Refludan (Lepirudin) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

PHARMACOKINETIC PROPERTIES

The pharmacokinetic properties of lepirudin following intravenous administration are well described by a two-compartment model. Distribution is essentially confined to extracellular fluids and is characterized by an initial half-life of approximately 10 minutes. Elimination follows a first-order process and is characterized by a terminal half-life of about 1.3 hours in young healthy volunteers. As the intravenous dose is increased over the range of 0.1 to 0.4 mg/kg, the maximum plasma concentration and the area-under-the-curve increase proportionally.

Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis of the parent drug. However, conclusive data are not available. About 48% of the administration dose is excreted in the urine which consists of unchanged drug (35%) and other fragments of the parent drug.

The systemic clearance of lepirudin is proportional to the glomerular filtration rate or creatinine clearance. Dose adjustment based on creatinine clearance is recommended (see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy ; Use in Renal Impairment). In patients with marked renal insufficiency (creatinine clearance below 15 mL/min) and on hemodialysis, elimination half-lives are prolonged up to 2 days.

The systemic clearance of lepirudin in women is about 25% lower than in men. In elderly patients, the systemic clearance of lepirudin is 20% lower than in younger patients. This may be explained by the lower creatinine clearance in elderly patients compared to younger patients.

Table 1 summarizes systemic clearance (Cl) and volume of distribution at steady state (Vss) of lepirudin for various study populations.

PHARMACODYNAMIC PROPERTIES

The pharmacodynamic effect of REFLUDAN on the proteolytic activity of thrombin was routinely assessed as an increase in aPTT. This was observed with increasing plasma concentrations of lepirudin, with no saturable effect up to the highest tested dose (0.5 mg/kg body weight intravenous bolus). Thrombin time (TT) frequently exceeded 200 seconds even at low plasma concentrations of lepirudin, which renders this test unsuitable for routine monitoring of REFLUDAN therapy.

The pharmacodynamic response defined by the aPTT ratio (aPTT at a time after REFLUDAN administration over an aPTT reference value, usually median of the laboratory normal range for aPTT) depends on plasma drug levels which in turn depend on the individual patient's renal function (see CLINICAL PHARMACOLOGY: Pharmacokinetic Properties). For patients undergoing additional thrombolysis, elevated aPTT ratios were already observed at low lepirudin plasma concentrations, and further response to increasing plasma concentrations was relatively flat. In other populations, the response was steeper. At plasma concentrations of 1500 ng/mL, aPTT ratios were nearly 3.0 for healthy volunteers, 2.3 for patients with heparin-induced thrombocytopenia, and 2.1 for patients with deep venous thrombosis.

CLINICAL TRIAL DATA

Heparin-induced thrombocytopenia (HIT) is described as an allergy-like adverse reaction to heparin. It can be found in about 1% to 2% of patients treated with heparin for more than 4 days. The clinical picture of HIT is characterized by thrombocytopenia alone or in combination with thromboembolic complications (TECs). These complications comprise the entire spectrum of venous and arterial thromboembolism including deep venous thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and occlusion of limb arteries, which may ultimately result in necroses requiring amputation. Furthermore, there is evidence to suggest that warfarin-induced venous limb gangrene may be associated with HIT. Without further treatment, the mortality in HIT patients with new TECs is about 20% to 30% (Fondu 1995; Greinacher 1995; Warkentin, Chong, et al., Warkentin, Elavathil, et al. 1997).

The conclusion that REFLUDAN is an effective treatment for HIT is based upon the data of two prospective, historically controlled clinical trials ("HAT-1" study and "HAT-2" study). The trials were comparable with regard to study design, primary and secondary objectives, and dosing regimens, as well as general study outline and organization. They both used the same historical control group for comparison. This historical control was mainly compiled from a recent retrospective registry of HIT patients.

Overall, 198 (HAT-1: 82, HAT-2: 116) patients were treated with REFLUDAN and 182 historical control patients were treated with other therapies. All except 5 (HAT-1: 1, HAT-2: 4) prospective patients and all historical control patients were diagnosed with HIT using the heparin-induced platelet activation assay (HIPAA) or equivalent assays for testing. In total, 113 (HAT-1: 54, HAT-2: 59) prospective patients ("REFLUDAN") and 91 historical control patients ("historical control") presented with TECs at baseline (day of positive test result) and qualified for direct comparison of clinical endpoints.

The gender distribution was found to be similar in REFLUDAN patients and historical control patients. Overall, REFLUDAN patients tended to be younger than historical control patients. Table 2 summarizes the demographic baseline characteristics of patients presenting with TECs at baseline.

The key criteria of efficacy from a laboratory standpoint (n=115 evaluable patients) were platelet recovery (increase in platelet count by at least 30% of nadir to values >100,000) and effective anticoagulation (aPTT ratio >1.5 with a maximum total 40% increase in the initial infusion rate). The proportions of REFLUDAN patients presenting with TECs at baseline who showed platelet recovery, effective anticoagulation, or both (laboratory responders) are shown in Table 3. Comparable rates for the historical control group cannot be given, because (1) platelet counts were not monitored as closely as in the REFLUDAN group, and (2) most historical control patients did not receive therapies affecting aPTT.

Comparisons of clinical efficacy were made between REFLUDAN patients and historical control patients with regard to the combined and individual incidences of death, limb amputation, or new TEC.

The original main analyses included all events that occurred after laboratory confirmation of HIT. This approach was revealed to be substantially confounded by the relative contribution of the pretreatment period (time between laboratory confirmation of HIT and start of treatment). Although short in duration (mean length 1.5 days in HAT-1 and 2.0 days in HAT-2), the pretreatment period accounted for 45% and 26% of events observed in the main analyses of HAT-1 REFLUDAN patients and HAT-2 REFLUDAN patients, respectively. Therefore, initiation of treatment was set as the starting point for the analyses. For the historical control group, the first treatment selected within 2 days of laboratory confirmation of HIT was used for reference.

Seven days after start of treatment, the cumulative risk of death, limb amputation, or new TEC was 3.7% in the HAT-1 REFLUDAN patients and 16.9% in the HAT-2 REFLUDAN patients, as compared to 24.9% in the historical control group. At 35 days, when approximately 10% of patients were still at risk, the cumulative risk was 13.0% in the HAT-1 REFLUDAN patients and 28.9% in the HAT-2 REFLUDAN patients, as compared to 47.8% in the historical control group.

In an additional meta-analysis, the pooled REFLUDAN patients of the HAT-1 and HAT-2 studies who presented with TECs at baseline were compared to the respective historical control patients. Seven and 35 days after start of treatment, the cumulative risks of death were 4.4% and 8.9% in the REFLUDAN group, as compared to 1.4% and 17.6% in the historical control group. The cumulative risks of limb amputation were 2.7% and 6.5% in the REFLUDAN group, as compared to 2.6% and 10.4% in the historical control group. Most importantly, the cumulative risks of new TEC were 6.3% and 10.1% in the REFLUDAN group, as compared to 22.2% and 27.2% in the historical control group. As shown in Fig 1, the differences in the cumulative risk of death, limb amputation, or new TEC between the groups were statistically significant in favor of REFLUDAN in the analysis of time to event (P = 0.004 according to log-rank test).

The immediate impact of treatment on the combined risk of death, limb amputation, or new TEC is demonstrated by comparing pretreatment period and treatment period in regard to average combined event rates per patient day. In the pretreatment period, these rates were found to be 0.075 in the HAT-1 REFLUDAN patients, 0.052 in the HAT-2 REFLUDAN patients, and 0.040 in the historical control group. In the treatment period, the rates showed a marked reduction in the REFLUDAN patients, where they dropped to 0.005 (HAT-1) and to 0.018 (HAT-2), while there was only a moderate decrease to 0.030 in the historical control group.

In conclusion, REFLUDAN substantially reduced the risk of serious sequelae of HIT in comparison to a historical control group.