A unifying model to predict variable drug response for personalised medicine

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Pharmacogenomics is a key component of personalized medicine. It promises a safer and more effective drug treatment by individualizing the choice of drug and dose based on an individual’s genetic profile 1,2 . The majority of commonly prescribed drugs are metabolized by a small set of Cytochrome P450 (CYP) enzymes 3 . In clinical practice, genetic biomarkers are being used to categorize patients into predefined *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. Yet, this approach has important limitations as it leaves a large part of variability in drug response unexplained 4,5 . Here, we present a novel approach and introduce a continuous scale (instead of categorical) assignments to predict metabolic enzyme activity. The proposed strategy uses full gene sequencing data, a neural network model and CYP2D6 mediated tamoxifen metabolism from a prospective study of 561 breast cancer patients. The model explains 79% of the interindividual variability in CYP2D6 activity compared to 54% with the conventional approach. It is capable of assigning accurate enzyme activity to alleles containing previously uncharacterized combinations of variants and were replicated in an independent cohort of tamoxifen treated patients, a cohort of Venlafaxine users as well as in vitro functional assays using HEK cells. These results demonstrate the advantage of a continuous scale and a completely phased genotype for prediction of CYP450 enzyme activity and thereby enables more accurate prediction of individual drug response.

Authors 14

1. Maaike van der Lee Aachen Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

   Leiden Network of Personalized Therapeutics

2. William G. Allard Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center

3. Rolf H. A. M. Vossen Aachen Department of Human Genetics Leiden Genome Technology Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center

   Leiden Genome Technology Center, Leiden University Medical Center

4. Renée F. Baak-Pablo Aachen Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

5. Roberta Menafra Aachen Department of Human Genetics Leiden Genome Technology Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center

   Leiden Genome Technology Center, Leiden University Medical Center

6. Birgit A. L. M. Deiman

   Catharina Ziekenhuis

   Affiliation as printed

   Clinical Laboratory, Catharina Hospital Eindhoven

7. Maarten J. Deenen Aachen Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center · Catharina Ziekenhuis

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

   Department of Clinical Pharmacy, Catharina Hospital Eindhoven

8. Patrick Neven

   Universitair Ziekenhuis Leuven

   Affiliation as printed

   University Hospital Leuven, Leuven, Belgium

9. Inger Johansson

   Karolinska Institutet

   Affiliation as printed

   Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum 5B Stockholm, Sweden

10. Stefano Gastaldello

    Karolinska Institutet

    Affiliation as printed

    Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum 5B Stockholm, Sweden

11. Magnus Ingelman‐Sundberg

    Karolinska Institutet

    Affiliation as printed

    Department of Physiology and Pharmacology, Karolinska Institutet, Biomedicum 5B Stockholm, Sweden

12. Henk‐Jan Guchelaar Aachen Department of Clinical Pharmacy and Toxicology

    Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

    Leiden Network of Personalized Therapeutics

13. Jesse Joachim Swen corresponding Aachen Department of Clinical Pharmacy and Toxicology

    Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

    Leiden Network of Personalized Therapeutics

14. Seyed Yahya Anvar corresponding Aachen Department of Clinical Pharmacy and Toxicology Department of Human Genetics Leiden Genome Technology Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center

    Department of Human Genetics, Leiden University Medical Center

    Leiden Genome Technology Center, Leiden University Medical Center

    Leiden Network of Personalized Therapeutics

    OKRA Technologies, Cambridge, United Kingdom