Simplified Aztreonam Dosing in Patients with End-Stage Renal Disease: Results of a Monte Carlo Simulation.

The manufacturer-recommended aztreonam dosing for patients with creatinine clearance values of <10 ml/min/1.73 m2 is complex. It is not known whether simpler posthemodialysis dosing administered once daily or thrice weekly can reliably achieve pharmacodynamic goals. We found that 1 or 2 g administered once daily after hemodialysis had >90% probability of target attainment up to MICs of 4 or 8 mg/liter, respectively. Thrice-weekly dosing should generally be avoided, except in nonsevere infections with MICs of ≤0.5 mg/liter.

Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis.

Aztreonam is a monocyclic ß-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment.

In vitro assessment of metabolic drug­drug interaction potential of AZD2624, neurokinin-3 receptor antagonist, through cytochrome P(450) enzyme identification, inhibition, and induction studies.

AZD2624 was pharmacologically characterized as a NK3 receptor antagonist intended for treatment of schizophrenia. The metabolic drug-drug interaction potential of AZD2624 was evaluated in in vitro studies. CYP3A4 and CYP3A5 appeared to be the primary enzymes mediating the formation of pharmacologically active ketone metabolite (M1), whereas CYP3A4, CYP3A5, and CYP2C9 appeared to be the enzymes responsible for the formation of the hydroxylated metabolite (M2). The apparent K(m) values were 1.5 and 6.3 µM for the formation of M1 and M2 in human liver microsomes, respectively. AZD2624 exhibited an inhibitory effect on microsomal CYP3A4/5 activities with apparent IC(50) values of 7.1 and 19.8 µM for midazolam and testosterone assays, respectively. No time-dependent inactivation of CYP3A4/5 activity (midazolam 1'-hydroxylation) by AZD2624 was observed. AZD2624 demonstrated weak to no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AZD2624 was not an inducer of CYP1A2 or CYP2B6. Although AZD2624-induced CYP3A4 activity in hepatocytes, the potential of AZD2624 to cause inductive drug interactions of this enzyme was low at relevant exposure concentration. Together with targeted low efficacious concentration, the results of this study demonstrated AZD2624 has a relatively low metabolic drug-drug interaction potential towards co-administered drugs. However, metabolism of AZD2624 might be inhibited when co-administrated with potent CYP3A4/5 inhibitors.