Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors

Keith T. Schmidt, Alwin D.R. Huitema, Thomas P.C. Dorlo, Cody J. Peer, Lisa M. Cordes, Linda Sciuto, Susan Wroblewski, Yves Pommier, Ravi A. Madan, Anish Thomas, William D. Figg

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4 Citaten (Scopus)

Samenvatting

Purpose: NLG207 (formerly CRLX101) is a nanoparticle–drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. Methods: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling. Results: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%). Conclusion: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.

Originele taal-2Engels
Pagina's (van-tot)475-486
Aantal pagina's12
TijdschriftCancer Chemotherapy and Pharmacology
Volume86
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 1 okt. 2020
Extern gepubliceerdJa

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