2008 - Marseille - France

PAGE 2008: Applications
Michael Barras

Individualized compared with conventional dosing of enoxaparin.

M.A.Barras(1,2), S.B.Duffull(3), J.J.Atherton(4), B Green(1)

(1)University of Queensland, Brisbane, Australia; (2)Mater Health Services, Brisbane, Australia; (3)University of Otago, Dunedin, New Zealand; (4)Cardiology Dept., Royal Brisbane & Women’s Hospital, Brisbane, Australia.

Introduction: There is widespread belief that individualizing dosing regimens of drugs will further optimize outcomes for each patient. However there are few prospective studies that have assessed the benefits or risks of such interventions. A compelling prior example showed that individualized pharmacokinetically guided chemotherapy in children with acute lymphoblastic leukemia provided a 15% improvement in 5-year complete remission over conventional dosing [1]. Enoxaparin is a low-molecular-weight-heparin used to treat thromboembolic disorders, however limited information is available that quantifies its safety in patients who are obese and / or have renal impairment. Two population PKPD studies [2, 3] have however quantified the influence of these covariates on the pharmacokinetics of enoxaparin and proposed individualized dosing regimens to maintain effectiveness and minimise toxicity.

Objectives: To evaluate if individualized enoxaparin dosing reduced the incidence of adverse events whilst ensuring therapeutic anti-Xa concentrations.

Methods: Two methods were used:

1. A confirmatory randomized, controlled, double blind clinical trial was performed to compare conventional (product label) with individualized dose guidelines. Patients randomized to the individualized arm were dosed using lean body weight if obese and total body weight if non-obese. Patients were dose adjusted at 48 hours according to renal function. Those in the conventional arm received a dose as determined by the treating physician, in accordance to the product label. The primary endpoint was the prevalence of bleeding events and the secondary endpoint a combination of bleeding or major bruising events (single bruise ≥ 20 cm2). This trial constituted the confirmatory component to the learn-confirm paradigm [4].

2. Within the confirmatory trial a learning component was included to quantify the result as a function of drug exposure. A categorical PKPD analysis was performed using NONMEM, to describe the severity of an adverse event as a function of exposure and demographic variables. Severity categories were defined a priori to match those used in the confirmatory component of the trial: S (0) no event or bruise < 1cm2; (S1) minor bruise (≥ 1 cm2 & < 20 cm2); and (S2) major bruise or bleed. The model was used to explore the likely occurrence of adverse events in patients with obesity and / or renal impairment dosed using either the individualized or conventional dose strategies.

Results: 118 patients were randomized to treatment; 56 in the individualized arm and 62 in the conventional arm. There were no significant differences between the two arms in their baseline demographics, mean duration of therapy and mean dose per day. The primary outcome (bleeding) occurred in one patient (2%) in the individualized arm and nine (15%) in the conventional arm (RR = 0.12, 95%CI = 0.01-0.89; P = 0.03). Six patients (11%) in the individualized arm and 21 (34%) in the conventional arm had a composite bleeding or major bruising event (RR = 0.30, 95%CI = 0.12-0.71; P = 0.003). In both arms of the study there were no recurrent thromboembolic events during treatment and no deaths had occurred at 30 days [5].

PD data were obtained from 103 of the 118 patients. The final categorical model included cumulative AUC (cAUC) & age:

Logit (S0) = 2.83 - 2.75 * cAUC / 23 IU ml/hr - 0.54 * Age / 61 yr

Logit (S1) = Logit (S0) + 2.05

Simulations showed that dose individualization reduces the probability of a major bruise or bleeding event. This was most noticeable in patients with both obesity and renal impairment.

To further support the confirmatory study, data (cAUC and age) from patients in both treatment arms were introduced into the final categorical model. Plots of the probability of a major bruise or bleeding event versus cAUC clearly demonstrate the benefits of using an individualized dosing strategy.

Conclusion: Individualized dosing regimens for enoxaparin, based on prior population PKPD analyses, reduce the prevalence and severity of bleeding and bruising events when compared to conventional dosing, without apparent loss of effectiveness.

[1] Evans W, Relling M, et al. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. New Engl J Med. 338: 499-505 (1998).
[2] Green B, Duffull SB. Development of a dosing strategy for enoxaparin in obese patients. Br J Clin Pharmacol. 54: 96-103 (2002).
[3] Green B, Greenwood M, et al. Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes. Br J Clin Pharmacol. 59 (3): 281-290 (2004).
[4] Sheiner LB. Learning versus confirming in clinical drug development. Clin Pharmacol Ther. 61 (3): 275-291 (1997).
[5] Barras MA, Duffull SB, Atherton JJ, Green B. Individualized compared to conventional dosing of enoxaparin. Clin Pharmacol Ther. Advance online 10 October (2007).

Reference: PAGE 17 (2008) Abstr 1259 [www.page-meeting.org/?abstract=1259]
Oral Presentation: Applications