Development of an Efficient Sampling Strategy to Predict Enoxaparin Pharmacokinetics in Stage 5 Chronic Kidney Disease

Abstract

Patients with renal dysfunction are at greater risk for hemorrhagic events than patients with normal renal function. The objective of this study was to develop an efficient sampling strategy that optimally predicts anti-Xa activity exposure after enoxaparin administration in patients with chronic kidney disease to optimize enoxaparin therapy. The antifactor Xa activity data of 8 anuric patients who were administered 1 mg/kg enoxaparin immediately after hemodialysis were used for the development of the optimal sampling strategies. Maximum A Posteriori Bayesian (MAPB) priors were developed by pharmacokinetic analysis. The 2, 3, and 4 D-optimal sampling designs were determined and Monte Carlo simulations using the MAPB estimator were performed. The original model with the estimator was used to determine the predictive power of the sampling schemes. The most efficient sampling scheme (OSS-2) was accurate and precise in predicting apparent enoxaparin clearance (-3.2% bias, 6.5% precision). The addition of a third sampling time at 30 minutes (OSS-3) was more accurate (P < 0.01) and precise (P < 0.01) than OSS-2 at predicting the rate of absorption (ka) but did not improve the accuracy (P > 0.05) or precision (P = 0.20) of the CLs/F estimate. The determination of antifactor Xa activity at 5 and 24 hours, along with the Bayesian estimators generated from this study, accurately and precisely predict the apparent clearance of antifactor Xa activity. This sampling strategy may be used for therapeutic drug monitoring of enoxaparin and for future clinical trials in patients with chronic kidney disease.

Correlation of Treatment Dose Enoxaparin with Anti-Xa Concentrations in Adult Hemodialysis Inpatients

“…Although routine monitoring of anti-Xa concentrations is not warranted in most patients without renal impairment who are receiving enoxaparin, the possibility of accumulating anti-Xa concentrations in patients with renal dysfunction poses a hemorrhagic risk and therefore is recommended. [6] The ideal time to draw anti-Xa concentrations in patients undergoing HD is at 5 and 24 hours after enoxaparin administration as shown by Overholser [7] and colleagues. Other studies have estimated that it takes seven half-lives, approximately 35 hours, for renally impaired patients to reach steady state, meaning that the ideal time to measure anti-Xa concentrations would be after the second or third dose for patients receiving once-daily treatment.…”

Review: An examination of effect estimation in factorial and standardly-tailored designs

“…The pharmaceutical literature presents examples [34][35][36] of Phase II clinical trials that use D-optimal designs [32] to pick the group of factor combinations, or time points in longitudinal trials [37] that optimize characteristics, such as minimum covariance, of specific model coefficients. Unlike factorial designs, D-optimal designs do not require independent (orthogonal) interventional components, thus parameter estimates may be correlated.…”

Enoxaparin Dosage Adjustment in Patients with Severe Renal Failure: Antifactor Xa Concentrations and Safety

“…A single-dose study of enoxaparin 1 mg/kg was conducted in eight patients undergoing hemodialysis. 14 The authors suggested that sampling antifactor Xa levels at 5 and 24 hours after drug administration accurately predicted the apparent clearance of antifactor Xa and may be used for therapeutic drug monitoring of enoxaparin in this population.…”