Abstract
PurposeThe established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing.MethodsModel simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance.ResultsNo clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100–146 kg versus 38–<100 kg, age ≥ 65 years versus <65 years, female versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK.ConclusionsIn patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100–146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.
Highlights
Polatuzumab vedotin is a CD79b-directed antibodydrug conjugate (ADC) that targets proliferating B cells and contains the small-molecule, anti-mitotic agent, monomethyl auristatin E (MMAE)
In patients with non-Hodgkin lymphoma (NHL), bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100–146 kg)
Given that pola dosing is based on bodyweight, there is a risk of overdosing patients with a higher bodyweight considering that the power coefficient is less than one (0.73) for the effect of bodyweight on antibody-conjugated monomethyl auristatin E (acMMAE) clearance (9)
Summary
Polatuzumab vedotin (pola) is a CD79b-directed antibodydrug conjugate (ADC) that targets proliferating B cells and contains the small-molecule, anti-mitotic agent, monomethyl auristatin E (MMAE). MMAE is covalently conjugated to anti-CD79b IgG1 monoclonal antibody at the site of reduced disulfide bonds in the hinge region via a protease-cleavable linker, maleimidocaproyl-valine-citrullinep-aminobenzyloxycarbonyl (MC-vc-PAB) (2,3). Upon binding of the monoclonal antibody to CD79b, a signaling component of the B cell receptor (4), pola is internalized to the major histocompatibility complex class II positive compartment and the linker is cleaved by proteases for subsequent delivery of MMAE into the CD79b-positive lymphoma cells. MMAE binds to microtubules, inhibiting cell division and inducing apoptosis preferentially in proliferating tumor cells (5). The recommended dose of pola is 1.8 mg/kg as an intravenous infusion over 90 min every 21 days for six cycles; subsequent infusions after the first cycle may be administered over a shorter duration of 30 min if the previous infusion is tolerated (6)
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