Population Pharmacokinetic Analyses for Arbekacin after Administration of ME1100 Inhalation Solution

Abstract

ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL ϭ (weight/52.2) 0.855 ·[(CLcrn-77)·0.0289 ϩ 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data (r 2 of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

“…The objective of this analysis was to use a previously developed population PK model (38), nonclinical PK-PD targets for efficacy (30)(31)(32)(33), in vitro surveillance data (28), and Monte Carlo simulation to assess PK-PD target attainment for ME1100 dosing regimens for the treatment of patients with HABP/VABP, including those with renal impairment. The first step of the assessments was to evaluate the results of the PK-PD target attainment analyses on day 1 among simulated patients with normal renal function (CLcr values Ͼ80 to Յ120 ml/min/1.73 m 2 ) for ME1100 dosing regimens FIG 3 Percent probabilities of PK-PD target attainment by MIC on day 1 based on total-drug ELF AUC/MIC ratio targets for K. pneumoniae among simulated patients with varying CLcr values after administration of ME1100 600 mg BID and dosing regimens adjusted for renal impairment, overlaid upon the MIC distribution for K. pneumoniae.…”

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

“…To date, there have been three phase I clinical studies that were completed examining the pharmacokinetic properties and safety profile of ME1100 in healthy volunteers (NCT01907776 and NCT01961830) and patients on mechanical ventilation (NCT02459158) [160,161]. A population pharmacokinetic model was subsequently developed from the results of these studies [162]. Nephrotoxicity is a major drug-related adverse effect related to arbekacin use and has been associated with both arkebacin trough concentrations and total cumulative doses [162].…”

“…A population pharmacokinetic model was subsequently developed from the results of these studies [162]. Nephrotoxicity is a major drug-related adverse effect related to arbekacin use and has been associated with both arkebacin trough concentrations and total cumulative doses [162]. This model estimates that approximately 19.5% of the inhaled dose of ME1100 reaches the systemic circulation, similar to inhaled amikacin [162,163].…”

“…Nephrotoxicity is a major drug-related adverse effect related to arbekacin use and has been associated with both arkebacin trough concentrations and total cumulative doses [162]. This model estimates that approximately 19.5% of the inhaled dose of ME1100 reaches the systemic circulation, similar to inhaled amikacin [162,163]. Of the subjects that received inhaled ME1100, 59/66 had a quantifiable ELF concentration [162].…”

“…This model estimates that approximately 19.5% of the inhaled dose of ME1100 reaches the systemic circulation, similar to inhaled amikacin [162,163]. Of the subjects that received inhaled ME1100, 59/66 had a quantifiable ELF concentration [162]. This formulation allows for the delivery of ME1100 directly to the lungs, rather than via penetration from the systemic circulation, allowing for optimal exposures for pneumonia patients whilst minimising the systemic effects [162].…”