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

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.

• Authors: 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
• Journal: Journal of pharmaceutical and biomedical analysis (J Pharm Biomed Anal) Vol. 181 Pg. 113073 (Mar 20 2020) ISSN: 1873-264X [Electronic] England
• PMID: 31927166 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: Published by Elsevier B.V.

Chemical References

• Benzamides
• Cyclodextrins
• IT-101
• Nitriles
• Phenylthiohydantoin
• enzalutamide
• Camptothecin

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use)
• Benzamides
• Camptothecin (blood, isolation & purification, pharmacokinetics, therapeutic use)
• Cyclodextrins (blood, isolation & purification, pharmacokinetics, therapeutic use)
• Drug Interactions
• Drug Stability
• Humans
• Male
• Middle Aged
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacokinetics, therapeutic use)
• Prostatic Neoplasms, Castration-Resistant (blood, drug therapy)