Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436)
©2014 American Association for Cancer Research..
PURPOSE: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship.
EXPERIMENTAL DESIGN: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.
RESULTS: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.
CONCLUSION: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2014 |
|---|---|
| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
|---|---|
| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 20(2014), 17 vom: 01. Sept., Seite 4449-58 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Falchook, Gerald S [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.07.2015 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/1078-0432.CCR-14-0887 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM239465113 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM239465113 | ||
| 003 | DE-627 | ||
| 005 | 20231224120015.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2014 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/1078-0432.CCR-14-0887 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0798.xml |
| 035 | |a (DE-627)NLM239465113 | ||
| 035 | |a (NLM)24958809 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Falchook, Gerald S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436) |
| 264 | 1 | |c 2014 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.07.2015 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2014 American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship | ||
| 520 | |a EXPERIMENTAL DESIGN: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data | ||
| 520 | |a RESULTS: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma | ||
| 520 | |a CONCLUSION: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Oximes |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins B-raf |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a dabrafenib |2 NLM | |
| 650 | 7 | |a QGP4HA4G1B |2 NLM | |
| 700 | 1 | |a Long, Georgina V |e verfasserin |4 aut | |
| 700 | 1 | |a Kurzrock, Razelle |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Kevin B |e verfasserin |4 aut | |
| 700 | 1 | |a Arkenau, H-Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Michael P |e verfasserin |4 aut | |
| 700 | 1 | |a Hamid, Omid |e verfasserin |4 aut | |
| 700 | 1 | |a Infante, Jeffrey R |e verfasserin |4 aut | |
| 700 | 1 | |a Millward, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Pavlick, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Chin, Melvin T |e verfasserin |4 aut | |
| 700 | 1 | |a O'Day, Steven J |e verfasserin |4 aut | |
| 700 | 1 | |a Blackman, Samuel C |e verfasserin |4 aut | |
| 700 | 1 | |a Curtis, C Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Lebowitz, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Ouellet, Daniele |e verfasserin |4 aut | |
| 700 | 1 | |a Kefford, Richard F |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Clinical cancer research : an official journal of the American Association for Cancer Research |d 1995 |g 20(2014), 17 vom: 01. Sept., Seite 4449-58 |w (DE-627)NLM09444479X |x 1557-3265 |7 nnns |
| 773 | 1 | 8 | |g volume:20 |g year:2014 |g number:17 |g day:01 |g month:09 |g pages:4449-58 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/1078-0432.CCR-14-0887 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 20 |j 2014 |e 17 |b 01 |c 09 |h 4449-58 | ||