Lung cancer (Amsterdam, Netherlands) · 2022
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.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.