iller cells (-47%). Allmonitored cell counts returned to, or were elevated above baseline levels on Day 29 and thereafter. Atbaseline, the median IgA, IgG, and IgM levels were 107 mg/dL (11-260), 834 mg/dL (387-3003), and42 mg/dL (6-380), respectively, and remained generally unchanged at the end of treatment.
12.3 Pharmacokinetics The pharmacokinetics (PK) of moxetumomab pasudotox-tdfk was studied in patients with HCL at dosesranging from 0.005 to 0.05 mg/kg (about 0.1 to 1.3 times the approved recommended dosage)administered intravenously over 30 minutes on Days 1, 3, and 5 of a 28-day cycle. Moxetumomabpasudotox-tdfk concentrations increased dose-proportionally over the studied dose range.
The meansteady state moxetumomab pasudotox-tdfk exposures at the approved recommended dosages were 379 ng/mL (range: 20 to 862; SD: 262) for Cmax and 626 nghour/mL (range: 5 to 1960; SD: 610) forAUC0-last. No systemic accumulation of moxetumomab pasudotox-tdfk was observed. Baseline CD19+ Bcells were eva luated for association with the PK exposure and higher PK exposures were significantlyassociated with low baseline CD19+ counts (p < 0.001).
Distribution
The population PK model estimated mean volume of distribution of moxetumomab pasudotox-tdfk was6.5 L (SD 2.4).
Elimination The mean elimination half-life of moxetumomab pasudotox-tdfk was 1.4 hours (range: 0.8 to 1.8; SD:0.35). The population PK model estimated mean systemic clearance of moxetumomab pasudotox-tdfkafter the first dose of the first cycle was 25 L/hour (SD: 29.0) and after subsequent dosing was 4 L/hour(SD: 4.4).
Metabolism
The metabolic pathway of moxetumomab pasudotox-tdfk in humans is unknown, however, other proteintherapeutics generally undergo proteolytic degradation into small peptides and amino acids via catabolicpathways.
Specific Populations
No clinically significant differences in the pharmacokinetics of moxetumomab pasudotox-tdfk wereobserved for age (36 to 84 years), sex, race (White and non-White), body weight (42 to 152 kg), mildhepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN, or total bilirubin > 1to 1.5 times ULN and any AST), mild renal impairment (CLcr 60-89 mL/min; n=40), or moderate renalimpairment (CLcr 30-59 mL/min; n=4) based on population PK analysis.
The pharmacokinetics of moxetumomab pasudotox-tdfk in patients with moderate to severe hepaticimpairment (total bilirubin > 1.5 ULN) or severe renal impairment (CrCl ≤ 29 mL/min) is unknown.Anti-Product Antibody Formation Affecting PKIn patients who were ADA-positive with high titers, the presence of ADA post-baseline was associatedwith statistically significant (p < 0.05) lower PK exposure (Cmax) at later cycles (Cycle 3 and beyond).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo studies have been conducted to assess the carcinogenic or genotoxic potential of moxetumomabpasudotox-tdfk. Animal fertility studies have not been conducted with moxetumomab pasudotox-tdfk.
13.2 Animal Toxicology and/or Pharmacology
At a human equivalent dose > 3 times the recommended dose, degeneration of heart tissue was observedin cynomolgus monkeys. At a human equivalent dose > 10 times the recommended dose, gliosis in thebrain, axonal degeneration in the spinal cord, and body tremors were observed in cynomolgus monkeys.
14 CLINICAL STUDIES
The efficacy of LUMOXIT |
