Dutch Pharmacogenetics Working Group

Project Description:


The Dutch Pharmacogenetics Working Group (DPWG) is established in 2005 by the Royal Dutch Pharmacist's Association (KNMP). The DPWG is multidisciplinary and includes clinical pharmacists, physicians, clinical pharmacologists, clinical chemists, epidemiologists, and toxicologists.

The objectives of the DPWG are:

  • To develop pharmacogenetics-based therapeutic (dose) recommendations.
  • To assist drug prescribers and pharmacists by integrating the recommendations into computerized systems for drug prescription and automated medication surveillance

Detailed information about the project can be found in:
PMID: 18253145
PMID: 21412232

The DPWG is funded by the KNMP.

Methods:

For each drug, a systematic search was carried out. The articles included in the reference lists were individually screened for additional material or papers. Wherever information relating to gene-drug interaction was present in the European Public Assessment Report, the manufacturer was asked to provide further details. Review articles, studies involving nonhuman subjects and in vitro experiments were excluded.

For each retrieved article two parameters were defined:

  • Level of evidence of the gene-drug interaction.
  • Clinical relevance of the potential adverse drug event, decreased therapeutic response, or other clinical effect resulting from the gene-drug interaction.
Level of evidence

The level of evidence of the gene-drug interaction indicates the quality of the evidence found in literature for the gene-drug interaction. The level of evidence was scored on a five-point scale with a range from 0 (lowest evidence) to 4 (highest evidence).

Level of Evidence

Definition (Download PDF: Levels of Evidence)

4

Published controlled studies of "good quality" relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints.
"Good quality" criteria include:

  • The use of concomitant medication with a possible effect on the phenotype is reported in the manuscript.
  • Confounders are reported (e.g. smoking status).
  • The reported data are based on steady-state kinetics.
  • Results are corrected for dose variability.

3

Published controlled studies of "moderate quality" relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. "Moderate" is defined as missing one or more of the "good quality" criteria.

2

Published case reports, well documented, and having relevant pharmacokinetic or clinical endpoints. Well documented case series.

1

Published incomplete case reports. Product information.

0

Data on file.

–

No evidence.

Clinical relevance

Clinical relevance of the potential adverse drug event, decreased therapeutic response, or other clinical effect resulting from the gene-drug interaction.
The clinical relevance was scored on a seven-point scale derived from the National Cancer Institute's Common Toxicity Criteria. A clinical or pharmacokinetic effect that was not statistically significant was classified as AA (lowest impact), whereas death, for example, was classified as F (highest impact). At every level of this point scale, new events are added after assessment by the DPWG.

Clinical Relevance

Definition (Download PDF: Classification of Clinical Relevance)

AA

Clinical effect (NS)
Kinetic effect (NS)

A

Minor clinical effect (S): QTc prolongation (<450 ms female, <470 ms male); INR increase < 4.5
Kinetic effect (S)

B

Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test.

C

Clinical effect (S): long-standing discomfort (48-168 hr) without permanent injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased bioavailability of tricyclic antidepressants, metoprolol, propafenone (central effects e.g. dizziness); INR 4.5-6.0; neutropenia 1.0-1.5x109/l; leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l.

D

Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea.

E

Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening complications from diarrhea.

F

Clinical effect (S): death; arrhythmia; unanticipated myelosuppression.

NS: not statistically significant difference; S: statistically significant difference; INR: international normalized ratio; ADE: adverse drug event.

Genotype to Phenotype translation

Members:

The current members are:

  • St. Antonius Hospital, Dept. Clinical Pharmacy
    V.H. Deneer, PharmD, PhD
  • KNMP, division Drug Information Centre
    L. Grandia, PharmD
    M. Nijenhuis, PhD
  • Utrecht University, Division of Pharmacoepidemiology and Clinical Pharmacology
    A. de Boer, MD, PhD
    A.H. Maitland-van der Zee, PharmD, PhD
    T. Schalekamp, PharmD, PhD
  • Leiden University Medical Center, Dept. of Clinical Pharmacy & Toxicology
    H.J. Guchelaar, PharmD, PhD
    J.J. Swen, PharmD, PhD
  • Wilhelmina Hospital Assen, Dept. of Clinical Pharmacy
    H. Mulder, PharmD, PhD
  • Erasmus University Medical Center, Dept. of Clinical Chemistry
    R.H. van Schaik, PhD
  • University Medical Center St. Radboud, Dept. of Pharmacology and Toxicology
    G.A. Rongen, MD, PhD
  • Central Hospital Pharmacy
    D.J. Touw, PharmD, PhD
  • St. Jansdal Hospital, Dept. of Clinical Chemistry
    J. van der Weide, PhD
  • University of Groningen, Dept. of Pharmacotherapy and Pharmaceutical Care
    B. Wilffert, PharmD, PhD

Former members:
A.L. de Goede, PharmD
J.M. Conemans, PharmD, PhD
T.C. Egberts, PharmD, PhD
R. Koopmans, MD, PhD
O.H. Klungel, PharmD, PhD
I. Wilting, PharmD, PhD

Contact Information:

m.nijenhuis@knmp.nl or l.grandia@knmp.nl

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