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Kalbitor

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Kalbitor

CLINICAL PHARMACOLOGY

Mechanism of Action

Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to Cl-esterase-inhibitor (Cl-INH) located on Chromosome 1 lq and inherited as an autosomal dominant trait. HAE is characterized by low levels of Cl-INH activity and low levels of C4. Cl-INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved n i the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.

KALBITOR (ecallantide injection) is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. KALBITOR (ecallantide injection) binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, KALBITOR (ecallantide injection) reduces the conversion of HMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.

Pharmacodynamics

No exposure-response relationships for KALBITOR (ecallantide injection) to components of the complement or kallikrein-kinin pathways have been established.

The effect of KALBITOR (ecallantide injection) on activated partial thromboplastin time (aPTT) was measured because of potential effect on the intrinsic coagulation pathway. Prolongation of aPTT has been observed following intravenous dosing of KALBITOR (ecallantide injection) at doses ≥ 20 mg/m². At 80 mg administered intravenously in healthy subjects, aPTT values were prolonged approximately two-fold over baseline values and returned to normal by 4 hours post-dose.

For patients taking KALBITOR (ecallantide injection) , no significant QT prolongation has been seen. In a randomized, placebo-controlled trial (EDEMA4) studying the 30 mg subcutaneous dose versus placebo, 12-lead ECGs were obtained at baseline, 2 hours and 4 hours post-dose (covering the time of expected Cmax), and at follow-up (day 7). ECGs were evaluated for PR interval, QRS complex, and QTc interval. KALBITOR (ecallantide injection) had no significant effect on the QTc interval, heart rate, or any other components of the ECG.

Pharmacokinetics

Following the administration of a single 30 mg subcutaneous dose of KALBITOR (ecallantide injection) to healthy subjects, a mean (± standard deviation) maximum plasma concentration of 586 ± 106 ng/mL was observed approximately 2 to 3 hours post-dose. The mean area under the concentration-time curve was 3017 ± 402 ng*hr/mL. Following administration, plasma concentration declined with a mean elimination half-life of 2.0 ± 0.5 hours. Plasma clearance was 153 ± 20 mL/min and the volume of distribution was 26.4 ± 7.8 L. Based on a population pharmacokinetic analysis, body weight, age, and gender were not found to affect KALBITOR exposure significantly. Ecallantide is a small protein (7054 Da) and renal elimination in the urine of treated subjects has been demonstrated.

No pharmacokinetic data are available in patients or subjects with hepatic or renal impairment.

Animal Toxicology

Reproductive Toxicology Studies

KALBITOR (ecallantide injection) has been shown to cause developmental toxicity in rats, but not rabbits. Treatment of rats with an intravenous dose of 15 mg/kg/day (approximately 13 times the MRHD on a mg/kg basis) caused increased numbers of early resorptions and percentages of resorbed conceptuses per litter in the presence of mild maternal toxicity. However, no development toxicity was observed in rats that received an intravenous dose of 10 mg/kg/day (approximately 8 times the MRHD on a mg/kg basis). KALBITOR (ecallantide injection) was not teratogenic in rats at subcutaneous doses up to 20 mg/kg/day (approximately 2.4 times the MRHD on an AUC basis) and rabbits that received intravenous doses up to 5 mg/kg/day (approximately 6 times the MRHD on an AUC basis).

Clinical Studies

The safety and efficacy of KALBITOR (ecallantide injection) was evaluated in 2 randomized, double-blind, placebo-controlled trials (EDEMA4 and EDEMA3) in 168 patients with HAE. Patients having an attack of hereditary angioedema, at any anatomic location, with at least 1 moderate or severe symptom, were treated with 30 mg subcutaneous KALBITOR (ecallantide injection) or placebo. Because patients could participate in both trials, a total of 143 unique patients participated. Of the 143 patients, 94 were female, 123 were Caucasian, and the mean age was 36 years. There were 64 patients with abdominal attacks, 55 with peripheral attacks, and 24 with laryngeal attacks.

In both trials, the effects of KALBITOR (ecallantide injection) were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). These measures evaluated the severity of attack symptoms at all anatomical locations (MSCS score) and response to therapy (TOS).

MSCS score is a point-in-time measure of symptom severity. At baseline, 4 hours, and 24 hours, patients rated the severity on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe) for symptoms at each affected anatomical location. Ratings were averaged to obtain the MSCS score. A decrease in MSCS score reflected an improvement in symptoms.

TOS is a measure of symptom response to treatment. At 4 hours and 24 hours, patient assessment of response characterized by their change from baseline in symptom severity and collected by anatomic site of attack involvement, was recorded on a categorical scale (significant improvement [100], improvement [50], same [0], worsening [-50], significant worsening [-100]). The response at each anatomic site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the TOS. A TOS value > 0 reflected an improvement in symptoms from baseline.

EDEMA4

EDEMA4 was a randomized, double-blind, placebo-controlled trial in which 96 patients were randomized 1:1 to receive KALBITOR (ecallantide injection) 30 mg subcutaneous or placebo for acute attacks of HAE. The primary endpoint was the change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with KALBITOR (ecallantide injection) demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients with placebo and the results were statistically significant (Table 2). At 24 hours, patients treated with KALBITOR (ecallantide injection) also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater TOS (89 vs. 55, p = 0.03).

Table 2: Change in MSCS Score and TOS at 4 Hours

  EDEMA4 EDEMA3
KALBITOR
(N=48)
Placebo
(N=48)
KALBITOR
(N=36)
Placebo
(N=36)
Change in MSCS Score at 4 Hours
  n 47 42 34 35
  Mean -0.8 -0.4 -1.1 -0.6
  95% CI -1.0,-0.6 -0.6,-0.1 -1.4,-0.8, -0.8, -0.4
  P-value 0.010   0.041  
TOS at 4 Hours
  n 47 42 34 35
  Mean 53 8 63 36
  95% CI 39,68 -12, 28 49,76 17,54
  P-value 0.003   0.045  
MSCS: Mean Symptom Complex Severity
TOS: Treatment Outcome Score
CI: confidence interval

More patients in the placebo group (24/48, 50%) required medical intervention to treat unresolved symptoms within 24 hours compared to the KALBITOR (ecallantide injection) -treated group (16/48,33%).

Some patients reported improvement following a second 30 mg subcutaneous dose of KALBITOR (ecallantide injection) , administered within 24 hours following the initial dose for symptom persistence or relapse, but efficacy was not systematically assessed for the second dose.

EDEMA3

EDEMA3 was a randomized, double-blind, placebo-controlled trial in which 72 patients were randomized 1:1 to receive KALBITOR (ecallantide injection) or placebo for acute attacks of HAE. EDEMA3 was similar in design to EDEMA4 with the exception of the order of the prespecified efficacy endpoints. In EDEMA3, the primary endpoint was the TOS at 4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hours. As in EDEMA4, patients treated with KALBITOR (ecallantide injection) demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients treated with placebo and the results were statistically significant (Table 2).

In addition, more patients in the placebo group (13/36, 36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the KALBITOR (ecallantide injection) -treated group (5/36, 14%).

Last reviewed on RxList: 12/14/2009
This monograph has been modified to include the generic and brand name in many instances.

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