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)

Abstract

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [fAUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (f_ub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with f_ub). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.

Keywords: Acinetobacter; minocycline; pharmacodynamics; pharmacokinetics; population pharmacokinetics.

FIG 1

Mean ± SD of the observed total and unbound plasma minocycline concentration-time data following a single i.v. infusion of 200 mg minocycline over 1 h to critically ill patients, presented on a linear (A) and semilog (B) scale. Red lines are total minocycline concentrations, and black lines are unbound minocycline concentrations.

FIG 2

Plot of fraction of minocycline bound versus total minocycline concentration using time-matched data from critically ill patients using all available data (A) and with focus on only those total minocycline concentrations less than 2 mg/liter (B). Green line and grey shaded region represent Loess smooth spline and 90% confidence interval.

FIG 3

Goodness-of-fit plots for the fit of the final two-compartment population PK model with constant fraction unbound to the total plasma minocycline concentration-time data from critically ill patients.

FIG 4

Goodness-of-fit plots for the fit of the final two-compartment population PK model with constant fraction unbound to the unbound plasma minocycline concentration-time data from critically ill patients.

FIG 5

Visual predictive check for the fit of the final two-compartment population PK model with constant fraction unbound to the total and unbound plasma minocycline concentration-time data from critically ill patients. Red (simulated) and blue (observed) indicate median and 90% prediction interval; black dots are observed data.

FIG 6

Percentage of simulated patients achieving the fAUC:MIC plasma targets of either 12 (net bacterial stasis) or 18 (1-log₁₀CFU kill) for the 200 mg i.v. Q12H minocycline dosing regimen at steady state conditions against (A) A. baumannii-A. calcoaceticus complex and (B) multidrug resistant (MDR) A. baumannii-A. calcoaceticus complex (7).

FIG 7

Model-predicted typical value of the fraction of minocycline bound (f_ub) versus albumin concentration, overlaid upon the individual post hoc f_ub values obtained using the final population PK model characterizing the total and unbound plasma minocycline concentration-time data from critically ill patients.