Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model
Abstract Molibresib (GSK525762) is an investigational, orally bioavailable, small‐molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. Molibresib was initially evaluated in a first‐time‐in‐human (FTIH) study BET115521 consisting of two parts: Par...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-07-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12639 |
| _version_ | 1818622464758906880 |
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| author | Anu Shilpa Krishnatry Alexander Voelkner Arindam Dhar Marita Prohn Geraldine Ferron‐Brady |
| author_facet | Anu Shilpa Krishnatry Alexander Voelkner Arindam Dhar Marita Prohn Geraldine Ferron‐Brady |
| author_sort | Anu Shilpa Krishnatry |
| collection | DOAJ |
| description | Abstract Molibresib (GSK525762) is an investigational, orally bioavailable, small‐molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. Molibresib was initially evaluated in a first‐time‐in‐human (FTIH) study BET115521 consisting of two parts: Part 1 of the study (dose escalation) was conducted in 94 patients with nuclear protein in testis midline carcinoma and other solid tumors, and Part 2 (expansion cohort) was conducted in 99 patients with different solid tumor types. Molibresib is metabolized by cytochrome P450 3A4 enzymes to produce two major active metabolites that are equipotent to the parent molecule. The metabolites are measured together after full conversion of one to the other and reported as an active metabolite composite (GSK3529246). The molibresib pharmacokinetic (PK) profile has been characterized by a decrease in exposure over time, with the decrease more pronounced at higher doses, and accompanied by a slight increase of the metabolite concentrations. Autoinduction of molibresib metabolism was suspected and confirmed in vitro. Here we report the development of a semimechanistic liver‐compartment population PK model using PK data from the FTIH study, which adequately describes the autoinduction of molibresib clearance and the PK of both molibresib and GSK3529246. Covariate analysis indicated body weight had a significant effect on the volume of distribution of molibresib and GSK3529246, and higher levels of aspartate aminotransferase resulted in the lower clearance of GSK3529246. This model was used to simulate individual patient exposures based on covariate information for use in future alternative dosing strategies and exposure–response analyses. |
| first_indexed | 2024-12-16T18:25:35Z |
| format | Article |
| id | doaj.art-eefdf1d93b6a4e2aa8182575ec74d43f |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-12-16T18:25:35Z |
| publishDate | 2021-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-eefdf1d93b6a4e2aa8182575ec74d43f2022-12-21T22:21:26ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062021-07-0110770972210.1002/psp4.12639Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction modelAnu Shilpa Krishnatry0Alexander Voelkner1Arindam Dhar2Marita Prohn3Geraldine Ferron‐Brady4Clinical Pharmacology Modelling and Simulation GlaxoSmithKline, Collegeville PA USAqPharmetra LLC Nijmegen the NetherlandsEpigenetics Research Unit GlaxoSmithKline Collegeville PA USAqPharmetra LLC Nijmegen the NetherlandsClinical Pharmacology Modelling and Simulation GlaxoSmithKline, Collegeville PA USAAbstract Molibresib (GSK525762) is an investigational, orally bioavailable, small‐molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. Molibresib was initially evaluated in a first‐time‐in‐human (FTIH) study BET115521 consisting of two parts: Part 1 of the study (dose escalation) was conducted in 94 patients with nuclear protein in testis midline carcinoma and other solid tumors, and Part 2 (expansion cohort) was conducted in 99 patients with different solid tumor types. Molibresib is metabolized by cytochrome P450 3A4 enzymes to produce two major active metabolites that are equipotent to the parent molecule. The metabolites are measured together after full conversion of one to the other and reported as an active metabolite composite (GSK3529246). The molibresib pharmacokinetic (PK) profile has been characterized by a decrease in exposure over time, with the decrease more pronounced at higher doses, and accompanied by a slight increase of the metabolite concentrations. Autoinduction of molibresib metabolism was suspected and confirmed in vitro. Here we report the development of a semimechanistic liver‐compartment population PK model using PK data from the FTIH study, which adequately describes the autoinduction of molibresib clearance and the PK of both molibresib and GSK3529246. Covariate analysis indicated body weight had a significant effect on the volume of distribution of molibresib and GSK3529246, and higher levels of aspartate aminotransferase resulted in the lower clearance of GSK3529246. This model was used to simulate individual patient exposures based on covariate information for use in future alternative dosing strategies and exposure–response analyses.https://doi.org/10.1002/psp4.12639 |
| spellingShingle | Anu Shilpa Krishnatry Alexander Voelkner Arindam Dhar Marita Prohn Geraldine Ferron‐Brady Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model CPT: Pharmacometrics & Systems Pharmacology |
| title | Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model |
| title_full | Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model |
| title_fullStr | Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model |
| title_full_unstemmed | Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model |
| title_short | Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model |
| title_sort | population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors a semimechanistic autoinduction model |
| url | https://doi.org/10.1002/psp4.12639 |
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