Personalized Medicine Lab of Translational Pharmacology

Research group Personalized Medicine - Laboratory of Translational Pharmacology

 

The laboratory of Translational Pharmacology is part of our research group. In this lab we determine drug concentrations of (novel) anti-cancer drugs or supporting agents (e.g. fentanyl), which our relevant for our clinical and pre-clinical studies.
Our group is involved in four main activities:

1. (Drug-drug/ drug-food) interaction studies
2. Lifestyle studies
3. Mechanistic pharmacokinetic, –dynamic, and -genetic studies
4. Personalized dosing strategies/TDM

1. Interaction studies.

Our group is well known for its clinical interaction studies, mainly focused on interactions at the level of phase I metabolism (Cytochrome P450 iso-enzymes). Classic examples involve interactions between chemotherapy (i.e. irinotecan and docetaxel) and strong CYP3A inhibitors or inducers (i.e. ketoconazole, St. John’s wort). But also potential interactions between targeted agents and commonly used co-medication (i.e. proton-pump inhibitors and statins) have been studied, to explore its implications for daily clinical practice.

A recent study involved the interaction between curcumin and tamoxifen treatment in breast cancer patients. See:https://www.mdpi.com/2072-6694/11/3/403

2. Lifestyle studies.

Although highly underrated during the last century, the effects of patient’s lifestyle on drug exposure and toxicity is enormous. At first, we became aware of the devastating effects of certain complementary and alternative medicine (CAM; i.e. St. John’s wort) on systemic drug concentrations of anti-cancer agents; then comparable effects of smoking (i.e. erlotinib, irinotecan) were published. But also the use of alcohol, a high-fat meal, grapefruit(juice), time of the day taking anti-cancer medication, the use of an acidic beverage, and adherence may (potentially) all affect the exposure to a drug or influence the number and/or severity of side effects.

3. Mechanistic pharmacokinetic, –dynamic, and -genetic studies.

If the mechanism behind an interaction is known in detail, it should also be possible to avoid severe drug-related toxicities. With this is mind, and in close collaboration with the group of prof Sparreboom (Ohio State University, USA) we studied cisplatin-related nephrotoxicity. We found an important role for the transporter OCT2 in regulating the uptake of this drug in the proximal tubules. Next, we explored if an OCT2 inhibitor was capable to reduce nephrotoxicity without reducing the systemic exposure to cisplatin. We also perform mechanistic studies for other drugs, like sorafenib (Bins et al, Clin Transl Sci 2017).

4. Personalized dosing strategies/ TDM

Currently, (most) chemotherapeutic agents are dosed on body-surface area, and oral compounds are given in a fixed dose. Although we know that these strategies are obsolete and not patient-tailored, the lack of good alternatives makes it hard to change daily practice. Nonetheless, nowadays oncologists are aware of the importance of giving the right dose to the right patient, as a clear dose-response relationship exists for most anti-cancer agents (Mathijssen et al, Nat Rev Clin Oncol 2014). This makes it possible to introduce pharmacogenetic based dosing (Henricks et al, Lancet Oncol 2018) and therapeutic drug monitoring (TDM) into clinical practice (see www.dpog.nl).

-The MULTOMAB study: ‘Prospective sampling in intravenously treated oncology patients: monoclonal antibodies (MULTOMAB)’. A recent paper which came from this project: https://www.ncbi.nlm.nih.gov/pubmed/30654225

-The ALPE2U study: ‘Improving the safety of fluoropyrimidine-based chemotherapy by combined DPYD genotype-guided and DPD phenotype-guided dose individualization: The ALPE2U study’.

Three key publications

• Van Leeuwen RWF, van Gelder T, Mathijssen RHJ, and Jansman FGA. Drug-drug interactions with tyrosine kinase inhibitors: a clinical perspective. Lancet Oncol. 15: e315-26, 2014. PubMed
• Van Leeuwen R.W.F., Peric R., Hussaarts K.G.A.M., Kienhuis E., IJzerman N.S., de Bruijn P., van der Leest C., Codrington H., Kloover J.S., van der Holt B., Aerts J.G., van Gelder T., and Mathijssen R.H.J. Influence of the acidic beverage cola on the absorption of erlotinib in patients with non-small-cell lung cancer. J. Clin. Oncol.  34(12): 1309-3014, 2016. PubMed
• Henricks L.M., Lunenburg C.A.T.C., de Man F.M., Meulendijks D., Frederix G.W.J., Kienhuis E., Creemers G.-J., Baars A., Dezentjé V.O., Imholz A.L.T., Jeurissen F., Portielje J.E.A., Jansen R.L.H., Hamberg P., ten Tije A.J., Droogendijk H.J., Koopman M., Nieboer P., van de Poel M.H.W., Mandigers C.M.P.W., Rosing H., Beijnen J.H., van Werkhoven E., van Kuilenburg A.B.P., van Schaik R.H.N., Mathijssen R.H.J., Swen J.J., Gelderblom H., Cats A., Guchelaar H.-J., and Schellens J.H.M. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: A prospective safety analysis. Lancet Oncol. 19 (11): 1459-1467, 2018. PubMed

Two recent publications

• Basak E.A., Koolen S.L.W., Hurkmans D.P., Schreurs M.W.J., Bins S., Oomen-de Hoop E., Wijkhuis A.J.M., den Besten I., Sleijfer S., Debets R., van der Veldt A.A.M., Aerts J.G.J.V., and Mathijssen R.H.J. Correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer. Eur. J. Cancer 109: 12-20, 2019. Pubmed
• de Man FM, Hussaarts KGAM, de With M, Oomen-de Hoop E, de Bruijn P, van Halteren HK, van der Burg-de Graauw NCHP, Eskens FALM, van Gelder T, van Leeuwen RWF, and Mathijssen RHJ. Influence of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib: A Randomized Crossover Pharmacokinetic Study. Clin Pharmacol Ther. 2019 Jun;105(6):1456-1461. PubMed

Collaborations inside Erasmus MC

• ACE Pharmacology & Therapeutics.
• Collaborations with multiple specialisms/departments within Erasmus MC.

Collaborations outside Erasmus MC

• Dutch Pharmacology Oncology Group (www.dpog.nl)

Our research is partyly funded by the following organizations:

• ZonMW
• Dutch Cancer Society
• Alpe d'HuZes
• Erasmus MC MRace
• Pharmacy

• Ron Mathijssen, MD PhD, Full Professor, PI
• Stijn Koolen, PhD, hospital-pharmacist and clinical pharmacologist, Assistant Professor
• Roelof van Leeuwen, PhD, hospital-pharmacist, Assistant Professor
• Sander Bins, MD, PhD, internist in training, post-doc
• Florence Atrafi, MD, PhD student
• Leni van Doorn, nurse practitioner, MANP, MSc, PhD student 
• Femke de Man, MD, PhD student
• Bodine Belderbos, MD, PhD student
• Edwin Basak, PhD student
• Koen Hussaarts, MD, PhD student
• Daan Hurkmans, MD, PhD student
• Louwrens Braal, pharmacist, PhD student
• Marijn Veerman, PhD student 
• Ruben van Eerden, PhD student
• Nikki IJzerman, MD, PhD student
• Wesley van de Geer, PhD student
• Mirjam de With, MD, PhD student
• Karlijn de Joode, MD, PhD student
• Stefan Buck, MD, PhD student
• Peter de Bruijn, Ing, senior research technician
• Inge Ghobadi-Moghaddam Helmantel, research technician
• Mei Lam, research technician
• Robert Porrazzo, research technician
• Carla Willink, research assistent
• Bimla Soman, analytical assistent
• Nadia van Doorn, MSc student
• Sanne Buijs, MSc student
• Bram Agema, MSc student

Lee Towers is mascot of the research group

Front Office team:

• Tanja van Dijk, medical student/ coördinator
  
• Lieke Seuren, medical student
  
• Joris Veraart, medical student
  
• Marien van der Stel, medical student
  
• Niels Heersche, medical student
• Stijn de Man, medical student
• Jessica Holster, medical student