NCT03369951

Minocycline Pharmacokinetics (ACUMIN)

Completed Phase 4 Results posted Last updated 3 December 2020

What this trial tests

Phase 4 trial testing Minocycline in Bacterial Infection in 58 participants. Completed in 20 July 2019.

Timeline

28 March 2018

Primary endpoint
20 July 2019

20 July 2019

Quick facts

Lead sponsor	National Institute of Allergy and Infectious Diseases (NIAID)
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	58
Start date	28 March 2018
Primary completion	20 July 2019
Estimated completion	20 July 2019
Sites	15 locations across United States

Drugs / interventions tested

• Minocycline (MINOCYCLINE) — full drug profile →

Conditions studied

• Bacterial Infection — all drugs for Bacterial Infection →

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Who can join

Adults 18 to 99, any sex, with Bacterial Infection. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Calculated Exposure Measures for Area Under the Curve 0 to 24 Hours After a Dose (AUC0-24) Primary · 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.

Group	Value	95% CI
Minocin® IV	24.3	± 7.88

Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Free-drug Concentrations Primary · 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.

Group	Value	95% CI
Minocin® IV	14.1	± 6.68

Calculated Exposure Measures for Area Under the Curve From 0 to Infinity (AUC0-inf) Using Total-drug Concentrations Primary · 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.

Group	Value	95% CI
Minocin® IV	46.6	± 19.7

Calculated Exposure Measures for Area Under the Curve to the Last Quantifiable Sample (AUC0-last) Primary · 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).

Group	Value	95% CI
Minocin® IV	10.5	± 3.91

Calculated Exposure Measures for Maximum Plasma Concentration (Cmax) Primary · 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.

Group	Value	95% CI
Minocin® IV	2.58	± 1.33

Calculated Exposure Measures for Plasma Concentration at 24 Hours After Dose (C24) Primary · 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.

Group	Value	95% CI
Minocin® IV	0.603	± 0.225

Magnitude of the Inter-individual Variability for Central Volume of Distribution (Vc) Primary · 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).

Group	Value	95% CI
Minocin® IV	49.9

Magnitude of the Inter-individual Variability for Distribution Clearance (CLd) Primary · 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%).

Group	Value	95% CI
Minocin® IV	0

Magnitude of the Inter-individual Variability for Peripheral Volume of Distribution (Vp) Primary · 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.

Group	Value	95% CI
Minocin® IV	34.2

Magnitude of the Inter-individual Variability for Total-drug Clearance (CL) Primary · 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).

Group	Value	95% CI
Minocin® IV	45.6

Population Mean PK Parameter Estimates for Central Volume of Distribution (Vc) Primary · 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.

Group	Value	95% CI
Minocin® IV	74.5	± 6.60

Population Mean PK Parameter Estimates for Distribution Clearance (CLd) Primary · 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.

Group	Value	95% CI
Minocin® IV	16.0	± 8.66

Adverse events — posted to ClinicalTrials.gov

Time frame: Serious Adverse Events (SAEs) were recorded and reported from the start of the Minocin IV infusion until 24 hours from the start of infusion.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Minocin® IV

Serious: 1/57 (2%)

Deaths: 1/57

Serious adverse events (1 terms)

Reaction	System	Minocin® IV
Cardio-Respiratory Arrest	Cardiac disorders	—

Most-reported serious reactions: Cardio-Respiratory Arrest.

Data from ClinicalTrials.gov NCT03369951 adverse events section.

Sponsor's own 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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).
   Lodise TP, Van Wart S, Sund ZM, Bressler AM, et al · · 2021 · cited 37× · PMID 33168615 · DOI 10.1128/aac.01809-20