| RRC ID |
64294
|
| 著者 |
Xiong W, Friese-Hamim M, Johne A, Stroh C, Klevesath M, Falchook GS, Hong DS, Girard P, El Bawab S.
|
| タイトル |
Translational pharmacokinetic-pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose.
|
| ジャーナル |
CPT Pharmacometrics Syst Pharmacol
|
| Abstract |
Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first-in-man trial, an efficacy-driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PK)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP-4 pancreatic cell-line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from pre- and post-dose paired tumor biopsies) from a first-in-man study were integrated with the longitudinal PK and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP-4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near-to-complete (>95%) phospho-MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose-dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established a RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy-driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non-small-cell lung cancer harboring MET exon 14 skipping.
|
| 巻・号 |
10(5)
|
| ページ |
428-440
|
| 公開日 |
2021-5-1
|
| DOI |
10.1002/psp4.12602
|
| PMID |
33818908
|
| PMC |
PMC8129711
|
| MeSH |
Administration, Oral
Animals
Clinical Trials, Phase II as Topic
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical*
Humans
Mice
Models, Theoretical*
Piperidines / administration & dosage
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Pyridazines / administration & dosage
Pyridazines / pharmacokinetics
Pyridazines / pharmacology*
Pyrimidines / administration & dosage
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Xenograft Model Antitumor Assays
|
| リソース情報 |
| ヒト・動物細胞 |
KP4(RCB1005) |
