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Clinical Pharmacokinetic and Pharmacodynamic Considerations in the (Modern) Treatment of Melanoma

  • Hannah Yejin KimEmail author
  • Parth J. Upadhyay
  • Alia Fahmy
  • Xiaoman Liu
  • Janna K. Duong
  • Alan V. Boddy
Review Article

Abstract

Targeted therapies, based on identification of common oncogenic mutations such as BRAF V600E/K and monoclonal antibody immunotherapies, have transformed the treatment of melanoma. Dual mitogen-activated protein kinase (MAPK) pathway inhibition of BRAF V600E/K and MEK 1/2 kinases with BRAF–MEK inhibitors using dabrafenib–trametinib, vemurafenib–cobimetinib and encorafenib–binimetinib is now the standard of care for BRAF V600E/K tumours. Monoclonal antibodies, such as pembrolizumab and nivolumab, against programmed cell death protein (PD-1) on T cells, as well as ipilimumab against cytotoxic T lymphocyte antigen-4 (CTLA-4), enable restoration of suppressed T-cell antitumour response, and have also shown improved clinical benefit compared with traditional chemotherapy. Exploration of different combination therapies, sequence of treatment, and dosing strategies is ongoing, and the understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of these new agents is fundamental in devising the optimal regimen. Preclinical and clinical studies, as well as population PK modelling, provide essential data in terms of PK parameters, metabolism, interpatient variability, drug interactions and PD effects at the target. This review gathers the current evidence and understanding of the clinical PK and PD of drugs used in the modern treatment of melanoma, and the factors determining drug disposition, exposure and clinical response, and also highlighting areas of further research.

Notes

Compliance with Ethical Standards

Conflict of interest

Hannah Yejin Kim, Parth J. Upadhyay, Alia Fahmy, Xiaoman Liu, Janna K. Duong, and Alan V. Boddy declare they have no conflicts of interest.

Funding

No sources of funding were used for this review.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Hannah Yejin Kim
    • 1
    Email author
  • Parth J. Upadhyay
    • 1
  • Alia Fahmy
    • 1
  • Xiaoman Liu
    • 1
  • Janna K. Duong
    • 1
  • Alan V. Boddy
    • 2
    • 3
  1. 1.School of Pharmacy, Faculty of Medicine and HealthThe University of SydneySydneyAustralia
  2. 2.School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
  3. 3.UniSA Cancer Research InstituteUniversity of South AustraliaAdelaideAustralia

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