A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients.
Everolimus (a drug from the class of mammalian target of rapamycin [mTOR] inhibitors) is associated with frequent toxicity-related dose reductions. Everolimus accumulates in erythrocytes, but the extent to which hematocrit affects everolimus plasma pharmacokinetics and pharmacodynamics is unknown. We aimed to investigate the everolimus pharmacokinetics/pharmacodynamics and the influence of hematocrit in cancer patients.



A semi-physiological pharmacokinetic model for everolimus was developed from pharmacokinetic data from 73 patients by non-linear mixed-effects modeling. Using a simulation study with a known pharmacodynamic model describing S6K1 (a downstream mTOR effector) inhibition, we investigated the impact of hematocrit.



The apparent volume of distribution of the central and peripheral compartment were estimated to be 207 L with a relative standard error (RSE) of 5.0 % and 485 L (RSE 4.2 %), respectively, with an inter-compartmental clearance of 72.1 L/h (RSE 3.2 %). The apparent intrinsic clearance was 198 L/h (RSE 4.3 %). A decrease in hematocrit from 45 % to 20 % resulted in a predicted reduction in whole-blood exposure of ~50 %, but everolimus plasma pharmacokinetics and pharmacodynamics were not affected. The predicted S6K1 inhibition was at a plateau level in the approved dose of 10 mg once daily.



A population pharmacokinetic model was developed for everolimus in cancer patients. Hematocrit influenced whole-blood pharmacokinetics, but not plasma pharmacokinetics or pharmacodynamics. Everolimus whole-blood concentrations should always be corrected for hematocrit. Since predicted mTOR inhibition was at a plateau level in the approved dose, dose reductions may have only a limited impact on mTOR inhibition.
Department of Pharmacy, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
Nielka P
NP
van Erp
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
Carla M
CM
van Herpen
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands.
Djoeke
D
de Wit
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
Annelieke
A
Willemsen
Department of Pharmacy, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
David M
DM
Burger
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Alwin D R
AD
Huitema
Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.
Ellen
E
Kapiteijn
Department of Pharmacy, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. r.terheine@radboudumc.nl.
Rob
R
Ter Heine
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006400:Hematocrit; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D000068338:Everolimus; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1