Specific Populations
No clinically significant differences in the pharmacokinetics of polatuzumab vedotin-piiq wereobserved based on age (20 to 89 years), sex, or race/ethnicity (Asian and non-Asian). Noclinically significant differences in the pharmacokinetics of acMMAE or unconjugated MMAEwere observed based on mild to moderate renal impairment (CLcr 30 to 89 mL/min). In mildhepatic impairment (AST or ALT >1.0 to 2.5 × ULN or total bilirubin >1.0 to 1.5 × ULN), therewas a 40% increase in MMAE exposure, which was not deemed clinically significant.
The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with orwithout dialysis, moderate to severe hepatic impairment (AST or ALT >2.5 × ULN or totalbilirubin >1.5 × ULN), or liver transplantation on the pharmacokinetics of acMMAE orunconjugated MMAE is unknown.
Drug Interaction StudiesNo dedicated clinical drug–drug interaction studies with POLIVY in humans have been
conducted.
Physiologically-Based Pharmacokinetic (PBPK) Modeling Predictions:Strong CYP3A Inhibitor: Concomitant use of polatuzumab vedotin-piiq with ketoconazole(strong CYP3A inhibitor) is predicted to increase unconjugated MMAE AUC by 45%.
Strong CYP3A Inducer: Concomitant use of polatuzumab vedotin-piiq with rifampin (strongCYP3A inducer) is predicted to decrease unconjugated MMAE AUC by 63%.
Sensitive CYP3A substrate: Concomitant use of polatuzumab vedotin-piiq is predicted not toaffect exposure to midazolam (a sensitive CYP3A substrate).
Population Pharmacokinetic (popPK) Modeling Predictions:
Bendamustine or Rituximab: No clinically significant differences in the pharmacokinetics ofacMMAE or unconjugated MMAE when polatuzumab vedotin-piiq is used concomitantly withbendamustine or rituximab.
In Vitro Studies Where Drug Interaction Potential Was Not Further eva luated Clinically:
Cytochrome P450 (CYP) Enzymes: MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, or CYP2D6. MMAE does not induce major CYP enzymes.
Transporter Systems: MMAE does not inhibit P-gp. MMAE is a P-gp substrate.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in animals have not been performed with polatuzumab vedotin-piiq or
MMAE.
MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study throughan aneugenic mechanism. MMAE was not mutagenic in the bacterial reverse mutation (Ames)assay or the L5178Y mouse lymphoma forward mutation assay.
Fertility studies in animals have not been performed with polatuzumab vedotin-piiq or MMAE.
However, results of repeat-dose toxicity in rats indicate the potential for polatuzumab vedotinpiiqto impair male fertility. In the 4-week repeat-dose toxicity study in rats with weekly dosingof 2, 6, and 10 mg/kg, dose-dependent testicular seminiferous tubule degeneration with abnormallumen contents in the epididymis was observed. Findings in the testes and epididymis did notreverse and correlated with decreased testes weight and gross findings of small and/or soft testesat recovery necropsy in males given doses 2 mg/kg (below the exposure at the recommendeddose based on unconjugated MMAE AUC).
14 CLINICAL STUDIES
14.1 Relapsed or Refractory Diffuse Large B-cell Lymphoma
The efficacy of POLIVY was eva luated in Study GO29365 (NCT02257567), an op |
