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Clinical Trial
. 2024 Nov 14;31(11):7155-7164.
doi: 10.3390/curroncol31110527.

Population Pharmacokinetics of Tamibarotene in Pediatric and Young Adult Patients with Recurrent or Refractory Solid Tumors

Takuya Azechi  1   2 , Yutaka Fukaya  1 , Chika Nitani  3 , Junichi Hara  3 , Hiroshi Kawamoto  4 , Tomoaki Taguchi  5 , Kenichi Yoshimura  6 , Akihiro Sato  7 , Naoko Hattori  8 , Toshikazu Ushijima  8 , Toshimi Kimura  1   2
Affiliations
Clinical Trial

Population Pharmacokinetics of Tamibarotene in Pediatric and Young Adult Patients with Recurrent or Refractory Solid Tumors

Takuya Azechi et al. Curr Oncol. .

Abstract

Tamibarotene is a synthetic retinoid that inhibits tumor cell proliferation and promotes differentiation. We previously reported on the safety and tolerability of tamibarotene in patients with recurrent or refractory solid tumors. Therefore, in this study, we aimed to evaluate the pharmacokinetic properties of tamibarotene and construct a precise pharmacokinetic model. We also conducted a non-compartmental analysis and population pharmacokinetic (popPK) analysis based on the results of a phase I study. _targeted pediatric and young adult patients with recurrent or refractory solid tumors were administered tamibarotene at doses of 4, 6, 8, 10, and 12 g/m2/day. Serum tamibarotene concentrations were evaluated after administration, and a popPK model was constructed for tamibarotene using Phoenix NLME. During model construction, we considered the influence of various parameters (weight, height, body surface area, and age) as covariates. Notably, 22 participants were included in this study, and 109 samples were analyzed. A two-compartment model incorporating lag time was selected as the base model. In the final model, the body surface area was included as a covariate for apparent total body clearance, the central compartment volume of distribution, and the peripheral compartment volume of distribution. Visual prediction checks and bootstrap analysis confirmed the validity and predictive accuracy of the final model as satisfactory.

Keywords: pediatric; population pharmacokinetics; tamibarotene; young adult.

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Conflict of interest statement

TU received a research grant from OHARA Pharmaceutical Co., Ltd. All other authors report no potential conflicts.

Figures

Figure 1
Figure 1
Plot of plasma tamibarotene concentration versus time profile in phase I patients.
Figure 2
Figure 2
Tamibarotene popPK final model goodness-of-fit plots. (A) Observed plasma concentration of tamibarotene vs. predicted plasma concentration (PRED). (B) Observed plasma concentrations of tamibarotene vs. individual predicted plasma concentrations (IPRED). (C) CWRES (conditional weighted residuals) vs. time.
Figure 3
Figure 3
A visual predictive check of the tamibarotene popPK final model. The quantile deviation (blue shaded) obtained from 1000 datasets using the final model was superimposed on the observed tamibarotene concentration of quantile deviation (red shaded). popPK, population pharmacokinetics.
See this image and copyright information in PMC

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