Praxbind (Page 3 of 4)

12.3 Pharmacokinetics

There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. A dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed.

Distribution
Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady state (Vss ) was 8.9 L (geometric coefficient of variation (gCV 24.8%)).

Elimination
Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and a terminal half-life of 10.3 h (gCV 18.9%). After intravenous administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a collection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.

Metabolism
Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis.

Specific Populations
Age, Sex, Race and Body Weight
Age, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses which included data from 220 volunteers and 486 patients.

Patients with Renal Impairment
Idarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance [CrCl] 60 to <90 mL/min, by Cockcroft-Gault equation) and 6 subjects with moderate impairment (CrCl30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading to an increase in idarucizumab’s area under the curve (AUC) by 43.5% and 83.5% in mild and moderate renal impairment, respectively. No dose adjustment is required in renally impaired patients.

Based on pharmacokinetic data from 347 patients with varying degrees of renal function (median CrCl 21 to 99 mL/min) it is estimated that mean idarucizumab exposure (AUC0–24h ) increased by 38%, 90%, and 146% in patients with mild renal impairment (CrCl 50 to <80 mL/min), moderate renal impairment (CrCl 30 to <50 mL/min) and severe renal impairment (CrCl 0 to <30 mL/min), respectively. Since dabigatran is also excreted primarily via the kidneys, increases in the exposure to dabigatran are also seen with worsening renal function.

13  NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with idarucizumab. No animal studies have been performed to evaluate the potential effects of idarucizumab on fertility in males or females or on reproduction and development.

14  CLINICAL STUDIES

The safety and effectiveness of PRAXBIND was investigated in three randomized placebo-controlled healthy volunteer trials, Trials 1321.1, 1321.2 and 1321.5 (NCT01688830, NCT01955720, NCT02028780), and in RE-VERSE AD (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial (NCT02104947), a single cohort case series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedure.

Healthy Volunteers Trials 1321.1, 1321.2 and 1321.5 in a total of 283 subjects assessed the safety, dose-response, and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and 30 subjects aged 65 years or older (overall mean age 36 years).

The tables below summarize the idarucizumab effect on coagulation parameters dTT, aPTT, ECT, TT, and ACT over time for 14 subjects treated in Trial 1321.2. Fourteen subjects received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as one 5 g intravenous infusion over five minutes. Table 1 shows the results of the idarucizumab treatment group and Table 2 shows the results of the placebo treatment group.

Table 1 Change in Coagulation Parameters in 14 Dabigatran-exposed Subjects Treated with 5 g Idarucizumab
Clotting Assay(Mean and Standard Deviation) Pre-Idarucizumab(N=14) End of infusion of Idarucizumab(N=14) 24 hours afterIdarucizumab(N=14)
dTT [s]66.6 (12.0)32.1 (1.38)33.0 (1.69)
aPTT [s]67.8 (14.5)29.2 (4.74)31.9 (5.71)
ECT [s]122 (42.2)34.7 (1.92)38.8 (2.86)
TT [s]127 (62.6)12.5 (0.786)19.3 (5.14)
ACT [s]236 (47.6)116 (7.71)140 (10.1)
Table 2 Change in Coagulation Parameters in 14 Dabigatran-exposed Subjects Treated with Placebo
Clotting Assay(Mean and Standard Deviation) Pre-Placebo(N=14) End of infusion of Placebo(N=14) 24 hours afterPlacebo(N=14)
dTT [s]64.7 (9.82)65.3 (12.1)36.1 (2.48)
aPTT [s]65.2 (14.0)66.5 (13.2)37.0 (7.10)
ECT [s]117 (29.8)122 (32.9)44.7 (5.39)
TT [s]132 (35.4)147 (46.7)39.5 (11.8)
ACT [s]219 (44.7)216 (50.5)148 (15.1)

The effect of idarucizumab on reducing unbound dabigatran in healthy volunteers is summarized in section 12.2, Pharmacodynamics.

RE-VERSE AD Patient Experience In RE-VERSE AD, 5 g idarucizumab was administered to patients treated with dabigatran who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint was the maximum percentage reversal of the pharmacodynamic anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT.

RE-VERSE AD included data for 503 patients: 301 patients with serious bleeding (Group A) and 202 requiring an urgent procedure (Group B). Approximately half of the patients in each group were male. The median age was 78 years and the median creatinine clearance was 53 mL/min. Approximately 62% of patients in Group A and 62% of patients in Group B had been treated with dabigatran 110 mg BID.

Reversal was evaluable only for those patients showing prolonged coagulation times prior to idarucizumab treatment. Among the evaluable patients, the median maximum reversal of the pharmacodynamic anticoagulant effect of dabigatran as measured by ECT, aPTT or dTT in the first 4 hours after administration of 5 g idarucizumab was 100%, with most patients achieving complete reversal as measured by ECT (82%), aPTT (93%) or dTT (99%). Reversal of the pharmacodynamics effects was evident immediately after administration. Results for Groups A and B were similar. In a limited number of patients, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., aPTT or ECT) have been observed. Eight patients were treated with more than 5 g idarucizumab due to rebleeding, a second emergency procedure and/or bleeding after an emergency surgical procedure. ECT measures over the 24-hour observation time are shown in Figure 6.

figure-6
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Activated partial thromboplastin time (aPTT) showed similar results to ECT (see Figure 7).

figure-7
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