Measurement of NLG207 (formerly CRLX101) nanoparticle-bound and released camptothecin in human plasma

Keith T. Schmidt, Cody J. Peer, Alwin D.R. Huitema, Monique D. Williams, Susan Wroblewski, Jan H.M. Schellens, Ravi A. Madan, William D. Figg

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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 (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.

Original languageEnglish
Article number113073
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume181
DOIs
Publication statusPublished - 20 Mar 2020
Externally publishedYes

Keywords

  • Anti-cancer
  • Bioanalytical
  • Clinical pharmacology
  • Mass spectrometry
  • Oncology
  • Pharmacokinetics
  • Topoisomerase I inhibitor

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