Clinical Pharmacology Laboratory

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The Laboratory of Clinical Pharmacology, headed by Prof. Balram Chowbay, focuses on translational research projects aimed at improving clinical outcomes through the optimisation of drug dosages based on pharmacokinetic (PK) and pharmacodynamic (PD) principles. The laboratory also focuses on applying pharmacogenomics tools and knowledge to explain inter-patient variability in drug response and toxicity. This is particularly important in the context of the multi-ethnic Asian population in Singapore because inter-ethnic differences in the polymorphisms of genes that encode drug metabolising enzymes and transporters may lead to marked variabilities in the PK and PD of anti-cancer drugs.

As a dynamic working unit, our laboratory has developed extensive capabilities over the years in the development and validation of bio-analytical assays, therapeutic drug monitoring, as well as PK and PD analyses of various anti-cancer agents. We also have considerable experience in the characterisation of variants in the genes encoding drug metabolising enzymes and transporters and their impact on drug disposition across different ethnic groups.

In addition, our laboratory provides the critical support and expertise necessary to effectively conduct early-phase clinical trials within the Department of Medical Oncology. Our participation ranges from concept proposal, study protocol design, clinical specimen acquisition, processing, analysis and storage to data analysis and results generation.

We are hopeful that such patient-oriented research will further augment existing treatment strategies to improve survival outcomes and clinical responses for cancer patients.

Figure 1: PHARMACOKINETICS & PHARMACODYNAMICS RELATIONSHIPS

Publications during the last 5 years:

1. Ng M, Chen S, Ong WS, Balachander A, Seet A, … Chowbay B. A phase 1b study of OXIRI in pancreatic adenocarcinoma patients and its immunomodulatory effects. Int J Cancer. 2022 Apr 12. (Online ahead of print) 
2. Edison PE, Chen S, Yeo CL, Allen JC Jr, Poon WB, Baral VR, Chowbay B. Pharmacokinetics of oral versus intravenous ibuprofen for closure of patent ductus arteriosus: A pilot randomised controlled study. J Paediatr Child Health. 2022 Mar;58(3)397-403. 
3. Ghoshdastider U, Rohatgi N, …, Chowbay B, Dasgupta R, Skanderup AJ. Pan-Cancer Analysis of Ligand-Receptor Cross-talk in the Tumor Microenvironment. Cancer Res. 2021 Apr 1;81(7):1802-1812. 
   
4. Pan S, Zhang Y, Natalia A, Lim CZJ, Ho NRY, Chowbay B, Loh TP, Tam JKC, Shao H. Extracellular vesicle drug occupancy enables real-time monitoring of targeted cancer therapy. Nat Nanotechnol. 2021 Jun;16(6):734-742. 
5. Mueller-Schoell A, … Chen S, Chowbay B, et al. Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach. Clin Pharmacol Ther. 2020 Jun 23. doi: 10.1002/cpt.1960
6. Chen S, Tan WZ, Sutiman N, et al. An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multi-ethnic Asian IBD patients. Pharmacogenomics J. 2020;20(3):505-515.
7. Leung YY, … Chowbay B, et al. Colchicine lack of effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): a randomized controlled trial. Osteoarthritis Cartilage. 2018;26(5):631-640.
8. Sutiman N, Chen S, Ling KL, et al. Predictive role of NUDT15 variants on thiopurine-induced myelotoxicity in Asian inflammatory bowel disease patients. Pharmacogenomics. 2018;19(1):31-43.
9. Schroth W, … Chowbay B, et al Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen. Front Pharmacol. 2017;8:582.
10. Tan DSW, … Chowbay B, et al. Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma. Nat Med. 2017;23(10):1167-1175.
11. Aung T,… Chowbay B, et al. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet. 2017;49(7):993-1004.
12. Kannan S, … Chowbay B, et al. Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib. Sci Rep. 2017;7(1):1540.
13. Marvalim C, Wong JX, Sutiman N, et al. Influence of the KDM4A rs586339 polymorphism on overall survival in Asian non-small-cell lung cancer patients. Pharmacogenet Genomics. 2017;27(3):120-123.
14. Rajasekaran T,…Chowbay B, et al. Metronomic chemotherapy: A relook at its basis and rationale. Cancer Lett. 2017;388:328-333.
15. Sutiman N, Tan SW, Tan EH, et al. EGFR mutation subtypes influence survival outcomes following first-line gefitinib therapy in advanced Asian NSCLC patients. J Thorac Oncol. 2017;12:529–538.
16. Lal S, Sutiman N, Ooi LL, et al. Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients. Pharmacogenomics J. 2017;17(4):337-343.
17. Chen S, Sutiman N, Chowbay B. Pharmacogenetics of drug transporters in modulating imatinib disposition and treatment outcomes in chronic myeloid leukemia & gastrointestinal stromal tumor patients. Pharmacogenomics. 2016;17(17):1941-1955.
18. Lee KO, … Chowbay B, et al. A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-Aspartate Angiotensin I in Healthy Subjects. Drugs R D. 2016;16(4):317-326.
19. Chen S, Sutiman N, Zhang CZ, et al. Pharmacogenetics of irinotecan, doxorubicin and docetaxel transporters in Asian and Caucasian cancer patients: a comparative review. Drug Metab Rev. 2016;48(4):502-540.
20. Li Z, … Chowbay B, et al. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study. Lancet Oncol. 2016;17(9):1240-7.
21. Sutiman N, Zhang Z, Tan EH, et al. Phase I study of oral vinorelbine in combination with erlotinib in advanced non-small cell lung cancer (NSCLC) using two different schedules. PLoS One. 2016;11(5):e0154316.
22. Sutiman N, Lim JS, Muerdter TE, et al. Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and their influence on tamoxifen disposition in Asian breast cancer patients. Clin Pharmacokinet. 2016;55:1239–1250.
23. Lim JS, Sutiman N, Muerdter TE, et al. Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients. Clin Pharmacol. 2016;81(6):1142-52.
24. Chu YH, … Chowbay B, et al. Association of ABCB1 and FLT3 Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma. PLoS One. 2015;10(8):e0134102.
25. Jain A, … Chowbay B, et al. Impact of Smoking and Brain Metastasis on Outcomes of Advanced EGFR Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. PLoS One. 2015 May 8;10(5):e0123587.
26. Leung YY, … Chowbay B, et al. Colchicine effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): study protocol for a randomized controlled trial. Trials. 2015;16:200.
27. Tan EH, … Chowbay B, et al. Metronomic vinorelbine (oral) in combination with sorafenib in advanced nonsmall cell lung cancer. Lung Cancer. 2015;88:289–296.
28. Aung T, … Chowbay B, et al. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet. 2015;47(4):387-92.
29. Saladores P, …, Chowbay B, et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J. 2015;15:84–94.
30. Chew SC, Lim J, Singh O, Chen X, Tan EH, Lee EJ and Chowbay B. Pharmacogenetic effects of regulatory nuclear receptors (PXR, CAR, RXRa and HNF4a) on docetaxel disposition in Chinese nasopharyngeal cancer patients. Eur J Clin Pharmacol. 2014 Feb;70(2):155-66.