title: Pharmacodynamic modeling of adverse effects of anti-cancer drug treatment.
abstract: OBJECTIVE
  Adverse effects related to anti-cancer drug treatment influence patient's quality of life, have an impact on the realized dosing regimen, and can hamper response to treatment. Quantitative models that relate drug exposure to the dynamics of adverse effects have been developed and proven to be very instrumental to optimize dosing schedules. The aims of this review were (i) to provide a perspective of how adverse effects of anti-cancer drugs are modeled and (ii) to report several model structures of adverse effect models that describe relationships between drug concentrations and toxicities.
  
  
  METHODS
  Various quantitative pharmacodynamic models that model adverse effects of anti-cancer drug treatment were reviewed.
  
  
  RESULTS
  Quantitative models describing relationships between drug exposure and myelosuppression, cardiotoxicity, and graded adverse effects like fatigue, hand-foot syndrome (HFS), rash, and diarrhea have been presented for different anti-cancer agents, including their clinical applicability.
  
  
  CONCLUSIONS
  Mathematical modeling of adverse effects proved to be a helpful tool to improve clinical management and support decision-making (especially in establishment of the optimal dosing regimen) in drug development. The reported models can be used as templates for modeling a variety of anti-cancer-induced adverse effects to further optimize therapy.
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. ah.d.vriesschultink@nki.nl.
authors.forename: A H M
authors.initials: AH
authors.lastname: de Vries Schultink
authors.affiliation: Department of Pharmacology, Clinical Pharmacology Unit, University Hospital of Cologne, Gleueler Str. 24, 50931, Cologne, Germany.
authors.forename: A A
authors.initials: AA
authors.lastname: Suleiman
authors.affiliation: Department of Clinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological
chemical_list: D000970:Antineoplastic Agents
keywords: Adverse effects; Anti-cancer drug treatment; Modeling; Pharmacodynamics