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. 2025 Mar 21;95(1):46.
doi: 10.1007/s00280-025-04769-6.

Population pharmacokinetic analysis of bevacizumab in Japanese cancer patients with proteinuria: a prospective cohort study

Takashi Masuda  1   2 , Taro Funakoshi  3 , Takahiro Horimatsu  3 , Sho Masui  1   2   4 , Daiki Hira  1 , Marin Inoue  4 , Kodai Yajima  4 , Shunsaku Nakagawa  1 , Yasuaki Ikemi  1 , Junzo Hamanishi  5 , Atsushi Takai  6 , Shinya Yamamoto  7 , Takeshi Matsubara  7 , Masaki Mandai  5 , Hiroshi Seno  6 , Motoko Yanagita  7   8 , Manabu Muto  3 , Tomohiro Terada  1 , Atsushi Yonezawa  9   10   11
Affiliations

Population pharmacokinetic analysis of bevacizumab in Japanese cancer patients with proteinuria: a prospective cohort study

Takashi Masuda et al. Cancer Chemother Pharmacol. .

Abstract

Purpose: Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics.

Methods: This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL).

Results: Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0.

Conclusion: We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.

Keywords: Bevacizumab; Population pharmacokinetics; Proteinuria; Urinary protein to creatinine ratio.

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Conflict of interest statement

Declarations. Conflict of interest: J.H. has received a research grant from Chugai Pharmaceutical Co., Ltd. M.Y. has received research grants and/or speaking fee from Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical CO., LTD., Astellas Pharma Inc., AstraZeneca K.K., Kyowa Kirin Co., Ltd., Bayer Yakuhin, Ltd., and Boehringer Ingelheim GmbH. M.Muto. has received a research grant and speaking fee from Chugai Pharmaceutical Co., Ltd. A.Y. has received a research grant from Shimadzu Corporation. Ethical approval: The current study adhered to the principles of the Declaration of Helsinki and was approved by the Medical Ethics Committee of the Kyoto University Graduate School and Faculty of Medicine (Approval No. R2643). Consent to participate: Written informed consent for participation in this study was obtained from all patients. Consent to publish: Patients signed informed consent regarding publishing their data.

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