Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer
Copyright © 2020 by The Author(s)..
Abemaciclib is an orally administered, potent inhibitor of cyclin-dependent kinases 4 and 6 and is metabolized extensively by CYP3A4. The effects of abemaciclib on several CYPs were qualified in vitro and subsequently evaluated in a clinical study. In vitro, human hepatocytes were treated with vehicle, abemaciclib, or abemaciclib metabolites [N-desethylabemaciclib (M2) or hydroxyabemaciclib (M20)]. mRNA levels for eight CYPs were measured using reverse-transcription quantitative polymerase chain reaction, and, additionally, catalytic activities for three CYPs were determined. In the clinical study, adult patients with cancer received a drug cocktail containing CYP substrates [midazolam (3A), warfarin (2C9), dextromethorphan (2D6), and caffeine (1A2)] either alone or in combination with abemaciclib. Plasma pharmacokinetics (PK) samples were analyzed for all substrates, caffeine metabolite paraxanthine, and abemaciclib; polymorphisms of CYP2C9, CYP2D6, CYP3A4, and CYP3A5 were evaluated. In vitro, downregulation of CYP mRNA, including 1A2, 2B6, 2C8, 2C9, 2D6, and 3A, by abemaciclib and/or M2 and M20 was observed at clinically relevant concentrations. In humans, abemaciclib did not affect the PK of CYP2D6 or CYP2C9 substrates. Minor statistically significant but clinically irrelevant changes were observed for midazolam [area under the concentration versus time curve from zero to infinity (AUC0-inf) (13% lower), Cmax (15% lower)], caffeine [AUC0-inf (56% higher)], and paraxanthine: caffeine [area under the concentration versus time curve from 0 to 24 hours ratio (was approximately 30% lower)]. However, given the magnitude of the effect, these changes are not considered clinically relevant. In conclusion, the downregulation of CYP mRNA mediated by abemaciclib in vitro did not translate into clinically meaningful drug-drug interactions in patients with cancer. SIGNIFICANCE STATEMENT: Despite observations that abemaciclib alters the mRNA of various CYP isoforms in vitro, a clinical study using a drug cocktail approach found no clinically meaningful drug-drug interactions between abemaciclib and a range of CYP substrates [midazolam (CYP3A4), S-warfarin (CYP2C9), dextromethorphan (CYP2D6), and caffeine (CYP1A2)]. This lack of translation suggests greater understanding of mechanisms of CYP downregulation is needed to accurately predict clinical drug-drug interaction risk from in vitro data.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:48 |
|---|---|
| Enthalten in: |
Drug metabolism and disposition: the biological fate of chemicals - 48(2020), 9 vom: 24. Sept., Seite 796-803 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Turner, P Kellie [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 13.09.2021 Date Revised 13.09.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1124/dmd.119.090092 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM311594387 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM311594387 | ||
| 003 | DE-627 | ||
| 005 | 20231225142603.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1124/dmd.119.090092 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1038.xml |
| 035 | |a (DE-627)NLM311594387 | ||
| 035 | |a (NLM)32581049 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Turner, P Kellie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer |
| 264 | 1 | |c 2020 | |
| 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 13.09.2021 | ||
| 500 | |a Date Revised 13.09.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 by The Author(s). | ||
| 520 | |a Abemaciclib is an orally administered, potent inhibitor of cyclin-dependent kinases 4 and 6 and is metabolized extensively by CYP3A4. The effects of abemaciclib on several CYPs were qualified in vitro and subsequently evaluated in a clinical study. In vitro, human hepatocytes were treated with vehicle, abemaciclib, or abemaciclib metabolites [N-desethylabemaciclib (M2) or hydroxyabemaciclib (M20)]. mRNA levels for eight CYPs were measured using reverse-transcription quantitative polymerase chain reaction, and, additionally, catalytic activities for three CYPs were determined. In the clinical study, adult patients with cancer received a drug cocktail containing CYP substrates [midazolam (3A), warfarin (2C9), dextromethorphan (2D6), and caffeine (1A2)] either alone or in combination with abemaciclib. Plasma pharmacokinetics (PK) samples were analyzed for all substrates, caffeine metabolite paraxanthine, and abemaciclib; polymorphisms of CYP2C9, CYP2D6, CYP3A4, and CYP3A5 were evaluated. In vitro, downregulation of CYP mRNA, including 1A2, 2B6, 2C8, 2C9, 2D6, and 3A, by abemaciclib and/or M2 and M20 was observed at clinically relevant concentrations. In humans, abemaciclib did not affect the PK of CYP2D6 or CYP2C9 substrates. Minor statistically significant but clinically irrelevant changes were observed for midazolam [area under the concentration versus time curve from zero to infinity (AUC0-inf) (13% lower), Cmax (15% lower)], caffeine [AUC0-inf (56% higher)], and paraxanthine: caffeine [area under the concentration versus time curve from 0 to 24 hours ratio (was approximately 30% lower)]. However, given the magnitude of the effect, these changes are not considered clinically relevant. In conclusion, the downregulation of CYP mRNA mediated by abemaciclib in vitro did not translate into clinically meaningful drug-drug interactions in patients with cancer. SIGNIFICANCE STATEMENT: Despite observations that abemaciclib alters the mRNA of various CYP isoforms in vitro, a clinical study using a drug cocktail approach found no clinically meaningful drug-drug interactions between abemaciclib and a range of CYP substrates [midazolam (CYP3A4), S-warfarin (CYP2C9), dextromethorphan (CYP2D6), and caffeine (CYP1A2)]. This lack of translation suggests greater understanding of mechanisms of CYP downregulation is needed to accurately predict clinical drug-drug interaction risk from in vitro data | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Aminopyridines |2 NLM | |
| 650 | 7 | |a Benzimidazoles |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Caffeine |2 NLM | |
| 650 | 7 | |a 3G6A5W338E |2 NLM | |
| 650 | 7 | |a Warfarin |2 NLM | |
| 650 | 7 | |a 5Q7ZVV76EI |2 NLM | |
| 650 | 7 | |a abemaciclib |2 NLM | |
| 650 | 7 | |a 60UAB198HK |2 NLM | |
| 650 | 7 | |a Dextromethorphan |2 NLM | |
| 650 | 7 | |a 7355X3ROTS |2 NLM | |
| 650 | 7 | |a CYP2C9 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.13.- |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP2C9 |2 NLM | |
| 650 | 7 | |a EC 1.14.13.- |2 NLM | |
| 650 | 7 | |a CYP1A2 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP1A2 |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP2D6 |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP3A |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a CYP3A4 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.14.55 |2 NLM | |
| 650 | 7 | |a Midazolam |2 NLM | |
| 650 | 7 | |a R60L0SM5BC |2 NLM | |
| 700 | 1 | |a Hall, Stephen D |e verfasserin |4 aut | |
| 700 | 1 | |a Chapman, Sonya C |e verfasserin |4 aut | |
| 700 | 1 | |a Rehmel, Jessica L |e verfasserin |4 aut | |
| 700 | 1 | |a Royalty, Jane E |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Yingying |e verfasserin |4 aut | |
| 700 | 1 | |a Kulanthaivel, Palaniappan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Drug metabolism and disposition: the biological fate of chemicals |d 1990 |g 48(2020), 9 vom: 24. Sept., Seite 796-803 |w (DE-627)NLM000015857 |x 1521-009X |7 nnns |
| 773 | 1 | 8 | |g volume:48 |g year:2020 |g number:9 |g day:24 |g month:09 |g pages:796-803 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1124/dmd.119.090092 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 48 |j 2020 |e 9 |b 24 |c 09 |h 796-803 | ||