Application of a Two-Analyte Integrated Population Pharmacokinetic Model to Evaluate the Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Polatuzumab Vedotin in Patients with Non-Hodgkin Lymphoma

• Published in: Pharmaceutical research Vol. 37; no. 12; p. 252
• Main Authors: Lu, Dan, Lu, Tong, Shi, Rong, Gibiansky, Leonid, Agarwal, Priya, Shemesh, Colby S., Dere, Randall C., Ogbu, Uzor, Hirata, Jamie, Chanu, Pascal, Girish, Sandhya, Jin, Jin Yan, Li, Chunze, Miles, Dale
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2020; Springer; Springer Nature B.V
• Subjects: B cells; Bayesian analysis; Bendamustine; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Care and treatment; Dose-response effects; Liver; Lymphoma; Medical Law; Monoclonal antibodies; Non-Hodgkin's lymphoma; Non-Hodgkin's lymphomas; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Research Paper; Rituximab; Targeted cancer therapy; Vincristine; integrated two-analyte; non-Hodgkin lymphoma; antibody-drug conjugate; population pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-020-02933-6

Purpose
The 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.
Methods
Model 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.
Results
No 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.
Conclusions
In 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.