Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on...
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MDPI AG
2020-08-01
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Series: | Pharmaceutics |
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Online Access: | https://www.mdpi.com/1999-4923/12/9/788 |
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doaj-69e6321bc030407588a58b71ba48089f |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Koen G. A. M. Hussaarts Leni van Doorn Karel Eechoute Jeffrey Damman Qiang Fu Nadia van Doorn Eric D. Eisenmann Alice A. Gibson Esther Oomen-de Hoop Peter de Bruijn Sharyn D. Baker Stijn L. W. Koolen Teun van Gelder Roelof W. F. van Leeuwen Ron H. J. Mathijssen Alex Sparreboom Sander Bins |
spellingShingle |
Koen G. A. M. Hussaarts Leni van Doorn Karel Eechoute Jeffrey Damman Qiang Fu Nadia van Doorn Eric D. Eisenmann Alice A. Gibson Esther Oomen-de Hoop Peter de Bruijn Sharyn D. Baker Stijn L. W. Koolen Teun van Gelder Roelof W. F. van Leeuwen Ron H. J. Mathijssen Alex Sparreboom Sander Bins Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib Pharmaceutics sorafenib probenecid hand-foot skin reaction (HFSR) pharmacokinetics OAT6 |
author_facet |
Koen G. A. M. Hussaarts Leni van Doorn Karel Eechoute Jeffrey Damman Qiang Fu Nadia van Doorn Eric D. Eisenmann Alice A. Gibson Esther Oomen-de Hoop Peter de Bruijn Sharyn D. Baker Stijn L. W. Koolen Teun van Gelder Roelof W. F. van Leeuwen Ron H. J. Mathijssen Alex Sparreboom Sander Bins |
author_sort |
Koen G. A. M. Hussaarts |
title |
Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib |
title_short |
Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib |
title_full |
Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib |
title_fullStr |
Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib |
title_full_unstemmed |
Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib |
title_sort |
influence of probenecid on the pharmacokinetics and pharmacodynamics of sorafenib |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2020-08-01 |
description |
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC<sub>0–12 h</sub>) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC<sub>0–12 h</sub> decreased by 27% (90% CI: −38% to −14%; <i>P</i> < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-<i>N</i>-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study. |
topic |
sorafenib probenecid hand-foot skin reaction (HFSR) pharmacokinetics OAT6 |
url |
https://www.mdpi.com/1999-4923/12/9/788 |
work_keys_str_mv |
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doaj-69e6321bc030407588a58b71ba48089f2020-11-25T03:11:30ZengMDPI AGPharmaceutics1999-49232020-08-011278878810.3390/pharmaceutics12090788Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of SorafenibKoen G. A. M. Hussaarts0Leni van Doorn1Karel Eechoute2Jeffrey Damman3Qiang Fu4Nadia van Doorn5Eric D. Eisenmann6Alice A. Gibson7Esther Oomen-de Hoop8Peter de Bruijn9Sharyn D. Baker10Stijn L. W. Koolen11Teun van Gelder12Roelof W. F. van Leeuwen13Ron H. J. Mathijssen14Alex Sparreboom15Sander Bins16Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDepartment of Pathology, Erasmus MC, 3015 CE Rotterdam, The NetherlandsDivision of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USADepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDivision of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USADepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDivision of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USADepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDepartment of Hospital Pharmacy, Erasmus MC, 3015 CE Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsDivision of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy & Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USADepartment of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The NetherlandsPrior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC<sub>0–12 h</sub>) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC<sub>0–12 h</sub> decreased by 27% (90% CI: −38% to −14%; <i>P</i> < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-<i>N</i>-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.https://www.mdpi.com/1999-4923/12/9/788sorafenibprobenecidhand-foot skin reaction (HFSR)pharmacokineticsOAT6 |