Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2   Pharmacodynamics

Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of calicheamicin to leukemic blast cells. Near maximal peripheral CD33 saturation was observed across studies after gemtuzumab ozogamicin dosing at dose levels of 2 mg/m2 and above.

At 9 mg/m2 gemtuzumab ozogamicin (2 doses, 14 days apart), the risk for VOD increases as the C max of the first dose of gemtuzumab ozogamicin increases. The increase in VOD is more prominent in patients with prior stem cell transplantation.

Pharmacokinetic Properties

12.3   Pharmacokinetics

There are no clinical PK data for the fractionated regimen. When gemtuzumab ozogamicin is administered at 9 mg/m2 (2 doses, 14 days apart), the Cmax following the first dose for patients who received 9 mg/m2 gemtuzumab ozogamicin was 3.0 mg/L and increased to 3.6 mg/L after the second dose.

Distribution

N-acetyl gamma calicheamicin dimethyl hydrazide is approximately 97% bound to human plasma proteins in vitro. Population PK analyses found the total volume of distribution of hP67.6 antibody (sum of V1 [6.31 L] and V2 [15.1 L]) to be approximately 21.4 L in patients.

Elimination

The clearance (CL) value of hP67.6 from plasma was 0.35 L/h after the first dose and 0.15 L/h after the second dose, a decrease of roughly 60%. The terminal plasma half-life (t ½) for hP67.6 was 62 hours after the first dose and 90 hours after the second dose.

Metabolism

In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolized, primarily via nonenzymatic reduction of the disulfide moiety.



Specific Populations

Age, race, sex, mild or moderate renal impairment (creatinine clearance [CLcr] 30-89 mL/min calculated by the Cockcroft-Gault equation) or mild hepatic impairment had no clinically significant effect on the pharmacokinetics of gemtuzumab ozogamicin. The pharmacokinetics of gemtuzumab ozogamicin in patients with severe renal impairment (CLcr 15-29 mL/min) or moderate (total bilirubin greater than 1.5x to 3.0x ULN) and severe hepatic impairment (total bilirubin greater than 3x ULN) is unknown.

Drug Interaction Studies

No clinical drug interaction studies have been performed.
In Vitro Studies

At clinically relevant concentrations, gemtuzumab ozogamicin had a low potential to: • Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.

At clinically relevant concentrations, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to:
• Inhibit CYP450 Enzymes: CYP1A2, CYP2B6 , CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
• Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.
• Inhibit UGT Enzymes: UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7.
• Inhibit Drug Transporters: P-gp (P-glycoprotein), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3.