Clinical Pharmacy and Toxicology 1

Heterogeneity of drug efficacy and toxicity in relation to individual pharmacokinetics, pharmacodynamics and pharmacogenetics

Principal investigators

Prof.Dr H.J. Guchelaar, Dr J.A.M. Wessels,  Dr R.J.H.M. van der Straaten, Dr J. den Hartigh

Aim and focus

The ultimate goal of the programme is to optimize individual drug treatment by understanding and managing inter- and intraindividual variation of drug response both with respect to drug efficacy and toxicity. This patient care oriented programme of translational research is of great clinical importance at two different aspects. First, it is focused on developing, expanding and refining scientific methods (chemical analysis, therapeutic drug monitoring, pharmacogenetics) concerning pharmacotherapy. Secondly, it aims at contributing to improvement of pharmacotherapy. Monitoring drug concentrations and assessing drug (surrogate) effects, developing and applying clinical pharmacokinetic (PK)/pharmacodynamic (PD) models on the basis of population PK provides the means of understanding (and predicting) the variability of drug effects. More specifically, genetic variability (such as single nucleotide polymorphisms, gene expression) will be taken into account and may explain variable drug response. The programme has a strong emphasis on drugs applied in oncology and immunology (rheumatoid arthritis, transplantation). It aims not only at a better understanding of mechanisms of variable drug efficacy and toxicity, but also at methods readily applicable in the treatment of patients with oncological and immunological disorders.

Position in international context

There is a strong collaboration with departments and (inter)national institutions involved in analysis (Clinical Chemistry), human genetics (Leiden Genome Technology Center; Clinical Epidemiology, Medical Statistics, Human Genetics), PK/PD modeling (Leiden Amsterdam Centre for Drug Research), Clinical Oncology, Rheumatology, Immunohematology, Hemato(onco)logy, and Transplantation. The research programme links on in subject matter to the research focal points of the LUMC, namely Genetics, Immunology, Transplantation and Oncology.

Content / highlights / achievements

Examples of current studies of  pharmacokinetics, pharmacodynamics and pharmacogenetics are the chemotherapeutic treatment of colorectal cancer and of breast cancer, the treatment of rheumatoid arthritis with methotrexate and antiTNF drugs, the immunosuppressive therapy in (renal, liver, islet) transplantation, and the implementation of pharmacogenetics into clinical practice.  Another line of activities in clinical pharmacy gives rise to a large amount of developmental research in immunotherapy and gene therapy, including the synthesis of GMP-grade peptides for human use and their formulation (for example, HPV16-vaccin) and the establishment of humanized culture conditions for cell lines (for example activated T-cells, pancreatic Islets).  Recents highlights of our research programme are the implementation of a novel approach of therapeutic drug monitoring in immunosuppressive therapy, the performance of several large multicenter pharmacogenetic studies in 1] chemotherapeutic treatment of colorectal cancer and breast cancer and in 2] rheumatoid arthritis, and the development of a HPV16 peptide-vaccine of which the clinical study is ongoing. One of the projects resulted in a USA and EU patent which is currently licensed. The department of Clinical Pharmacy & Toxicology is contuining to make major investments in equipment for pharmacogenetic analysis and established a platform for clinical and experimental pharmacogenetics with a variety of methods for assessement of DNA and RNA analysis. In addition, the Laboratory for Drug Analysis is well equipped for sophisticated analysis of xenobiotics in biological material (f.e. LC-MS-MS).

Future themes

In the future, clinical PK/PD modeling and PG research will be extended to novel drugs in oncology and immunology which will become available for clinical research or regular use. Moreover, a novel approach including PK, PD and PG will be explored, leading to integrated systems pharmacology. Novel technologies in the field of drug analysis and molecular biology will be implemented in our laboratories. As a contribution to immunotherapy, new synthetic peptides along with adjuvants for peptide vaccines will be designed.

Cohesion within LUMC

This research is conducted in extensive collaboration with the departments of Medical Oncology, Rheumatology and Transplantation.

Key publications

Dezentjé VO, Guchelaar HJ, Nortier JW, van de Velde CJ, Gelderblom H. Clinical implications of CYP2D6 genotyping in tamoxifen treatment for breast cancer. Clin Cancer Res. 2009 Jan 1;15(1):15-21.
IF 6.488

Kweekel DM, Gelderblom H, Van der Straaten T, Antonini NF, Punt CJ, Guchelaar HJ; Dutch Colorectal Cancer Group study. UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study. Br J Cancer. 2008 Jul 22;99(2):275-82.
IF 4.846

Kweekel DM, Koopman M, Antonini NF, Van der Straaten T, Nortier JW, Gelderblom H, Punt CJ, Guchelaar HJ. GSTP1 Ile105Val polymorphism correlates with progression-free survival in MCRC patients treated with or without irinotecan: a study of the Dutch Colorectal Cancer Group. Br J Cancer. 2008 Oct 21;99(8):1316-21.
IF 4.846

van Erp NP, Gelderblom H, Karlsson MO, Li J, Zhao M, Ouwerkerk J, Nortier JW, Guchelaar HJ, Baker SD, Sparreboom A. Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res. 2007 Dec 15;13(24):7394-400.
IF 6.488

van der Straaten T, Swen J, Baak-Pablo R, Guchelaar HJ. Use of plasmid-derived external quality control samples in pharmacogenetic testing. Pharmacogenomics. 2008 Sep;9(9):1261-6.
IF 3.551

Swen JJ, Huizinga TW, Gelderblom H, de Vries EG, Assendelft WJ, Kirchheiner J, Guchelaar HJ. Translating pharmacogenomics: challenges on the road to the clinic. PLoS Med. 2007 Aug;4(8):1317-1324.
IF 12.185

Speetjens FM, Kuppen PJ, Welters MJ, Essahsah F, Voet van den Brink AM, Lantrua MG, Valentijn AR, Oostendorp J, Fathers LM, Nijman HW, Drijfhout JW, van de Velde CJ, Melief CJ, van der Burg SH. Induction of p53-specific immunity by a p53 synthetic long peptide vaccine in patients treated for metastatic colorectal cancer. Clin Cancer Res. 2009 Feb 1;15(3):1086-95.
IF 6.488

Press RR, Ploeger BA, den Hartigh J, van der Straaten T, van Pelt J, Danhof M, de Fijter JW, Guchelaar HJ. Explaining variability in tacrolimus pharmacokinetics to optimize early exposure in adult kidney transplant recipients. Ther Drug Monit. 2009 Apr;31(2):187-97.
IF 2.401

Albers HM, Wessels JA, van der Straaten RJ, Brinkman DM, Suijlekom-Smit LW, Kamphuis SS, Girschick HJ, Wouters C, Schilham MW, le Cessie S, Huizinga TW, Ten Cate R, Guchelaar HJ .Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis. Arthritis Rheum. 2009 Jan 15;61(1):46-51.
IF 6.787

Wessels JA, van der Kooij SM, le Cessie S, Kievit W, Barerra P, Allaart CF, Huizinga TW, Guchelaar HJ; Pharmacogenetics Collaborative Research Group. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis..Arthritis Rheum. 2007 Jun;56(6):1765-75.
IF 6.787