An LC-MS/MS Method for Absolute Quantification of Nivolumab in Human Plasma: Application to Clinical Therapeutic Drug Monitoring

Therapeutic Drug Monitoring - Tập 40 Số 6 - Trang 716-724 - 2018
Kei Irie1,2, Akira Okada3,4, Yuta Yamasaki1, Chiyuki Kokan5, Akito Hata5, Reiko Kaji5, Keizo Fukushima3, Nobuyuki Sugioka3, Yutaka Okada2, Nobuyuki Katakami5, Shoji Fukushima1
1Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, Chuo−ku, Kobe;
2Division of Pharmacy, Institute of Biomedical Research and Innovation Hospital, Chuo−ku, Kobe. Dr. Irie is now with the Department of Pharmacy, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, Chuo−ku, Kobe;
3Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Science, Kobe Gakuin University, Chuo−ku, Kobe;
4Department of Regulatory Science, Faculty of Pharmacy, Musashino University, Nishitokyo−shi; and
5Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Chuo−ku, Kobe, Japan.

Tóm tắt

Background: Nivolumab is a fully humanized IgG4 monoclonal antibody that targets the programmed death-1 (PD-1) receptor, disrupting PD-1–mediated signaling and restoring antitumor immunity. The objective of this study was to develop a nivolumab quantification method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to evaluate its application in clinical therapeutic drug monitoring. Methods: Nivolumab was purified from human plasma using rProtein A resin and then digested with trypsin. The ASGITFSNSGMHWVR peptide (multiple reaction monitoring transition: m/z 550.6→661.4) was detected as a surrogate peptide of nivolumab by triple quadrupole mass spectrometry. Plasma samples (126) were collected from 14 patients with non–small cell lung cancer who were undergoing clinical dosing regimen with nivolumab. The pharmacokinetic data were analyzed using Phoenix NLME software (Version 7.0, Certara, St. Louis, MO) based on a previously reported population pharmacokinetics (PPK) model of nivolumab. Results: Nivolumab was selectively detected in human plasma and the linear range was 5–200 mcg/mL (R2 = 0.99). The accuracy and intraday and interday imprecision were within ±15% of the quality control values of 5 (lower limit of quantification), 10 (low), 80 (medium), and 160 (high) mcg/mL. The nivolumab concentrations measured using LC-MS/MS were consistent with those of previously reported PPK models, and the pharmacokinetic parameters could be adequately predicted from a single trough concentration using a Bayesian approach. Conclusions: An absolute quantification method for nivolumab using LC-MS/MS was successfully developed and validated. Combined with PPK analysis, this method should be useful for the therapeutic drug monitoring of nivolumab in clinical practice.

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Therapeutic Drug Monitoring

Tập 40 Số 6

716-724

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