Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose
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‐human (FIH) trial, an efficacy‐driven translational modeling approach w...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-05-01
|
| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12602 |
| _version_ | 1818650050155249664 |
|---|---|
| author | Wenyuan Xiong Manja Friese‐Hamim Andreas Johne Christopher Stroh Manfred Klevesath Gerald S. Falchook David S. Hong Pascal Girard Samer El Bawab |
| author_facet | Wenyuan Xiong Manja Friese‐Hamim Andreas Johne Christopher Stroh Manfred Klevesath Gerald S. Falchook David S. Hong Pascal Girard Samer El Bawab |
| author_sort | Wenyuan Xiong |
| collection | DOAJ |
| description | 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‐human (FIH) trial, an efficacy‐driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/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 predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs 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 an 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. |
| first_indexed | 2024-12-17T01:44:03Z |
| format | Article |
| id | doaj.art-336092d3d9d74e2798fde9141c4ad366 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-12-17T01:44:03Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-336092d3d9d74e2798fde9141c4ad3662022-12-21T22:08:15ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062021-05-0110542844010.1002/psp4.12602Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II doseWenyuan Xiong0Manja Friese‐Hamim1Andreas Johne2Christopher Stroh3Manfred Klevesath4Gerald S. Falchook5David S. Hong6Pascal Girard7Samer El Bawab8Merck Institute of Pharmacokinetics (an affiliate of Merck KGaA, Darmstadt, Germany) Lausanne SwitzerlandMerck KGaA Darmstadt GermanyMerck KGaA Darmstadt GermanyMerck KGaA Darmstadt GermanyMerck KGaA Darmstadt GermanySarah Cannon Research Institute at HealthONE Denver Colorado USAMD Anderson Cancer Center Houston Texas USAMerck Institute of Pharmacokinetics (an affiliate of Merck KGaA, Darmstadt, Germany) Lausanne SwitzerlandMerck KGaA Darmstadt GermanyAbstract 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‐human (FIH) trial, an efficacy‐driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/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 predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs 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 an 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.https://doi.org/10.1002/psp4.12602 |
| spellingShingle | Wenyuan Xiong Manja Friese‐Hamim Andreas Johne Christopher Stroh Manfred Klevesath Gerald S. Falchook David S. Hong Pascal Girard Samer El Bawab Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose CPT: Pharmacometrics & Systems Pharmacology |
| title | Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose |
| title_full | Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose |
| title_fullStr | Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose |
| title_full_unstemmed | Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose |
| title_short | Translational pharmacokinetic‐pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose |
| title_sort | translational pharmacokinetic pharmacodynamic modeling of preclinical and clinical data of the oral met inhibitor tepotinib to determine the recommended phase ii dose |
| url | https://doi.org/10.1002/psp4.12602 |
| work_keys_str_mv | AT wenyuanxiong translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT manjafriesehamim translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT andreasjohne translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT christopherstroh translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT manfredklevesath translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT geraldsfalchook translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT davidshong translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT pascalgirard translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose AT samerelbawab translationalpharmacokineticpharmacodynamicmodelingofpreclinicalandclinicaldataoftheoralmetinhibitortepotinibtodeterminetherecommendedphaseiidose |