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

Abstract

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.

Keywords: Drug release; NLMEM; Nanoparticle; Population pharmacokinetics; Topoisomerase I.

Conflict of interest statement

The author(s) declare that they have no competing interests.

Figures

Fig. 1

Overview of the four-compartment model describing disposition of nanoparticle-bound (conjugated) and free CPT, and the associated calculated parameters. Plasma sample quantitation enabled CMT1 and CMT3 observations for conjugated and free CPT concentrations, respectively. The model can be divided into two portions: conjugated CPT distribution described via estimates V1, V2, and Q1, and free CPT distribution described via estimates V3, V4, and Q3. CL1, or the conversion of conjugated to free CPT, was described using two additive clearance terms: CLB is the “base” rate of conversion, and CLF is a “fast” clearance rate that is modified via a simulated first-order decay term with estimated half-life, t1/2

Fig. 2

Goodness-of-fit plots for the pharmacokinetic model. Separate plots were generated for the evaluation of conjugated CPT (a–d) and free CPT (e–h). Plots include population prediction against observed data (a, e), individual prediction against observed data (b, f), conditional weighted residuals against population prediction (c, g), and conditional weighted residuals against time after dose (d, h). The solid black lines represent either the line of unity (a, b, e, f) or the zero line (c, d, g, h). Solid blue lines represent the local regression fit of the values

Fig. 3

Visual predictive checks (VPCs) of conjugated (a) and free CPT (b) for timepoints up to ~ 50 h post-dose of NLG207. “Observations” are reported in units of ng/mL using log scale axis, and “time after dose” is reported in hours. Solid black lines depict the observed median and dashed lines represent the 2.5% and 97.5% percentile concentrations. 95% prediction intervals of the simulated mean and the 2.5 and 97.5% percentiles are represented by dark- and light-gray areas, respectively. Round dots represent observations and asterisks highlight observed percentiles outside of the prediction area