Wunderink, MD
• Organization: Northwestern University of Feinberg School of Medicine

r-wunderink@northwestern.edu

312-695-1878

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2017
• First Posted: December 12, 2017
• Study Start: March 28, 2018
• Primary Completion: July 20, 2019
• Study Completion: July 20, 2019
• Last Updated: December 3, 2020
• Results First Posted: August 27, 2020

Record last verified: 2017-12-04

Locations

US (15)