Background: ORIN1001, a first-in-class oral IRE1-α endoribonuclease inhibitor to block the activation of XBP1, is currently in clinical development for inhibiting tumor growth and enhancing the effect of chemical or targeted therapy. Early establishment of a population pharmacokinetic (PopPK) model could characterize the pharmacokinetics (PK) of ORIN1001 and evaluate the effects of individual-specific factors on PK, which will facilitate the future development of this investigational drug.Methods: Non-linear mixed effect model was constructed by Phoenix NLME software, utilizing the information from Chinese patients with advanced solid tumors in a phase I clinical trial (Register No. NCT05154201). Statistically significant PK covariates were screened out by a stepwise process. The final model, after validating by the goodness-of-fit plots, non-parametric bootstrap, visual predictive check and test of normalized prediction distribution errors, was further applied to simulate and evaluate the impact of covariates on ORIN1001 exposure at steady state up to 900 mg per day as a single agent.Results: A two-compartment model with first-order absorption (with lag-time)/elimination was selected as the best structural model. Total bilirubin (TBIL) and lean body weight (LBW) were considered as the statistically significant covariates on clearance (CL/F) of ORIN1001. They were also confirmed to exert clinically significant effects on ORIN1001 steady-state exposure after model simulation. The necessity of dose adjustments based on these two covariates remains to be validated in a larger population.Conclusion: The first PopPK model of ORIN1001 was successfully constructed, which may provide some important references for future research.

2-hydroxyglutarate has limited abundance in normal tissues but a high level under certain pathologic conditions. To clarify the diagnostic value of two chiral isomers of 2-hydroxyglutarate in plasma and urine of Chinese cancer patients, an ultra-high performance liquid chromatography-tandem mass spectrometric method was developed for simultaneous quantification of D-/L-2-hydroxyglutarate. The selected D-/L-2-hydroxyglutarate-d₅ as internal standards were added to samples before the SPE on Waters Oasis® MAX 96-Well plate (30 μm, 60 mg). A derivatization step with (+)-O,O′-diacetyl-L-tartaric anhydride permitted the chromatography separation of D-/L-2-hydroxyglutarate on an ACQUITY UPLC-HSS T3 column (50 × 2.1 mm, i.d. 1.8 μm) with acetonitrile and water (containing 0.1% formic acid and 10 mmol ammonium acetate) as the mobile phase. The calibration curves showed good linearity (R ≥ 0.99) over the concentration ranges of 200–5,000 ng/mL and 500–20,000 ng/mL for analysis of D-/L-2-hydroxyglutarate in plasma and urine samples, respectively. Intra- and inter-run precision were ≤ 12.33%, and the accuracy was within the range of −10.44 to 13.90%. This method was further successfully applied to clinical sample analysis in isocitrate dehydrogenase 1/2 mutated Chinese cancer patients.

Background: TQ-B3101 is a novel kinase inhibitor currently in development for the treatment of advanced malignant solid tumor and relapsed or refractory ALK-positive anaplastic large cell lymphoma.Methods: A population pharmacokinetic model was developed using data collected from a Phase 1 study and a Phase 2 study to characterize the pharmacokinetic of TQ-B3101 and its active metabolite (TQ-B3101M). The final model was used to optimize dosing of TQ-B3101 for pediatric patients (6-<18 years) with anaplastic large cell lymphoma.Results: The pharmacokinetic of TQ-B3101 and TQ-B3101M was adequately described by a 1-compartment model with first-order absorption and elimination for parent drug coupled with a 2-compartment model with time-dependent clearance for the metabolite. The clearance of TQ-B3101M decreased over time with a maximum fractional reduction of 0.41. The estimated apparent clearance and apparent volume of distribution of TQ-B3101 were 2850 L/h and 4200 L, respectively. The elimination half-life of TQ-B3101 was 1.0 h. The distribution and elimination half-lives of TQ-B3101M at steady state were 4.9 and 39.4 h, respectively. The projected exposure of TQ-B3101M in virtual pediatric population following the body surface area tiered dosing regimen was similar to that in children pediatric patients after the recommended pediatric dose of crizotinib (280 mg/m2 twice daily), an analog of TQ-B3101M.Conclusion: A population pharmacokinetic model was developed to provide optimal dose of regimen for further development of TQ-B3101 in pediatric patients with anaplastic large cell lymphoma.