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Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours

AIMS: In vitro data show that talazoparib is a substrate for P‐glycoprotein (P‐gp) and breast cancer resistance protein transporters. This open‐label, 2‐arm, drug–drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P‐gp inhibitor (itraconazole) and a P‐gp...

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Autores principales: Elmeliegy, Mohamed, Láng, István, Smolyarchuk, Elena A., Chung, Chin‐Hee, Plotka, Anna, Shi, Haihong, Wang, Diane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098856/
https://www.ncbi.nlm.nih.gov/pubmed/31770456
http://dx.doi.org/10.1111/bcp.14178
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author Elmeliegy, Mohamed
Láng, István
Smolyarchuk, Elena A.
Chung, Chin‐Hee
Plotka, Anna
Shi, Haihong
Wang, Diane
author_facet Elmeliegy, Mohamed
Láng, István
Smolyarchuk, Elena A.
Chung, Chin‐Hee
Plotka, Anna
Shi, Haihong
Wang, Diane
author_sort Elmeliegy, Mohamed
collection PubMed
description AIMS: In vitro data show that talazoparib is a substrate for P‐glycoprotein (P‐gp) and breast cancer resistance protein transporters. This open‐label, 2‐arm, drug–drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P‐gp inhibitor (itraconazole) and a P‐gp inducer (rifampicin) on the pharmacokinetics of a single dose of talazoparib. The safety and tolerability of a single dose of talazoparib with and without itraconazole or rifampicin were also assessed. METHODS: Thirty‐six patients were enrolled (Arm A [itraconazole], n = 19; Arm B [rifampicin], n = 17). Patients in both arms received 2 single oral doses of talazoparib (0.5 mg, Arm A; 1 mg, Arm B) alone and with multiple daily oral doses of itraconazole (Arm A) or rifampicin (Arm B). RESULTS: Coadministration of itraconazole and talazoparib increased talazoparib area under the plasma concentration–time profile from time 0 extrapolated to infinity by ~56% and maximum observed plasma concentration by ~40% relative to talazoparib alone. Coadministration of rifampicin and talazoparib increased talazoparib maximum observed plasma concentration by approximately 37% (geometric mean ratio 136.6% [90% confidence interval 103.2–180.9]); area under the curve was not affected relative to talazoparib alone (geometric mean ratio 102.0% [90% confidence interval 94.0–110.7]). Talazoparib had an overall safety profile consistent with that observed in prior studies in which talazoparib was administered as a single dose. CONCLUSION: Coadministration of itraconazole increased talazoparib plasma exposure compared to talazoparib alone. A reduced talazoparib dose is recommended if coadministration of potent P‐gp inhibitors cannot be avoided. Similar exposure was observed when talazoparib was administered alone and with rifampicin suggesting that the effect of rifampicin on talazoparib exposure is limited.
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spelling pubmed-70988562020-03-27 Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours Elmeliegy, Mohamed Láng, István Smolyarchuk, Elena A. Chung, Chin‐Hee Plotka, Anna Shi, Haihong Wang, Diane Br J Clin Pharmacol Original Articles AIMS: In vitro data show that talazoparib is a substrate for P‐glycoprotein (P‐gp) and breast cancer resistance protein transporters. This open‐label, 2‐arm, drug–drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P‐gp inhibitor (itraconazole) and a P‐gp inducer (rifampicin) on the pharmacokinetics of a single dose of talazoparib. The safety and tolerability of a single dose of talazoparib with and without itraconazole or rifampicin were also assessed. METHODS: Thirty‐six patients were enrolled (Arm A [itraconazole], n = 19; Arm B [rifampicin], n = 17). Patients in both arms received 2 single oral doses of talazoparib (0.5 mg, Arm A; 1 mg, Arm B) alone and with multiple daily oral doses of itraconazole (Arm A) or rifampicin (Arm B). RESULTS: Coadministration of itraconazole and talazoparib increased talazoparib area under the plasma concentration–time profile from time 0 extrapolated to infinity by ~56% and maximum observed plasma concentration by ~40% relative to talazoparib alone. Coadministration of rifampicin and talazoparib increased talazoparib maximum observed plasma concentration by approximately 37% (geometric mean ratio 136.6% [90% confidence interval 103.2–180.9]); area under the curve was not affected relative to talazoparib alone (geometric mean ratio 102.0% [90% confidence interval 94.0–110.7]). Talazoparib had an overall safety profile consistent with that observed in prior studies in which talazoparib was administered as a single dose. CONCLUSION: Coadministration of itraconazole increased talazoparib plasma exposure compared to talazoparib alone. A reduced talazoparib dose is recommended if coadministration of potent P‐gp inhibitors cannot be avoided. Similar exposure was observed when talazoparib was administered alone and with rifampicin suggesting that the effect of rifampicin on talazoparib exposure is limited. John Wiley and Sons Inc. 2020-01-07 2020-04 /pmc/articles/PMC7098856/ /pubmed/31770456 http://dx.doi.org/10.1111/bcp.14178 Text en © 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Elmeliegy, Mohamed
Láng, István
Smolyarchuk, Elena A.
Chung, Chin‐Hee
Plotka, Anna
Shi, Haihong
Wang, Diane
Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours
title Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours
title_full Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours
title_fullStr Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours
title_full_unstemmed Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours
title_short Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours
title_sort evaluation of the effect of p‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098856/
https://www.ncbi.nlm.nih.gov/pubmed/31770456
http://dx.doi.org/10.1111/bcp.14178
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