Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E, or MMAE) to B-cells, which results in the killing of malignant B-cells. The polatuzumab vedotin molecule consists of MMAE covalently attached to a humanized immunoglobulin G1 monoclonal antibody via a cleavable linker. The monoclonal antibody binds with high affinity and selectivity to CD79b, a cell surface component of the B-cell receptor. CD79b expression is restricted to normal cells within the B-cell lineage (with the exception of plasma cells) and malignant B-cells; it is expressed in >95% of diffuse large B-cell lymphoma. Upon binding CD79b, polatuzumab vedotin is rapidly internalized and the linker is cleaved by lysosomal proteases to enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.
Polatuzumab vedotin did not prolong the mean QTc interval to any clinically relevant extent based on ECG data from two open-label studies in patients with previously treated B-cell malignancies at the recommended dosage.
Antibody-conjugated MMAE (acMMAE) plasma exposure increased dose-proportionally over the 0.1 to 2.4 mg/kg polatuzumab vedotin dose range. After the first 1.8 mg/kg polatuzumab vedotin dose, the acMMAE mean maximum concentration (Cmax) was 803 (±233) ng/mL and the area under the concentration-time curve from time zero to infinity (AUCinf) was 1860 (±966) day•ng/mL. Based on the population PK analysis, Cycle 3 acMMAE AUC increased by approximately 30% over Cycle 1 AUC, and achieved more than 90% of the Cycle 6 AUC. The terminal half-life at Cycle 6 was approximately 12 days (95% CI of 8.1-19.5 days) for acMMAE. Based on population PK analysis, the predicted acMMAE concentration at the end of Cycle 6 is approximately 80% of the theoretical steady-state value. Exposures of unconjugated MMAE, the cytotoxic component of polatuzumab vedotin, increased dose proportionally over the 0.1 to 2.4 mg/kg polatuzumab vedotin dose range. MMAE plasma concentrations followed formation rate limited kinetics. After the first 1.8 mg/kg polatuzumab vedotin dose, the Cmax was 6.82 (±4.73) ng/mL, the time to maximum plasma concentration is approximately 2.5 days, and the terminal half-life is approximately 4 days. Plasma exposures of unconjugated MMAE are <3% of acMMAE exposures. Based on the population PK analysis there is a decrease of plasma unconjugated MMAE exposure (AUC) after repeated everythree-week dosing.
Based on population pharmacokinetics simulations, a post-hoc analysis predicted exposure to unconjugated MMAE for patients with bodyweight over 100 kg to be increased by not more than 55%.
Polatuzumab vedotin is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
The population estimate of central volume of distribution for acMMAE was 3.15 L, which approximated plasma volume. In vitro, MMAE is moderately bound (71%-77%) to human plasma proteins. MMAE does not significantly partition into human red blood cells in vitro; the blood to plasma ratio is 0.79 to 0.98.
In vitro data indicate that MMAE is a P-gp substrate but does not inhibit P-gp at clinically relevant concentrations.
Polatuzumab vedotin is expected to undergo catabolism in patients, resulting in the production of small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE related catabolites. The levels of MMAE metabolites have not been measured in human plasma.
In vitro studies indicate that MMAE is a substrate for CYP3A4/5 but does not induce major CYP enzymes. MMAE is a weak time-dependent inhibitor of CYP3A4/5 but does not competitively inhibit CYP3A4/5 at clinically relevant concentrations.
MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
Based on a population PK analysis, the conjugate (acMMAE) is primarily eliminated by non-specific linear clearance pathway with a value of 0.9 L/day. In vivo studies in rats dosed with polatuzumab vedotin (radiolabel on MMAE) demonstrate that the majority of radioactivity is excreted in faeces and the minority of radioactivity is excreted in urine.
No studies have been conducted to investigate the pharmacokinetics of polatuzumab vedotin in the paediatric population (<18 years old).
Age did not have an effect on the pharmacokinetics of acMMAE and unconjugated MMAE based on population PK analyses with patients aged 19-89 years. No significant difference was observed in the pharmacokinetics of acMMAE and unconjugated MMAE among patients <65 years of age (n=394) and patients ≥65 years of age (n=495) based on population PK analyses.
In patients with mild (CrCL 60-89 mL/min, n=361) or moderate (CrCL 30-59 mL/min, n=163) renal impairment, acMMAE and unconjugated MMAE exposures are similar to patients with normal renal function (CrCL ≥ 90 mL/min, n=356), based on population PK analyses. There are insufficient data to assess the impact of severe renal impairment (CrCL 15-29 mL/min, n=4) on PK. No data are available in patients with end-stage renal disease and/or who are on dialysis.
In patients with mild hepatic impairment [AST or ALT >1.0 to 2.5 × ULN or total bilirubin >1.0 to 1.5 × ULN, n=133], acMMAE exposures are similar whereas unconjugated MMAE AUC are not more than 40% higher compared to patients with normal hepatic function (n=737), based on population PK analyses.
There are insufficient data to assess the impact of moderate hepatic impairment (total bilirubin >1.5-3 × ULN, n=11) on PK. Limited data are available in patients with severe hepatic impairment or liver transplantation.
In both rats and cynomolgus monkeys, the predominant systemic toxicities associated with administration of MMAE and polatuzumab vedotin included reversible bone marrow toxicity and associated peripheral blood cell effects.
No dedicated mutagenicity studies have been performed with polatuzumab vedotin. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.
MMAE was genotoxic in the rat bone marrow micronucleus study probably through an aneugenic mechanism. This mechanism is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent.
No dedicated carcinogenicity studies have been performed with polatuzumab vedotin and/or MMAE.
No dedicated fertility studies in animals have been performed with polatuzumab vedotin. However, results of the 4-week rat toxicity study indicate the potential for polatuzumab vedotin to impair male reproductive function and fertility. Testicular seminiferous tubule degeneration did not reverse following a 6-week treatment-free period and correlated with decreased testes weight and gross findings at recovery necropsy of small and/or soft testes in males given ≥2 mg/kg.
No dedicated teratogenicity studies in animals have been performed with polatuzumab vedotin. However, treatment of pregnant rats with MMAE at 0.2 mg/kg caused embryolethality and foetal malformations (including protruding tongue, malrotated limbs, gastroschisis, and agnathia). Systemic exposure (AUC) in rats at a dose of 0.2 mg/kg MMAE is approximately 50% of the AUC in patients who received the recommended dose of 1.8 mg/kg polatuzumab vedotin every 21 days.
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