Development of population pharmacokinetics model of icotinib with non-linear absorption characters in healthy Chinese volunteers to assess the CYP2C19 polymorphism and food-intake effect

Hu, Pei; Chen, Jia; Liu, Dongyang; Zheng, Xin; Zhao, Qian; Jiang, Ji

doi:10.1007/s00228-015-1864-5

Cited by 4 publications

(2 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There have been studies on the traditional PK of flurbiprofen in healthy volunteers or highly selected patients. 8 – 12 However, population PK (PPK) modeling is a scientific and highly efficient approach to describe the PK behavior of the investigated drug and to evaluate potential covariates that may contribute to PK intra-and intersubject variability, 13 wherein participants can be more representative of the target population treated with the drug. 14 It has been assumed that patient characteristics may contribute to interindividual differences in drug responses, and it is essential to take into account the influence of these covariates on the PPK of flurbiprofen.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetic modeling of flurbiprofen, the active metabolite of flurbiprofen axetil, in Chinese patients with postoperative pain

Zhang

Zhao

et al. 2018

JPR

View full text Add to dashboard Cite

BackgroundFlurbiprofen axetil, a lipid-microsphere-carrier targeting preparation, is a non-steroidal anti-inflammatory drug indicated for the treatment of postoperative pain.AimThe aim of the study was to develop a population pharmacokinetic (PPK) model of flurbiprofen, the active metabolite of flurbiprofen axetil, and optimize the treatment of flurbiprofen axetil in Chinese patients.MethodsA total of 144 therapeutic drug-monitoring samples of flurbiprofen axetil from 72 patients were included in this study. The pharmacologically active metabolite flurbiprofen was used as the analytical target and determined 5–45 minutes after intravenous administration. The PPK model for flurbiprofen was developed using Phoenix NLME 1.3 with a nonlinear mixed-effect model. Bootstrap and visual predictive checks were used simultaneously to validate the final PPK model. Potential covariates of age, sex, body weight, height, and body-mass index were tested for PK parameters.ResultsThe PPK model of flurbiprofen was explained by a one-compartment model with first-order elimination, in which a hypothetical-effect compartment was linked to a PK compartment. Population mean values of PK parameters estimated in the final model were θKe=0.0015/h, θVd=7.91 L, and θCL=1.55 L/h. Analysis of covariates showed that height and weight influenced the Ke of flurbiprofen. The final model was proved to be robust.ConclusionThe final PPK model was demonstrated to be appropriate and effective, and can be used to assess the PK parameters of flurbiprofen in Chinese patients with postoperative pain.

show abstract

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetic modeling of flurbiprofen, the active metabolite of flurbiprofen axetil, in Chinese patients with postoperative pain

Zhang

Zhao

et al. 2018

JPR

View full text Add to dashboard Cite

show abstract

“…Dose-dependent increases in icotinib C max and AUC were observed over the dose ranges of 250-350 mg and 400-625 mg, which may be due to the drug's solubility in water (Fig. 1).This trend was also seen in a population PK study, in which icotinib displayed a saturated absorption rate of 204 (icotinib 350 mg), and 245 (icotinib 600 mg) mg per hour in healthy persons [8]. In addition, no dose, exposure, safety/efficacy relationship was found in our study.…”

Section: Investigator's Analysismentioning

confidence: 55%

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

Liu

et al. 2016

The Oncologist

View full text Add to dashboard Cite

Lessons LearnedThis phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib.Background.Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC.Methods.Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study.Results.Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease.Conclusion.This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC.

show abstract

Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension

Kodati

Kotakonda

Yellu

2016

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

show abstract

Development of population pharmacokinetics model of icotinib with non-linear absorption characters in healthy Chinese volunteers to assess the CYP2C19 polymorphism and food-intake effect

Abstract: The developed model can capture icotinib pharmacokinetics well in healthy volunteers. Food intake can increase icotinib exposure. Three covariates, age, albumin concentration, and CYP2C19 genotype, were identified to significantly affect icotinib PK profiles in healthy subjects.

Cited by 4 publications

References 19 publications

Population pharmacokinetic modeling of flurbiprofen, the active metabolite of flurbiprofen axetil, in Chinese patients with postoperative pain

Population pharmacokinetic modeling of flurbiprofen, the active metabolite of flurbiprofen axetil, in Chinese patients with postoperative pain

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension

Contact Info

Product

Resources

About