Group leader: Prof. dr. Alwin Huitema
The focus of the Huitema group is precision dosing of anticancer drugs and drugs used in supportive care in pediatric oncology. This is an essential part of precision medicine and aims at delivering the right dose to each patient. To achieve this aim, pharmacological studies are initiated and/or embedded in (early) clinical trials and translation research. The research group is strongly associated with the Pharmacy at the Princess Máxima Center.
Pharmacology in early clinical trials
In collaboration with the Zwaan group, pharmacological research is integrated in early clinical trials in children. Dose finding of novel anticancer agents in children is complex and requires multidisciplinary input including pharmacokinetic and pharmacodynamic data including translation of adult knowledge to children. Input from clinical pharmacists from the Princess Máxima Center ensures coherence with clinical practice. Many of these studies are conducted in multicenter networks such as ITCC.
Optimal dosing of anticancer drugs in infants
In the PINOCCHIO study, pharmacokinetic data is obtained from several anticancer drugs in children with a special focus on infants. These data will be used to develop evidence-based dosing guidelines of these agents in infants. This study is conducted in collaboration with the Zwaan group. Comprehensive clinical care is instituted by interaction of the clinical pharmacists with the reseach group, translating pharmacological issues in clinical care to research questions and vice versa.
Pharmacogenetics and pharmacogenomics
Another important explanation for the variety in drug response is the genetic variation in children. Pharmacogenetics and pharmacogenomics (PGx) is the study on how genetic variants could predict a person’s response to a drug. Pharmacogenetic testing can be a useful tool to select the most appropriate treatment for an individual patient, tailored to his or her genetic predisposition. Using existing whole exome sequencing (WES) data, a retrospective study design is used to analyse drug-gene interactions. Eventually, this should result in practical evidence-based guidelines for pediatricians to perform pre-emptive genotyping for chemotherapy and supportive care drugs in pediatric oncology.
Drug assays for pediatric oncology
Measuring blood concentrations is essential to describe the kinetics of a drug. Drug assays to measure drug concentrations offer important research results and serve as a basis for drug development in children. Moreover, it helps in converting adult drug applications into pediatrics. And, once a drug is used in children, it may be important to check whether the child has the required amount of the drug in the blood, or whether it needs modification to optimize therapy.
Other pharmacology topics
Pharmacological studies are a part of many ongoing research programs. Examples of ongoing studies are:
- Pharmacology within the hematopoietic stem cell transplantation and CAR-T program
- Development of novel pediatric dosage forms of anticancer agents
- PK/PD of agents used in supportive care
The Huitema Group has a strong collaboration with the University Medical Center Utrecht (UMCU). Several PhD students perform their projects in a joint effort of both pharmacies. Members of the Huitema group join the regular research meetings of the UMCU pharmacy. The bioanalytical facilities of the UMCU are used for TDM and other analyses.
Furthermore, we collaborate with the Department of Pharmacy & Pharmacology of the Netherlands Cancer Institute (NKI) with regard to clinical pharmacology of anticancer agents. The Princess Máxima Center and the NKI are the only centers in the Netherlands that are fully specialized in cancer care and research and offer highly specialized care with a fine line between research and care. The facilities, knowledge and experience of the two institutions are complementary to each other and highly specialized. This gives a great opportunity for synergy.
Concerning pharmacogenetics we have regular meetings with pharmacists from the department of clinical pharmacy and toxicology of the Leiden University Medical Center (LUMC).
- PATIO study: Pharmacokinetic study on Anticancer Treatment in Infant acute lymphoblastic leukemia to support Optimal dosing; ZonMW grant (Good Use of Medicines Programme on more effective, more efficient, and safer use of medicines in day-to-day health care). Main applicant: prof ADR Huitema, Project leader: dr MHM Diekstra. In collaboration with Zwaan Group
- E.C. Bernsen, dr. F.K. Engels, drs. A.M.L. Peek, dr. G. van den Berg, dr. M.H.M. Diekstra. Severe acute kidney injury after high-dose methotrexate in a patient with polymorphisms in ABCB1 and ABCBG2. Ned Tijdschr Oncol 2023;20:25–32.
- E.C. Bernsen, V.J. Hogenes, B. Nuijen, L.M. Hanff, A.D.R. Huitema, M.H.M. Diekstra. Practical recommendations for the manipulation of kinase inhibitor formulations to suitable pediatric dosage forms. Pharmaceutics. 2022 Dec 17;14(12):283414, 2834. PubMed PMID: 36559327
- E.C. Bernsen, L.M. Hanff, L.M. Haveman, B.B.J. Tops, M. van der Lee, J.J. Swen, A.D.R. Huitema, M.H.M. Diekstra. Genetic variants found in paediatric oncology patients with severe chemotherapy-induced toxicity: a case series. J Oncol Pharm Pract. 2022 Dec
4;10781552221137302. PubMed PMID: 36464835
- Emma C Bernsen, Melanie M Hagleitner, Theodorus W Kouwenberg, Lidwien M Hanff. Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology. Front Pharmacol. 2020 Aug 5;11:1184. PubMed PMID: 32848787
- Julie M Janssen, Thomas P C Dorlo, Neeltje Steeghs, Jos H Beijnen, Lidwien M Hanff, Natasha K A van Eijkelenburg, Jasper van der Lugt, C Michel Zwaan, Alwin D R Huitema. Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology. Clin Pharmacol Ther. 2020 Sep;108(3):494-505. Pubmed PMID: 32022898