A pharmacological rationale for improved everolimus dosing in oncology and transplant patients

R Ter Heine; N P van Erp; H J Guchelaar; J W de Fijter; M E J Reinders; C M van Herpen; D M Burger; D J A R Moes

doi:10.1111/bcp.13591

A pharmacological rationale for improved everolimus dosing in oncology and transplant patients

Br J Clin Pharmacol. 2018 Jul;84(7):1575-1586. doi: 10.1111/bcp.13591. Epub 2018 May 6.

Authors

R Ter Heine¹, N P van Erp¹, H J Guchelaar², J W de Fijter³, M E J Reinders³, C M van Herpen⁴, D M Burger¹, D J A R Moes²

Affiliations

¹ Radboudumc, Department of Pharmacy, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
² Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Radboudumc, Department of Medical Oncology, Nijmegen, The Netherlands.

Abstract

Aims: Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin-free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment-limiting toxicity.

Methods: We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens.

Results: We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75-1 mg twice daily (BID) results in subtherapeutic trough levels (<6 μg l^-1 ) and that a higher starting dose of 2.25-3 mg BID is required.

Conclusion: For oncological indications, our results encourage the investigation of dosing everolimus 3.75 mg BID in terms of superiority in safety and noninferiority in efficacy.

Keywords: cancer; dose individualization; everolimus; nonmem; population pharmacokinetics; transplant.

Publication types

Equivalence Trial
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
Biological Availability
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Therapy, Combination / adverse effects
Drug Therapy, Combination / methods
Everolimus / administration & dosage*
Everolimus / adverse effects
Everolimus / pharmacokinetics
Female
Graft Rejection / immunology
Graft Rejection / prevention & control*
Humans
Immunosuppressive Agents / administration & dosage*
Immunosuppressive Agents / adverse effects
Immunosuppressive Agents / pharmacokinetics
Kidney Transplantation / adverse effects
Male
Metabolic Clearance Rate
Middle Aged
Models, Biological
Neoplasms / drug therapy*
Neoplasms / immunology
Prednisolone / administration & dosage
Prednisolone / pharmacokinetics
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / immunology
Tacrolimus / administration & dosage
Tacrolimus / adverse effects
Tacrolimus / pharmacokinetics
Transplantation, Homologous / adverse effects
Treatment Outcome

Substances

Immunosuppressive Agents
Everolimus
Prednisolone
MTOR protein, human
TOR Serine-Threonine Kinases
Tacrolimus