Early change in the clearance of pembrolizumab reflects the survival and therapeutic response: A population pharmacokinetic analysis in real-world non-small cell lung cancer patients. (November 2022)

• Record Type: Journal Article
• Authors: Ohuchi, Mayu; Yagishita, Shigehiro; Jo, Hitomi; Akagi, Kazumasa; Inaba Higashiyama, Ryoko; Masuda, Ken; Shinno, Yuki; Okuma, Yusuke; Yoshida, Tatsuya; Goto, Yasushi; Horinouchi, Hidehito; Makino, Yoshinori; Yamamoto, Noboru; Ohe, Yuichiro; Hamada, Akinobu
• Is Part Of: Lung cancer. Volume 173(2022)
• Page Start: 35
• Page End: 42
• Publication Date: 2022-11
• Subjects: Lung cancer -- Population pharmacokinetics -- Pembrolizumab -- Monoclonal antibody -- Immune checkpoint inhibitor; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2022.08.018
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: PPK model of 200 mg Q3W pembrolizumab in Japanese patients with NSCLC is developed. Early change in CL of pembrolizumab correlated with treatment effect and survival. The time-varying CL reflects the general condition improvement with pembrolizumab. The CL of pembrolizumab 200 mg Q3W in Japanese is lower than that of Westerners. Abstract: Objectives: The dosing pattern of pembrolizumab is based on population pharmacokinetic (Pop-PK) analysis of clinical trials. Data for Japanese patients or patient populations with poor conditions such as cachexia are scarce. In this study, we performed a Pop-PK analysis of Japanese non-small cell lung cancer patients and analyzed the relationship between exposure, treatment effect, and survival. Materials and Methods: A total of 270 blood samples from 76 patients who received 200 mg pembrolizumab every 3 weeks between March 2017 and December 2018 were included. Blood concentrations of pembrolizumab were measured using mass spectrometry, and Pop-PK analysis was conducted using the Phoenix NLME software with a one-compartment model. Results: The estimated median of clearance (CL) in this analysis population was 0.104 L/day, about half of the historical data for Western data. Overall, pembrolizumab CL decreased over time, with some populations showing increased CL early in the treatment and others showing decreased CL over time. When the time-varying CL was stratified by quartile, the group with decreasing CL showed significantly better treatment response and survival than the group with increasing CL, even though the group included more patients with cachexia. Detailed analysis suggested that the patient population that responded to pembrolizumab treatment had an improved general condition and reduced protein catabolism, further decreasing CL. Conclusion: In populations that benefit from pembrolizumab treatment, CL may be reduced early in their treatment, which may be a predictive and prognostic factor. However, further prospective validation of our findings is needed.