Measurement of NLG207 (formerly CRLX101) nanoparticle-bound and released camptothecin in human plasma
Schmidt, Keith T; Peer, Cody J; Huitema, Alwin D R; Williams, Monique D; Wroblewski, Susan; Schellens, Jan H M; Madan, Ravi A; Figg, William D
(2020) Journal of Pharmaceutical and Biomedical Analysis, volume 181, pp. 1 - 9
(Article)
Abstract
Camptothecin (CPT), a potent inhibitor of topoisomerase I and HIF-1α, failed to demonstrate utility as an anti-cancer agent in early clinical trial investigations, primarily due to limited clinical activity and significant toxicity attributable to unfavorable physicochemical properties (e.g. low plasma solubility, pH-labile lactone ring). NLG207 (formerly CRLX101), a nanoparticle-drug conjugate
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(NDC) of CPT designed to optimize plasma pharmacokinetics and facilitate drug delivery to tumors, is included as part of combination treatment in two Phase II clinical trials ongoing at the National Cancer Institute (NCT02769962 and NCT03531827). To better understand the potential for drug-drug interactions and to correlate drug exposure to clinical outcomes and pharmacodynamic biomarkers, a robust analytical method was developed to measure CPT in human plasma. Two sample processing methods were developed to quantify both NDC-bound CPT and free CPT, primarily via alteration of pH conditions. A solid-phase extraction recovered >79 % of CPT prior to quantitative analysis by ultra HPLC-MS/MS. Dynamic calibration ranges of 10 to 10,000 ng/mL and 1 to 1000 ng/mL for total and free CPT, respectively were utilized to capture clinical ranges. NLG207 NDCs demonstrated significant rates of CPT release in human plasma at room temperature after 2 h but were shown to be stable at 4 °C for 24 h and through 4 freeze/thaw cycles. This assay was used to quantitate CPT plasma concentrations in clinical samples to confirm clinical utility following NLG207 treatment in subjects with advanced prostate cancer.
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Keywords: Anti-cancer, Bioanalytical, Clinical pharmacology, Mass spectrometry, Oncology, Pharmacokinetics, Topoisomerase I inhibitor, Analytical Chemistry, Pharmaceutical Science, Drug Discovery, Spectroscopy, Clinical Biochemistry
ISSN: 0731-7085
Publisher: Elsevier
Note: Funding Information: This study was funded in part by the Intramural Research Program of the NIH, National Cancer Institute, and in part by a CRADA between the National Cancer Institute and NewLink Genetics (#03089). This is US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government. We thank the nursing staff of the National Cancer Institute and the fellows of the Medical Oncology Service at the National Cancer Institute for their care of our patients. Most importantly, we appreciate the patients with cancer who enroll in investigational trials to advance the knowledge of this disease. Funding Information: This study was funded in part by the Intramural Research Program of the NIH, National Cancer Institute , and in part by a CRADA between the National Cancer Institute and NewLink Genetics ( #03089 ). This is US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government. We thank the nursing staff of the National Cancer Institute and the fellows of the Medical Oncology Service at the National Cancer Institute for their care of our patients. Most importantly, we appreciate the patients with cancer who enroll in investigational trials to advance the knowledge of this disease. Appendix A Publisher Copyright: © 2019
(Peer reviewed)