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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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).

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

Individual post-hoc PK parameter estimate for AUC0-24 was calculated for each patient, summarized by mean and standard deviation, and reported as outcome measure 1 calculated exposure measures for area under the curve 0 to 24 hours after a dose (AUC0-24).

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.

Individual post-hoc PK parameter estimate for free-drug AUC0-inf was calculated for each patient, summarized by mean and standard deviation, and reported as outcome measure 2 Calculated exposure measures for area under the curve from 0 to infinity (AUC0-inf) using free-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.

Individual post-hoc PK parameter estimate for total AUC0-inf was calculated for each patient, summarized by mean and standard deviation, and reported as outcome measure 3 calculated exposure measures for area under the curve from 0 to infinity (AUC0-inf) using total-drug concentrations.

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).

Individual AUC0-last were calculated as part of the Non-compartmental analysis using the linear trapezoidal rule, summarized by mean and standard deviation, and reported as outcome measure 4 calculated exposure measures for area under the curve to the last quantifiable sample (AUC0-last).

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.

Individual post-hoc PK parameter estimate for total-drug Cmax was calculated for each patient, summarized by mean and standard deviation, and reported as outcome measure 5 calculated exposure measures for maximum plasma concentration (Cmax).

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.

Individual post-hoc PK parameter estimate for total-drug C24 was calculated for each patient, summarized by mean and standard deviation, and reported as outcome measure 6 calculated exposure measures for plasma concentration at 24 hours after dose (C24).

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).

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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%).

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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).

The model was fit with total drug clearance and then fraction unbound so the magnitude of the inter-individual variability was estimated for those parameters rather than free-drug.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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).

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.

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.

PK population which is defined as participants who (1) received the full infusion of study drug, (2) had at least one PK specimen was processed per the Manual of Procedures, and (3) had at least one such sample provided a quantifiable minocycline concentration available for analysis.