Pharmacokinetic Optimization of Everolimus Dosing in Oncology: A Randomized Crossover Trial

Remy B. Verheijen; Florence Atrafi; Jan H M Schellens; Jos H Beijnen; Alwin D R Huitema; Ron H J Mathijssen; Neeltje Steeghs

doi:10.1007/s40262-017-0582-9

Pharmacokinetic Optimization of Everolimus Dosing in Oncology: A Randomized Crossover Trial

Remy B. Verheijen, Florence Atrafi, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema, Ron H J Mathijssen, Neeltje Steeghs

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. [email protected].
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (Cmax) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking.

METHODS: We performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28.

RESULTS: Eleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, Cmax, minimum concentration (Cmin), and area under the concentration-time curve from time zero to 24 h (AUC24) were 61.5 ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV% 35.0), and 435 ng h/mL (CV% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of Cmaxto 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC24at 436 ng h/mL (CV% 34.8) (p = 0.952). Cminincreased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in Cmaxwas 21.2 ng/mL, or 32.7%. The Cmax/Cminratio was reduced from 6.44 (CV% 36.2) to 3.18 (CV% 35.5) (p < 0.001).

CONCLUSIONS: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces Cmaxwithout negatively impacting Cminor AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.

REGISTRATION: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).

Original language	English
Pages (from-to)	637–644
Number of pages	8
Journal	Clinical Pharmacokinetics
Volume	57
Issue number	5
DOIs	https://doi.org/10.1007/s40262-017-0582-9
Publication status	Published - Jun 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s40262-017-0582-9

Verheijen2018_Article_PharmacokineticOptimizationOfEFinal published version, 665 KB

Cite this

@article{ddd25af6225e4263a14f0c491f925745,

title = "Pharmacokinetic Optimization of Everolimus Dosing in Oncology: A Randomized Crossover Trial",

abstract = "BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (Cmax) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking.METHODS: We performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28.RESULTS: Eleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, Cmax, minimum concentration (Cmin), and area under the concentration-time curve from time zero to 24 h (AUC24) were 61.5 ng/mL [mean percentage coefficient of variation (CV\%) 29.6], 9.6 ng/mL (CV\% 35.0), and 435 ng h/mL (CV\% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of Cmaxto 40.3 ng/mL (CV\% 46.6) (p = 0.013), while maintaining AUC24at 436 ng h/mL (CV\% 34.8) (p = 0.952). Cminincreased to 13.7 ng/mL (CV\% 53.9) (p = 0.018). The overall reduction in Cmaxwas 21.2 ng/mL, or 32.7\%. The Cmax/Cminratio was reduced from 6.44 (CV\% 36.2) to 3.18 (CV\% 35.5) (p < 0.001).CONCLUSIONS: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces Cmaxwithout negatively impacting Cminor AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.REGISTRATION: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).",

author = "Verheijen, \{Remy B.\} and Florence Atrafi and Schellens, \{Jan H M\} and Beijnen, \{Jos H\} and Huitema, \{Alwin D R\} and Mathijssen, \{Ron H J\} and Neeltje Steeghs",

year = "2018",

month = jun,

doi = "10.1007/s40262-017-0582-9",

language = "English",

volume = "57",

pages = "637–644",

journal = "Clinical Pharmacokinetics",

issn = "0312-5963",

publisher = "Adis",

number = "5",

}

TY - JOUR

T1 - Pharmacokinetic Optimization of Everolimus Dosing in Oncology

T2 - A Randomized Crossover Trial

AU - Verheijen, Remy B.

AU - Atrafi, Florence

AU - Schellens, Jan H M

AU - Beijnen, Jos H

AU - Huitema, Alwin D R

AU - Mathijssen, Ron H J

AU - Steeghs, Neeltje

PY - 2018/6

Y1 - 2018/6

N2 - BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (Cmax) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking.METHODS: We performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28.RESULTS: Eleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, Cmax, minimum concentration (Cmin), and area under the concentration-time curve from time zero to 24 h (AUC24) were 61.5 ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV% 35.0), and 435 ng h/mL (CV% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of Cmaxto 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC24at 436 ng h/mL (CV% 34.8) (p = 0.952). Cminincreased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in Cmaxwas 21.2 ng/mL, or 32.7%. The Cmax/Cminratio was reduced from 6.44 (CV% 36.2) to 3.18 (CV% 35.5) (p < 0.001).CONCLUSIONS: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces Cmaxwithout negatively impacting Cminor AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.REGISTRATION: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).

AB - BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (Cmax) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking.METHODS: We performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28.RESULTS: Eleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, Cmax, minimum concentration (Cmin), and area under the concentration-time curve from time zero to 24 h (AUC24) were 61.5 ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV% 35.0), and 435 ng h/mL (CV% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of Cmaxto 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC24at 436 ng h/mL (CV% 34.8) (p = 0.952). Cminincreased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in Cmaxwas 21.2 ng/mL, or 32.7%. The Cmax/Cminratio was reduced from 6.44 (CV% 36.2) to 3.18 (CV% 35.5) (p < 0.001).CONCLUSIONS: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces Cmaxwithout negatively impacting Cminor AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.REGISTRATION: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).

U2 - 10.1007/s40262-017-0582-9

DO - 10.1007/s40262-017-0582-9

M3 - Article

C2 - 28762135

SN - 0312-5963

VL - 57

SP - 637

EP - 644

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

IS - 5

ER -

Pharmacokinetic Optimization of Everolimus Dosing in Oncology: A Randomized Crossover Trial

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this