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
N1 - Funding Information:
Funding This investigator-initiated study was supported by Novartis. The funding source had no involvement in the study design, collection, analysis and interpretation of the data, writing of the report, or in the decision to submit the article for publication.
Publisher Copyright:
© 2017, The Author(s).
PY - 2018/5
Y1 - 2018/5
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 (C
max) 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, C
max, minimum concentration (C
min), and area under the concentration-time curve from time zero to 24 h (AUC
24) 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 C
max to 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC
24 at 436 ng h/mL (CV% 34.8) (p = 0.952). C
min increased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in C
max was 21.2 ng/mL, or 32.7%. The C
max/C
min ratio 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 C
max without negatively impacting C
min or AUC
24. 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 (C
max) 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, C
max, minimum concentration (C
min), and area under the concentration-time curve from time zero to 24 h (AUC
24) 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 C
max to 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC
24 at 436 ng h/mL (CV% 34.8) (p = 0.952). C
min increased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in C
max was 21.2 ng/mL, or 32.7%. The C
max/C
min ratio 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 C
max without negatively impacting C
min or AUC
24. 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).
KW - Adult
KW - Aged
KW - Antineoplastic Agents/administration & dosage
KW - Breast Neoplasms/drug therapy
KW - Carcinoma, Renal Cell/drug therapy
KW - Cross-Over Studies
KW - Everolimus/administration & dosage
KW - Female
KW - Humans
KW - Immunosuppressive Agents/administration & dosage
KW - Male
KW - Middle Aged
KW - Neuroendocrine Tumors/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85026513162&partnerID=8YFLogxK
U2 - 10.1007/s40262-017-0582-9
DO - 10.1007/s40262-017-0582-9
M3 - Article
C2 - 28762135
AN - SCOPUS:85026513162
SN - 0312-5963
VL - 57
SP - 637
EP - 644
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 5
ER -