Based on population pharmacokinetic analysis, following intravenous infusion of KADCYLA, the clearance of the ADC was 0.68 L/day and the elimination half-life (t1/2) was approximately 4 days. No accumulation of KADCYLA was observed after repeated dosing of intravenous infusion every 3 weeks.
 
Based on population pharmacokinetic analysis (n=671), body weight, sum of longest diameter of target lesions by RECIST, HER2 extracellular domain (ECD) concentrations, AST, albumin, and baseline trastuzumab concentrations were identified as statistically significant covariates for ado-trastuzumab emtansine clearance. However, the magnitude of effect of these covariates on ado-trastuzumab emtansine exposure suggests that, with the exception of body weight, these covariates are unlikely to have a clinically meaningful effect on KADCYLA exposure. Therefore, the body weight based dose of 3.6 mg/kg every 3 weeks without correction for other covariates is considered appropriate.
 
Effect of Renal Impairment

Based on population pharmacokinetic analysis in 668 patients, including moderate (CLcr 30 - 59 mL/min, n=53) and mild (CLcr 60 - 89 mL/min, n=254) renal impairment, indicate that pharmacokinetics of the ADC is not affected by mild to moderate renal impairment as compared to normal renal function (CLcr ≥ 90 mL/min, n=361). Data from only one patient with severe renal impairment (CLcr < 30 mL/min) is available [see Use in Specific Populations (8.7)].
 
Effects of Age and Race

Based on population pharmacokinetic analysis, age (< 65 (n=577); 65 - 75 (n=78); > 75 (n=16)) and race (Asian (n=73); non-Asian (n=598)) do not have a clinically meaningful effect on the pharmacokinetics of ado-trastuzumab emtansine.
 
12.6 Cardiac Electrophysiology
 
The effect of multiple doses of KADCYLA (3.6 mg/kg every 3 weeks) on the QTc interval was eva luated in an open label, single arm study in 51 patients with HER2-positive metastatic breast cancer. No large changes in the mean QT interval (i.e., > 20 ms) were detected in the study.
 
13 NONCLINICAL TOXICOLOGY
 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
 
Carcinogenicity studies have not been conducted with ado-trastuzumab emtansine.
 
DM1 was aneugenic or clastogenic in an in vivo single-dose rat bone marrow micronucleus assay at exposures that were comparable to mean maximum concentrations of DM1 measured in humans administered KADCYLA. DM1 was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.
 
Based on results from animal toxicity studies, KADCYLA may impair fertility in humans. In a single-dose toxicity study of ado-trastuzumab emtansine in rats, degeneration of seminiferous tubules with hemorrhage in the testes associated with increased weights of testes and epididymides at a severely toxic dose level (60 mg/kg; about 4 times the clinical exposure based on AUC) were observed. The same dose in female rats resulted in signs of hemorrhage and necrosis of the corpus luteum in ovaries. In monkeys dosed with ado-trastuzumab emtansine once every three weeks for 12 weeks (four doses), at up to 30 mg/kg (about 7 times the clinical exposure based on A