The evaluation of an individualised dosing strategy derived from population PK modelling and simulation

Background: Recently published enoxaparin dosing guidelines for obese and renally impaired patients are purported to increase the probability of achieving and maintaining anti-Xa (aXa) concentrations within the therapeutic range (TR) of 500-1000 IU/L. Exposure-response data indicate that concentrations greater than the TR increase the risk of bleeding, while concentrations less than the TR increase mortality.

Aim: To determine if new individualised dose guidelines for enoxaparin are more likely to achieve concentrations within the TR compared to conventional label based dosing. 

Methods: A randomised controlled clinical trial (RCT) was conducted at the Royal Brisbane & Women’s hospital in which patients were allocated to either an individualised or conventional dosing arm. Three to four aXa concentrations were collected during sampling windows previously determined using D-Optimality. Due to the variability in sampling, which often occurred during the first dosing interval, a matched comparison of the two groups was undertaken using individual model predicted concentrations.

A full population PK model was developed using NONMEM® (version V) with the FOCE method and INTERACTION option which explored the influence of covariates including creatinine clearance (CLCR), body composition, age and sex. Using the final covariate model, individual predicted aXa concentrations for all subjects were determined at 30 minute intervals over a time period of four days, the typical duration of enoxaparin treatment. This equated to 192 aXa concentrations per patient. The effectiveness of the dosing guidelines was determined by comparing the proportion of concentrations within the TR.

Three patient groups were compared: all patients; patients with a total body weight (Wt) ≥ 100kg (defined as obese in the RCT); and patients with impaired renal function (GFR < 50 ml/min using the Cockcroft-Gault formula, where Wt was substituted for ideal body weight). A relative risk reduction with 95% CI was used to compare groups.

Results: 118 patients were randomised in the trial with 62 allocated to the conventional arm and 56 to the individualised arm. A total of 349 anti Xa concentrations were collected. A 2-compartment PK model with first-order absorption and elimination was found to best fit the data with lean body weight describing the variability in both clearance and central volume of distribution. The proportion of patients within the TR was greater in the individualised arm in all three populations evaluated (refer table).

Patient

 group

Individualised arm

Conventional arm

Relative risk

(95% CI)

Total

54.9

51.1

1.07 (1.05 – 1.10)

Obese

63.5

49.1

1.26 (1.16 – 1.36)

Renal impairment

61.4

45.0

1.36 (1.29 – 1.43)

Table: Percentage of aXa concentrations within the TR for each patient group per arm.

Conclusion: The individualised dose strategy is more effective than conventional dosing at achieving and maintaining a TR and will decrease both bleeding side effects and mortality.