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Rede uitgesproken bij de aanvaarding van het ambt van hoogleraar Cancer Pharmacology aan de Faculteit der Medische Wetenschappen van de Radboud Universiteit en het Radboudumc op vrijdag 25 maart 2022, Inaugural lecture, Contains fulltext : 250508.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Certain drugs inherently have unfavourable pharmacokinetic properties; for example, they are poorly absorbed or broken down too quickly in the liver. In some cases, the addition of a pharmacokinetic excipient, thus deliberately causing an interaction, may offer a solution. To date, this concept has been most widely applied in HIV treatment where addition of the CYP3A inhibitors ritonavir and cobicistat greatly increases plasma levels of other HIV medications. For the same reason, ritonavir has been added to the new oral antiviral drug against the SARS CoV-2 virus, nirmatrelvir. In addition to a better and/or longer effect, theoretically lower doses can also be used, resulting in cost savings. Deliberately inducing a pharmacokinetic interaction is not without risk: after all, interactions with other CYP3A substrates can also occur. Nevertheless, we believe that with good interaction management, CYP3A inhibitors can be used safely with benefits for patients and society.

Radboud University, 01 december 2022, Promotores : Erp, P.H. van, Schalken, J.A. Co-promotores : Mehra, N., Oort, I.M. van, Contains fulltext : 284399.pdf (Publisher’s version ) (Open Access)

Radboud University, 12 oktober 2020, Promotores : Gerritsen, W.R., Herpen, C.M.L. van Co-promotores : Erp, P.H. van, Tol, J., Contains fulltext : 222328.pdf (publisher's version ) (Open Access)

Radboud University, 11 december 2019, Promotores : Burger, D.M., Gelderblom, A.J., Herpen, C.M.L. van Co-promotor : Erp, P.H. van, Contains fulltext : 212494.pdf (publisher's version ) (Open Access)

Radboud University, 9 december 2019, Promotores : Burger, D.M., Schalken, J.A. Co-promotores : Erp, P.H. van, Oort, I.M. van, Contains fulltext : 210166.pdf (publisher's version ) (Open Access)

Contains fulltext : 172044.pdf (Publisher’s version ) (Open Access), INTRODUCTION AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.