DOCETAXEL PHARMACOGENETICS AND ITS INFLUENCE ON THE PHARMACOKINETICS / PHARMACODYNAMICS OF DOCETAXEL IN ASIAN NASOPHARYNGEAL CANCER PATIENTS Chew Sin Chi B. Health Sciences (Hons), University of Adelaide A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2013 DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. ---------------------Chew Sin Chi (21 November 2013) i ACKNOWLEDGEMENTS First and foremost, I would like to thank my supervisor, Professor Balram Chowbay for his support, guidance and invaluable insights throughout my postgraduate studies. Four-year stint under his guidance has helped me to mature as a student and a researcher. I would also like to express my gratitude to Professor Edmund Lee for his constructive and insightful comments during project discussions. I was very fortunate to be acquainted with another PhD candidate, Joanne Lim Siok Liu, who has shared weal and woe with me throughout the training process. Completing this work would have been more difficult were it not for the support and friendship that she offered. I am also grateful to the colleagues in Clinical Pharmacology Laboratory, National Cancer Centre Singapore who have provided technical support in my work. I am thankful to Dr Tan Eng Huat and Dr Darren Lim Wan Teck from the Department of Medical Oncology for providing the clinical samples for this study, as well as the patients who were involved in this study. For the financial support, I would like to thank National Medical Research Council Singapore for study grants (NMRCB1011 and NMCCG10122) and National University of Singapore for the research scholarship. Last but not least, I would like to express my deepest thanks to my family and people who are close to me for their unwavering support and encouragement. Their presence has provided me the strength to persevere through the difficult times. ii TABLE OF CONTENTS CONTENTS SUMMARY PUBLICATIONS AND ABSTRACTS LIST OF TABLES LIST OF FIGURES LIST OF ABBREVIATIONS 1.INTRODUCTION 1.1.Regulatory nuclear receptors 1.1.1.Pregnane X receptor (PXR) 1.1.1.1.Pharmacogenetics of PXR 1.1.2.Constitutive androstane receptor (CAR) 1.1.2.1.Pharmacogenetics of CAR 1.1.3.Retinoid X receptor alpha (RXRα) 1.1.3.1.Pharmacogenetics of RXRα 1.1.4.Hepatocyte nuclear factor 4-alpha (HNF4α) 1.1.4.1.Pharmacogenetics of HNF4α 1.2.Drug metabolising enzymes 1.2.1.Phase I biotransformation reactions 1.2.1.1.Pharmacogenetics of cytochrome (CYP) P450 enzymes 1.2.1.1.1.Cytochrome P450, family 3, subfamily A, polypeptide (CYP3A4) 1.2.1.1.2.Cytochrome P450, family 3, subfamily A, polypeptide (CYP3A5) 1.2.2.Phase II biotransformation reactions 1.2.2.1.Pharmacogenetics of phase II drug metabolising enzymes 1.2.2.1.1.Uridine diphosphate glucuronyltransferase family, polypeptide A1 (UGT1A1) 1.3.Drug transporters 1.3.1.Influx transporters 1.3.1.1.Solute carrier (SLC) superfamily 1.3.1.2.Role of hepatic organic anion transporter polypeptide member 1B1 (OATP1B1) and 1B3 (OATP1B3) in drug disposition 1.3.1.3.Pharmacogenetics of influx transporters PAGE ix xii xiv xviii xx 12 15 18 20 23 25 28 28 32 32 35 38 39 39 42 42 43 44 45 iii CONTENTS 1.3.1.3.1.Solute carrier organic anion transporter family, member 1B1 (SLCO1B3) 1.3.2.Efflux transporters 1.3.2.1.ATP binding cassette (ABC) superfamily 1.3.2.2.Role of ABC transporter proteins in drug disposition and chemoresistance 1.3.2.2.1.ATP-binding cassette, subfamily B, member (ABCB1) 1.3.2.2.2.ATP-binding cassette, subfamily C, member (ABCC2) 1.3.2.2.3.ATP-binding cassette, subfamily G, member (ABCG2) 1.3.2.3.Pharmacogenetics of drug efflux transporters 1.3.2.3.1.ATP-binding cassette, subfamily B, member (ABCB1) 1.3.2.3.2.ATP-binding cassette, subfamily C, member (ABCC2) 1.3.2.3.3.ATP-binding cassette, subfamily G, member (ABCG2) 1.4.Clinical pharmacology of docetaxel 1.4.1.Introduction 1.4.2.Physicochemical properties of docetaxel 1.4.3.Mechanism of action 1.4.4.Pharmacokinetics 1.4.4.1.Administration and distribution 1.4.4.2.Metabolism 1.4.4.3.Excretion 1.4.4.4.Factors affecting pharmacokinetics 1.4.5.Pharmacodynamics 1.5.Nasopharyngeal cancer and docetaxel treatment 1.5.1.Incidence and trends 1.5.2.Nasopharyngeal cancer chemotherapy and regimens 1.5.3.Taxane-based chemotherapy in metastatic nasopharyngeal cancer 1.6.Knowledge gaps in docetaxel pharmacogenetics 1.6.1.Study hypothesis 1.6.2.Objectives 2.MATERIALS AND METHODS 2.1.Study design 2.2.Study population PAGE 45 47 48 52 52 53 54 56 56 57 59 61 61 61 63 66 66 67 69 71 73 79 79 79 81 83 85 86 88 88 89 iv CONTENTS 2.2.1.Healthy subjects 2.2.2.Nasopharyngeal cancer patients 2.2.2.1.Inclusion criteria 2.2.2.2.Exclusion criteria 2.2.2.3.Screening evaluations 2.2.2.4.Docetaxel administration, dosing schedule and concomitant therapy 2.3.Chemicals, reagents and equipments 2.4.Pharmacogenetics analysis 2.4.1.DNA extraction from whole blood 2.4.2.Gene screening and SNP selection 2.4.3.Amplification of target genes by polymerase chain reactions (PCR) and primer design 2.4.4.Purification 2.4.5.DNA sequencing 2.4.5.1.Cycle sequencing 2.4.5.2.Ethanol precipitation 2.4.6.SNP detection, genotyping and labelling 2.4.7.Pharmacogenetics of regulatory nuclear receptors 2.4.7.1.Pregnane X receptor (PXR) 2.4.7.2.Constitutive androstane receptor (CAR) 2.4.7.3.Retinoid X receptor (RXRα) 2.4.7.4.Hepatocyte nuclear factor 4-alpha (HNF4α) 2.4.8.Pharmacogenetics of metabolism enzymes 2.4.8.1.Cytochrome P450 3A4 (CYP3A4) 2.4.8.2.Cytochrome P450 3A5 (CYP3A5) 2.4.9.Pharmacogenetics of influx transporters 2.4.9.1.Solute carrier organic anion transporter, family member 1B3 (SLCO1B3) 2.4.10.Pharmacogenetics of efflux transporters 2.4.10.1.ATP Binding Cassette, subfamily B, member (ABCB1) 2.4.10.2.ATP Binding Cassette, subfamily C, member (ABCC2) 2.4.10.3.ATP Binding Cassette, subfamily G, member (ABCG2) 2.5.Pharmacokinetics and pharmacodynamics of docetaxel 2.5.1.Pharmacokinetics 2.5.1.1.High performance liquid chromatography (HPLC) assay PAGE 89 89 90 91 92 94 95 96 96 98 101 104 104 104 105 106 107 107 109 111 116 118 118 118 119 119 121 121 122 122 123 123 123 v CONTENTS 2.5.1.1.1.Instrumentation and chromatographic conditions 2.5.1.1.2.Standard stock solutions, calibration and quality control samples 2.5.1.1.3.Sample preparation and analysis 2.5.1.1.4.Estimation of pharmacokinetic parameters 2.5.2.Pharmacodynamics 2.5.2.1.Hematological toxicity 2.5.2.2.Non-hematological toxicity 2.6.Statistical analysis 2.6.1.Pharmacogenetic analysis 2.6.2.In-silico analysis of SNPs 2.6.3.Pharmacokinetic / pharmacodynamicpharmacogenetic correlations 3.RESULTS AND DISCUSSIONS 3.1.Patient demographic and clinical characteristics (N = 50) 3.2.Pharmacokinetics of docetaxel 3.3.Pharmacodynamics of docetaxel 3.4.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations of regulatory nuclear receptors 3.4.1.Pregnane X receptor (PXR) 3.4.1.1.PXR Pharmacogenetics in healthy populations 3.4.1.1.1.In-silico prediction of SNP effects 3.4.1.2.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations 3.4.1.3.Discussion 3.4.2.Constitutive androstane receptor (CAR) 3.4.2.1.CAR pharmacogenetics in healthy populations 3.4.2.1.1.In-silico prediction of SNP effects 3.4.2.1.2.Linkage and tag-SNPs derivation 3.4.2.2.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations 3.4.2.2.1.Single SNP association PAGE 123 124 124 125 127 127 127 128 128 128 129 131 131 133 141 148 148 148 149 151 158 162 162 169 169 176 176 vi CONTENTS 3.4.2.3.Discussion 3.4.3.Retinoid X receptor-alpha (RXRα) 3.4.3.1.RXRα pharmacogenetics in healthy populations 3.4.3.1.1.In-silico prediction of SNP effects 3.4.3.1.2.Linkage and tag-SNPs derivation 3.4.3.2.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations 3.4.3.2.1.Single SNP association 3.4.3.2.2.Haplotype association 3.4.3.2.2.1.Haplotype derivations in patients 3.4.3.2.2.2.Haplotype associations with docetaxel pharmacokinetics 3.4.3.3.Discussion 3.4.4.Hepatocyte nuclear factor alpha (HNF4α) 3.4.4.1.HNF4α pharmacogenetics in healthy populations 3.4.4.1.1.In-silico prediction of SNP effects 3.4.4.1.2.Linkage and tag-SNPs derivation 3.4.4.2.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations 3.4.4.2.1.Single SNP association 3.4.4.2.2.Haplotype association 3.4.4.2.2.1.Haplotype derivations in patients 3.4.4.2.2.2.Haplotype associations with docetaxel pharmacokinetics 3.4.4.3.Discussion 3.5.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations of drug metabolism enzymes 3.5.1.Cytochrome 3A4/5 3.5.1.1.CYP3A4/5 pharmacogenetics in healthy and patient populations 3.5.1.2.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations 3.5.1.3.Discussion 3.6.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations of drug influx transporter PAGE 183 186 186 187 205 209 209 220 220 223 226 229 229 242 247 251 251 266 266 269 271 276 276 276 277 277 282 vii CONTENTS 3.6.1.Solute carrier organic anion transporter family, member 1B3 (SLCO1B3) 3.6.1.1.SLCO1B3 pharmacogenetics in healthy populations 3.6.1.1.1.Linkage and haplotypetagging SNPs (htSNPs) derivation 3.6.1.1.2.In-silico prediction of SNP effects 3.6.1.2.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations 3.6.1.2.1.Single SNP association 3.6.1.2.2.Haplotype association 3.6.1.3.Discussion 3.7.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations of drug efflux transporter 3.7.1.ATP-binding cassette, B1, C2 and G2 (ABCB1, ABCC2 and ABCG2) 3.7.1.1.ABCB1, ABCC2 and ABCG2 pharmacogenetics in healthy and patient populations 3.7.1.2.Pharmacokinetic / pharmacodynamic-pharmacogenetic correlations 3.7.1.3.Discussion 3.8.Pharmacokinetic of the outliers 3.8.1.Detection of pharmacokinetic outliers 3.8.2.Demographic and baseline clinical characteristics of pharmacokinetic outliers 3.8.3.Pharmacodynamics of pharmacokinetic outliers 3.8.4.Investigation of the genetic basis of pharmacokinetic outliers 3.8.5.Discussion 4.CONCLUSIONS AND FUTURE DIRECTIONS BIBLIOGRAPHY APPENDICES PAGE 282 282 296 297 308 308 319 324 328 328 328 333 340 345 345 347 348 349 352 354 361 viii SUMMARY This is a study aimed at elucidating the genetic basis of inherited differences in docetaxel pharmacokinetics and pharmacodynamic in local Chinese nasopharyngeal cancer patients (N = 50). The following genes involved in the biochemical pathways of docetaxel were studied: regulatory nuclear receptors (PXR, CAR, RXRα, HNF4α), drug metabolism enzymes (CYP3A4, CYP3A5) and drug transporters (ABCB1, ABCC2, ABCG2, SLCO1B3). The docetaxel pharmacokinetic profile of the patients was characterised by high degree of interindividual variability, with approximately 4- to 6-fold variations observed in Cmax, AUC0-∞ and CL. Grade 3/4 haematological and non-haematological toxicity events across all cycles occurred in 30% of the patients (N = 15). An exposure-toxicity relationship was observed, in which patients with grade 3/4 toxicities exhibited a trend towards higher Cmax, AUC0-∞ and lower CL in the first cycle compared to those who did not have toxicities. Wide interpatient difference in percentage decrease of nadir haemoglobin, absolute neutrophil count and platelet from baseline in cycle was also observed. 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Nucleic Acids Res 40:D216-221. 397 [...]... 2001) In light of the central role of PXR in drug disposition and its broad ligand / substrate specificity, functional genetic polymorphisms in the gene encoding PXR may have pronounced impact on drug pharmacokinetics Therefore, the exploration of the pharmacogenetics influences of PXR may provide insight on the interindividual variability in the disposition of PXR ligands substrates 1.1.1.1 Pharmacogenetics. .. results in the formation of haplotype blocks that consist of the particular combination of alleles (Gabriel, 2002) The tendency of a genetic variant in causing functional effects depends on its type and location Firstly, variants in the promoter region can affect the transcriptional activity of the gene, resulting in altered level of gene expression Secondly, genetic alterations in the coding region of a... each) and Chinese nasopharyngeal cancer patients (N = 50) In- silico functional predictions of RXRα polymorphisms RXRα SNPs and their relationships with pharmacokinetics and pharmacodynamics of docetaxel in Chinese nasopharyngeal cancer patients (N = 50) RXRα LD block haplotypes and diplotypes in Chinese nasopharyngeal cancer patients (N = 50) Influence of RXRα haplotypes on docetaxel pharmacokinetics. .. DESCRIPTION Demographic and clinical characteristics of Chinese nasopharyngeal cancer patients (N = 50) Summary of docetaxel pharmacokinetics in Chinese nasopharyngeal cancer patients (N = 50) Summary of percentage decrease of nadir blood count from baseline in cycle 1 in Chinese nasopharyngeal cancer patients (N = 50) Summary of the incidence of grade 3 & 4 docetaxel toxicity in Asian nasopharyngeal cancer. .. deletion of 37 amino acids in the ligand-binding domain The lack of ligand binding ability might be responsible for the failure of this transcript in transactivating the target genes (Gardner-Stephen et al., 2004) PXR is ubiquitously expressed in the xenobiotics detoxification organs, such as liver, intestine and kidney While the DNA binding domain is highly conserved at 96% similarity, the ligand binding... DESCRIPTION In- silico functional predictions of HNF4α polymorphisms HNF4α SNPs and their relationships with pharmacokinetics and pharmacodynamics of docetaxel in Chinese nasopharyngeal cancer patients (N = 50) HNF4α LD block haplotypes and diplotypes in Chinese nasopharyngeal cancer patients (N = 50) Influence of HNF4α haplotypes on docetaxel pharmacokinetics Genotype and allelic frequencies of CYP3A4 and. .. metabolism and excretion of a drug molecule and its metabolites Pharmacodynamics, on the other hand, is a study on the biochemical and physiological effects of a drug molecule and its metabolites The perturbations in these parameters are the consequences of polygenic traits Alterations in the expression or function of drug metabolism enzymes, drug transporters or drug targets due to the presence of cis-acting... 2001) These receptors remain in this category despite the subsequent characterisation of specific ligands Typically, nuclear receptors have three main functional domains: an amino terminal domain that contains activation function 1 (AF-1), a highly conserved DNA binding domain (DBD), and a carboxyl terminal ligand binding domain (LBD) that contains dimerisation motif and ligand-dependent transcriptional... due to the altered local efflux of the docetaxel in blood cells in the presence of variants Our data showed that several SNPs and haplotypes in the genes along the biochemical pathway of docetaxel might contribute to the interindividual variability in the pharmacokinetics and pharmacodynamics of docetaxel Apart from pharmacogenetics, environmental factors and clinical characteristics are among the plausible... involved in the metabolism of a broad range of clinical drugs Thus, the administration of PXR ligands can lead to accelerated drug clearance and drug-drug interaction This is of clinical importance in view of the promiscuous nature of PXR in binding ligands, and its extensive regulatory effects on majority of the disposition genes PXR modulates the expressions of a wide range of disposition genes To . DOCETAXEL PHARMACOGENETICS AND ITS INFLUENCE ON THE PHARMACOKINETICS / PHARMACODYNAMICS OF DOCETAXEL IN ASIAN NASOPHARYNGEAL CANCER PATIENTS Chew Sin Chi B. Health Sciences (Hons),. and Chowbay B. 3. American Society of Clinical Oncology (ASCO), USA 2012. Docetaxel pharmacogenetics: The influence of RXRα and HNF4α genetic variations on docetaxel disposition in Asian nasopharyngeal. polymorphisms and their relationships with pharmacokinetics and pharmacodynamics of docetaxel in Chinese nasopharyngeal cancer patients (N = 50). 30 9 Table 3.26 Influence of SLCO1B3 haplotype constructs