Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2   Pharmacodynamics
The exposure-response relationships and the time course of pharmacodynamic response for ELZONRIS have not been fully characterized.

Pharmacokinetic Properties

12.3    Pharmacokinetics
Following administration of tagraxofusp 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) area under the plasma drug concentration over time curve (AUC) was 231 (123) hr·mcg/L and maximum plasma concentration (Cmax) was 162 (58.1) mcg/L.

Distribution
Mean (SD) volume of distribution of tagraxofusp is 5.1 (1.9) L in patients with BPDCN.

Elimination
Mean (SD) clearance is 7.1 (7.2) L/hr in patients with BPDCN. Mean (SD) terminal half-life of tagraxofusp is 0.7 (0.3) hours.

Specific Population
No clinically significant differences in the pharmacokinetics of tagraxofusp were observed based on age (22 to 84 years), sex, mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2, estimated by MDRD), mild (total bilirubin ≤ ULN and AST >ULN, or total bilirubin 1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment or body weight after adjusting dose by body weight. The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), or severe hepatic impairment (total bilirubin >3 times ULN and any AST) on tagraxofusp pharmacokinetics is unknown.

Drug Interaction Studies
No drug-drug interaction studies have been conducted with ELZONRIS.
12.4    Immunogenicity

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ELZONRIS with the incidences of antibodies to other products may be misleading. Immune response to ELZONRIS was evaluated by assessment of serum binding reactivity against ELZONRIS (anti-drug antibodies; ADA) and neutralizing antibodies by inhibition of functional activity. Immune response to ELZONRIS was assessed using two immunoassays. The first assay detected reactivity directed against ELZONRIS (ADA), and the second assay detected reactivity against the interleukin-3 (IL-3) portion of ELZONRIS. Two cell-based assays were used to investigate the presence of neutralizing antibodies by inhibition of a cell-based functional activity.

In 130 patients treated with ELZONRIS in 4 clinical trials:



•    96% (115/120) of patients evaluable for the presence of pre-existing ADA at baseline before treatment were confirmed positive with 21% being positive for the presence of neutralizing antibodies.
The high prevalence of ADA at baseline was anticipated due to diphtheria immunization.

•    99% (107/108) of patients evaluable for treatment-emergent ADA tested positive with most patients showing an increase in ADA titer by the end of Cycle 2 of ELZONRIS.

•    85% (86/101) of ADA-positive patients evaluable for the presence of neutralizing antibodies were neutralizing antibody-positive.

•    68% (73/108) of patients evaluable for treatment-emergent anti-IL-3 antibodies tested positive with most patients testing positive by Cycle 3 of ELZONRIS.

Anti-Product Antibody Effects on Pharmacokinetics
The presence of ADA had a clinically significant effect on the pharmacokinetics of tagraxofusp.
Pharmacokinetic data obtained following doses given in Cycle 3 showed increased titers of anti-drug antibodies and reduced free ELZONRIS concentration in most plasma samples. Following administration of tagraxofusp 12 mcg/kg via 15-minute infusion in patients with pre-existing anti-drug antibodies, the mean (SD) volume of distribution of tagraxofusp is 21.2 (25.4) L, clearance is 13.9 (19.4) L/hr, AUC is 151 (89.2) hr·mcg/L and Cmax is 80.0 (82.2) mcg/L.