nstitution and dilution. After reconstitution with 7.2 mL of Sterile Water forInjection, USP, the final concentration is 20 mg/mL with a pH of approximately 5.3. Eachsingle-dose vial delivers 140 mg of polatuzumab vedotin-piiq, polysorbate-20 (8.4 mg), sodiumhydroxide (3.80 mg), succinic acid (8.27 mg), sucrose (288 mg).
The POLIVY vial stoppers are not made with natural rubber latex.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Polatuzumab vedotin-piiq is a CD79b-directed antibody-drug conjugate with activity againstdividing B cells. The small molecule, MMAE is an anti-mitotic agent covalently attached to theantibody via a cleavable linker. The monoclonal antibody binds to CD79b, a B-cell specificsurface protein, which is a component of the B-cell receptor. Upon binding CD79b, polatuzumabvedotin-piiq is internalized, and the linker is cleaved by lysosomal proteases to enableintracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells byinhibiting cell division and inducing apoptosis.
12.2 Pharmacodynamics
Over polatuzumab vedotin-piiq dosages of 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approvedrecommended dosage), a higher exposure was associated with higher incidence of some adversereactions (e.g., ≥Grade 2 peripheral neuropathy, ≥Grade 3 anemia) and a lower exposure wasassociated with lower efficacy.
Cardiac Electrophysiology
Polatuzumab vedotin-piiq did not prolong the mean QTc interval to any clinically relevant extentbased on ECG data from two open-label studies in patients with previously treated B-cellmalignancies at the recommended dosage.
12.3 Pharmacokinetics
The exposure parameters of antibody-conjugated MMAE (acMMAE) and unconjugated MMAE(the cytotoxic component of polatuzumab vedotin-piiq) are summarized in Table 6. The plasmaexposure of acMMAE and unconjugated MMAE increased proportionally over a polatuzumabvedotin-piiq dose range from 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommendeddosage). Cycle 3 acMMAE AUC were predicted to increase by approximately 30% over Cycle 1AUC, and achieved more than 90% of the Cycle 6 AUC. Unconjugated MMAE plasmaexposures were <3% of acMMAE exposures and the AUC and Cmax were predicted to decreaseafter repeated every-3-week dosing.
Table 6 Exposure Parameters of acMMAE and Unconjugated MMAEa
acMMAE
Mean (± SD)
Unconjugated MMAE
Mean (± SD)
Cmax (ng/mL) 803 (± 233) 6.82 (± 4.73)
AUCinf (day*ng/mL) 1860 (± 966) 52.3 (± 18.0)
Cmax=maximum concentration, AUCinf = area under the concentration-time curve from time zero to
infinity
a After the first polatuzumab vedotin-piiq dose of 1.8 mg/kg.
Distribution
The acMMAE central volume of distribution estimated based on population PK analysis is
3.15 L. For human, MMAE plasma protein binding is 71% to 77% and the blood to plasma ratio
is 0.79 to 0.98, in vitro.
Elimination
The acMMAE terminal half-life is approximately 12 days (95% CI: 8.1 to 19.5 days) at Cycle 6with predicted clearance of 0.9 L/day. The unconjugated MMAE terminal half-life isapproximately 4 days after the first polatuzumab vedotin-piiq dose.
Metabolism
Polatuzumab vedotin-piiq catabolism has not been studied in humans; however, it is expected toundergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugatedMMAE-related catabolites. MMAE is a substrate for CYP3A4.
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