Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2         Pharmacodynamics
A protective threshold for rabies virus neutralizing activity (RVNA) has never been established.
However, the WHO has generally accepted a RVNA of at least 0.5 IU/mL measured 14 days after initiation of post-exposure prophylaxis as protective.

Pharmacokinetic Properties

12.3         Pharmacokinetics
A randomized, single-dose, two-period, two-treatment, two-sequence, double-blind, crossover study assessed the pharmacokinetics of KamRAB. Twenty-six healthy volunteer subjects were randomized to receive a single IM injection of 20 IU/kg HRIG on two separate occasions (KamRAB or Comparator HRIG). Subjects received the second treatment (A or B) following the 42-day test period and a 21-day washout period. Single dose IM injection of KamRAB resulted in maximum plasma RVNA levels of 0.25 IU/mL. The median Tmax was 7 days (range: 3-14 days). The elimination half-life was approximately 17.9 days. A statistical analysis of the pharmacokinetic parameters showed that KamRAB was not bioequivalent to the Comparator HRIG (Table 4).
Table 4:         Statistical Analysis of Rabies Virus Neutralizing Antibody Pharmacokinetic Parameters - Crossover Study of KamRAB
Parameter        Units           Geometric LS Mean Values            Test/Reference        90% Confidence KamRAB          Comparator               (%)                 Interval HRIG                                         (%)

Cmax             IU/mL              0.24             0.30                 81.71               75.34-88.62 AUC0-last        Day*IU/mL          5.08             6.17                 82.35               77.39-87.63 AUC0-inf         Day*IU/mL          6.64             7.86                 84.44               78.63-90.68 Abbreviations: AUC: area under the concentration-time curve; Cmax: maximum concentration; inf: infinity; IU: international units; mL: milliliter; PK: Pharmacokinetic; RVNA: rabies virus neutralizing antibody 
A plot of plasma rabies virus neutralizing antibody titer concentration versus time (Figure 1) demonstrated that, in both treatment groups, plasma rabies virus neutralizing antibody concentrations declined in a biphasic manner after the absorption phase was complete.


Figure 1:     Plasma HRIG Concentrations [Mean (±SD)] at Scheduled PK Sampling Days (Semi-log Scale), Phase 2/3 Study, Pharmacokinetic Analysis



Additionally, a prospective, randomized, double-blind, non-inferiority, study evaluated the pharmacokinetics, safety, and effectiveness of simulated post-exposure prophylaxis with KamRAB with co-administration of active rabies vaccine in 118 healthy subjects. Subjects were randomized into two treatment groups (59 per treatment group) to receive intramuscular KamRAB or comparator HRIG at a dose of 20 IU/kg on Day 0, and rabies vaccine on Days 0, 3, 7, 14 and 28. The peak plasma RVNA was 71.9 IU/mL and 53.9 IU/mL for KamRAB and comparator HRIG respectively. For both treatment groups, the median Tmax was 14 days (range: 14-49 days). The half-lives were 48.6 hours and 52.7 hours for KamRAB and comparator HRIG respectively.
Bioequivalent assessment showed that KamRAB was not bioequivalent to the comparator HRIG when co-administered with a five-dose rabies vaccine regimen (Table 5). Furthermore, the RVNA on Day 3 was lower in the KamRAB with rabies vaccine group relative to the comparator HRIG with vaccine group (0.188+0.051 vs 0.229+0.054, P=0.0005). However, these pharmacokinetic differences are not expected to affect clinical outcomes.


Table 5:         Pharmacokinetic Comparison of Rabies Virus Neutralizing Antibody between KamRAB and a Comparator HRIG Administered with Rabies
Vaccine
Parameter          Units          Geometric LS Mean Values             Test/Referen       90% Confidence ce               Interval
KamRAB            Comparator
(Test)             HRIG                 (%)                 (%)
(Reference)
Cmax            IU/mL                 44.87                36.02            124.59           90.62-171.28 AUC0-last       Day*IU/mL            1741.40            1686.03             103.28           79.03-134.98 AUC0-inf        Day*IU/mL            2045.87            1916.90             106.73           80.48-141.54 Abbreviations: AUC: area under the concentration-time curve; Cmax: maximum concentration; inf: infinity; IU: international units; mL: milliliter; RVNA: rabies virus neutralizing antibody Please see Clinical Studies (13) section for clinical efficacy.