Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

10.2 Pharmacodynamics
In an exposure-response analysis, higher enfortumab vedotin exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥ 2 peripheral neuropathy, Grade ≥ 3 hyperglycemia). The exposure response relationship for efficacy has not been fully characterized.
Cardiac Electrophysiology
At the recommended dose, PADCEV had no large QTc prolongation (> 20 msec).

Pharmacokinetic Properties

10.3 Pharmacokinetics
Population pharmacokinetic analysis included data from 748 patients based five studies. Enfortumab vedotin pharmacokinetics were characterized after single and multiple doses in patients with locally advanced or metastatic urothelial carcinoma and other solid tumors.
The exposure parameters of ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin) are summarized in Table 9 below. Peak ADC concentrations were observed near the end of intravenous infusion while peak MMAE concentrations were observed approximately 2 days after enfortumab vedotin dosing.
Minimal accumulation of the ADC and MMAE was observed following repeat administration of enfortumab vedotin in patients. Steady-state concentrations of ADC and MMAE were reached after 1 treatment cycle.


Table 9. Exposure parameters of ADC and unconjugated MMAE after first treatment cycle of 1.25 mg/kg of enfortumab vedotin dose of Days 1, 8 and 15
ADC                                 Unconjugated MMAE
Mean (± SD)                               Mean (± SD)

Cmax              28 (6.1) µg/mL                              5.5 (3.0) ng/mL 
AUC0-28d            110 (26) µg∙d/mL                             85 (50) ng∙d/mL 
Ctrough,0-28d           0.31 (0.18) µg/mL                           0.81 (0.88) ng/mL Cmax = maximum concentration, AUC0-28d = area under the concentration-time curve from time zero to 28 days, Ctrough,0-28d = pre-dose concentration on day 28
Distribution
The estimated mean steady-state volume of distribution of ADC was 12.8 liters following administration of enfortumab vedotin. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.
Elimination
ADC and MMAE exhibited multi-exponential declines with an elimination half-life of 3.6 days and 2.6 days, respectively. The mean clearance (CL) of enfortumab vedotin and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h, respectively, in patients. Elimination of MMAE appeared to be limited by its rate of release from enfortumab vedotin.
Metabolism
Enfortumab vedotin catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites.
Enfortumab vedotin releases MMAE via proteolytic cleavage, and MMAE is primarily metabolized by CYP3A4 in vitro.
Excretion
The excretion of enfortumab vedotin is not fully characterized. Following a single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after enfortumab vedotin administration.
Specific Populations
Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of enfortumab vedotin were observed based on age (24 to 90 years), sex, or race/ethnicity (Caucasian, Asian, Black, or others).
Hepatic Impairment
Based on population pharmacokinetics analysis, there was a 37% AUC0-28d increase in unconjugated MMAE exposure observed in patients with mild hepatic impairment (total bilirubin of 1 to 1.5 × ULN and AST any, or total bilirubin ≤ ULN and AST > ULN, n=65) compared to normal hepatic function. Enfortumab vedotin has only been studied in limited number of patients with moderate hepatic impairment and has not been evaluated in patients with severe hepatic impairment. The effect of moderate or severe hepatic impairment (total bilirubin > 1.5 x ULN and AST any) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.
Renal Impairment
The pharmacokinetics of enfortumab vedotin and unconjugated MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin to patients with mild (creatinine clearance; CrCL > 60–90 mL/min; n=272), moderate (CrCL 30–60 mL/min; n=315) and severe (CrCL < 30 mL/min; n=25) renal impairment. No significant differences in exposure (AUC) of ADC and MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. The effect of end stage renal disease with or without dialysis on the pharmacokinetics of ADC or unconjugated MMAE is unknown.
Drug Interaction Trials
No clinical trials evaluating the drug-drug interaction potential of enfortumab vedotin have been conducted.


Physiologically Based Pharmacokinetic (PBPK) Modeling Predictions:
Dual P-gp and Strong CYP3A4 Inhibitor: Concomitant use of enfortumab vedotin with ketoconazole (a dual P-gp and strong CYP3A4 inhibitor) is predicted to increase unconjugated MMAE Cmax by 15% and AUC by 38%.
Dual P-gp and Strong CYP3A4 Inducer: Concomitant use of enfortumab vedotin with rifampin (a dual P-gp and strong CYP3A4 inducer) is predicted to decrease unconjugated MMAE Cmax by 28% and AUC by 53%.
Sensitive CYP3A4 Substrates: Concomitant use of enfortumab vedotin is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate).
In Vitro Studies
Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.