Pharmacogenetics and Personalised Medication PDF

Pharmacogeneti cs and personalised medication By Rida Jamil Individual Variation Variability is a serious problem and if not considered, it can result in: Lack of efficacy Unexpected harmful effects Types of variability may be classified as: Pharmacokinetic Pharmacodyna...

Pharmacogeneti cs and personalised medication By Rida Jamil Individual Variation Variability is a serious problem and if not considered, it can result in: Lack of efficacy Unexpected harmful effects Types of variability may be classified as: Pharmacokinetic Pharmacodynamic The main causes of variability are: Age Genetic factors Immunological factors Disease Drug interactions Ethnicity Anthropologists question the value of the concept of ethnicity, defining it as pertaining to race Diversity exists within racial groups, challenging the notion of homogenous characteristics Ethnic categories based on outward appearance lack precision and are insufficient for personalizing medicine Comprehensive genetic testing offers a more accurate approach, moving away from outdated ethnic classifications Individual genetic markers provide insights into personalized medicine, transcending broad ethnic categories Age Age influences drug action primarily due to less efficient drug elimination in newborns and older individuals Drugs commonly have greater and prolonged effects at the extremes of life due to inefficient elimination Other age-related factors, like variations in pharmacodynamic sensitivity, also play a role with certain drugs Changes in body composition occurs with age, such as higher proportion of fat in elderly, altering drug distribution volume Elderly individuals typically consume more drugs, increasing the potential for drug interactions For more comprehensive information on drug therapy in paediatrics and the elderly, refer to chapters on renal and hepatic disease Effect of age on renal excretion of drugs Glomerular filtrate rate (GFR) in newborns, normalised to body SA, is only about 20% Renally eliminated drugs have longer plasma elimination half-lives in neonates compared to adults due to immature renal function Renal function in term babies reaches values like young adults within a week and peaks at approx. twice the adult value by 6 months of age Improvement in renal function is slower in premature infants, impacting drug elimination Premature newborns may require dose reduction or spacing out of doses to avoid drug toxicity, as exemplified by gentamicin with a prolonged half-life GFR declines gradually from around 20 yrs old, decreasing by about 25% at 50 yrs and 50% at 75 yrs Renal clearance of drugs like digoxin correlates closely with creatinine clearance, reflecting GFR Chronic administration of the same drug dose over the years can lead to increased plasma concentration and toxicity in elderly individuals Despite age-related decline in GFR, plasma creatinine concentration may remain within normal adult range due to reduced creatinine synthesis from decreased muscle mass Normal plasma creatinine in elderly individuals doesn’t necessarily indicate normal GFR, potentially leading to drug toxicity if drug doses are not adjusted accordingly Effect of age of drug metabolism Several important enzymes (hepatic microsomal oxidase, glucuronyltransferase, acetyltransferase and plasma esterases) have low activity in neonates, especially if premature These enzymes take 8 weeks or longer to reach adult levels of activity Lack of conjugating activity in newborns can lead to serious conditions like kernicterus and ‘grey-baby’ syndrome due to drug accumulation Kernicterus caused by drug displacement of bilirubin from albumin ‘Grey baby’ syndrome is caused by accumulation of chloramphenicol due to slow hepatic conjugation Slow conjugation in newborns means drugs like morphine are avoided during labour to prevent prolonged respiratory depression in newborns Hepatic microsomal enzyme activity declines slowly with age, increasing half-life of lipid soluble drugs like diazepam Elderly individuals have an increased volume of distribution for lipid-soluble drugs due to higher body fat proportion Increased drug half-life in elderly can lead to insidious effects, often mistaken for age-related memory impairment Variability in drug half-life between individuals increases with age, causing some elderly people to have significantly reduced drug metabolism rates Drug regulatory authorities require studies in elderly individuals for drugs likely to be used in older populations, like requirements for paediatric use Age-related variation in sensitivity to drugs Same plasma concentration of a drug can have different effects in young and old subjects BZDs cause more confusion and less sedation in elderly compared to young subjects Hypotensive drugs more commonly cause postural hypotension in elderly patients than in younger patients Pregnancy Pregnancy causes physiological changes affecting drug disposition in both mother and foetus Maternal plasma albumin concentration is reduced, impacting drug protein binding Increased cardiac output leads to increased renal flow, GFR and renal elimination of drugs Lipophilic molecules cross the placenta barrier rapidly; hydrophobic drug transfer is slow, limiting fetal exposure after a single maternal dose The placenta barrier effectively excludes some drugs, like LMWH’s, allowing chronic administration to the mother without affecting the foetus Drugs transferred to the foetus are eliminated more slowly than from mother due to reduced activity of fetal liver drug-metabolising enzymes The fetal kidney is inefficient for drug elimination as excreted drugs enter the amniotic fluid (fluid surrounding foetus) which is swallowed by the foetus Disease Impacts drug metabolism and excretion, particularly in major organs like the liver and kidneys Impaired renal or hepatic function can lead to toxicity due to increased drug concentration from a standard dose Gastric stasis (e.g. migraine or diabetic neuropathy) slows drug absorption Malabsorptive issues (e.g. ileal or pancreatic disease, heart failure, nephrotic syndrome) can lead to incomplete drug absorption Nephrotic syndrome: Characterised by heavy proteinuria, oedema, and reduced plasma albumin Alters drug absorption and disposition Causes insensitivity to diuretics like furosemide due to drug binding to albumin in tubular fluid Hypothyroidism  Increases sensitivity to drugs like pethidine Hypothermia  common in elderly, reduces clearance of many drugs Drugs affecting receptors: Myasthenia Gravis: Autoimmune disease with antibodies against nicotinic acetylcholine receptors Increases sensitivity to neuromuscular-blocking agents and drugs affecting neuromuscular transmission X-linked Nephrogenic Diabetes Insipidus: Abnormal ADH receptors cause insensitivity to ADH Familial Hypercholesterolemia: Inherited LDL receptor disease and homozygous form resistant to stains; heterozygous form responds well Diseases affecting signal-transduction mechanisms Pseudohypoparathyroidism: Impaired coupling of G protein-coupled receptors with adenylyl cyclase. Familial Precocious Puberty and Hyperthyroidism: Caused by mutations in G protein-coupled receptors that remain active without hormones. Drug interactions Many patients, especially the elderly, are treated continuously with multiple drugs for chronic diseases (e.g., hypertension, heart failure, osteoarthritis). Acute events (e.g., infections, myocardial infarction) often require additional drug treatments, increasing the potential for drug interactions. Drug interactions account for 5%–20% of adverse drug reactions (ADRs), with approximately 30% of fatal ADRs due to drug interactions. Drugs can also interact with dietary constituents (e.g., grapefruit juice down-regulates CYP3A4 in the gut) and herbal remedies (e.g., St John’s wort). Drug interactions occur through two general mechanisms: 1. Pharmacodynamic Interaction: Modifying the pharmacological effect of another drug (B) without altering its concentration in tissue fluid. 2. Pharmacokinetic Interaction: Altering the concentration of another drug (B) at its site of action. Pharmaceutical Interactions: Drugs can interact in vitro, leading to inactivation without pharmacological principles involved (e.g., thiopental and suxamethonium should not be mixed in the same syringe). Heparin, being highly charged, can inactivate basic drugs if injected without clearing the line with saline. Pharmacodynamic Interactions β-Adrenoreceptor Antagonists: Reduce the effectiveness of β-adrenoreceptor agonists (e.g., salbutamol). Diuretics: Lower plasma K+ concentration, increasing the risk of digoxin toxicity and toxicity with class III antidysrhythmic drugs. Sildenafil: Inhibits phosphodiesterase type V, enhancing the effect of organic nitrates and potentially causing severe hypotension. Monoamine Oxidase Inhibitors: Increase noradrenaline in nerve terminals, interacting dangerously with drugs (e.g., ephedrine) and tyramine-rich foods (e.g., fermented cheeses). Warfarin: Competes with vitamin K, and its anticoagulant effect is increased if vitamin K production is inhibited (e.g., by antibiotics). Risk of Bleeding with Warfarin: Increased by drugs that cause bleeding by different mechanisms (e.g., aspirin). Sulphonamides and Trimethoprim: synergistically inhibit folic acid synthesis, valuable in treating Pneumocystis infection. NSAIDs: Inhibit prostaglandin synthesis, increasing blood pressure in hypertensive patients and causing salt/water retention and cardiac decompensation in heart failure patients. May also involve pharmacokinetic interactions, competing with diuretics for renal tubular secretion. Histamine H1-Receptor Antagonists: Cause drowsiness, worsened by alcohol, leading to increased risk of accidents. Pharmacokinetic interaction Pharmacokinetic Processes: The four major processes are absorption, distribution, metabolism, and excretion (ADME). Absorption and Distribution Interactions: These can occur between compounds that share transporters. Further Information: Detailed coverage of pharmacokinetic interactions is provided in Chapter 9 and Chapter 10. Genetic Variation in drug responsiveness Genetic Influence on Drug Response: Drug response can be influenced by rare genetic traits or complex multifactorial traits involving genetic and environmental factors. Complex traits involve multiple gene variants interacting with environmental factors, leading to varied drug responses. Pharmacogenetic Markers: Measurable differences in gene expression or functional deficiencies can indicate pharmacogenetic variations. Variations include somatic or germline mutations and chromosomal abnormalities. Mutations: Heritable DNA changes that may or may not alter the protein's amino acid sequence. Germline Mutations: Passed through reproductive cells, affecting all cells in offspring. Somatic Mutations: Occur in non-reproductive cells during a lifetime, often with no clinical consequence unless affecting key pathways (e.g., cancer). Genomic Testing: Germline mutations: Assessed via blood samples using microarrays or genome/exome sequencing. Somatic mutations: Assessed via tumour samples, guiding drug selection based on mutation presence. Genetic Variation: Not always harmful and may provide environmental advantages (e.g., G6PD deficiency provides malaria resistance but increases haemolysis risk). Polymorphisms: Common genetic variants found in >1% of a population. Can result in functional changes, influencing drug response and disease susceptibility. Single nucleotide polymorphisms (SNPs) are the most common, occurring once every 300 bases in the human genome. SNPs: May occur in coding and non-coding regions of the genome. Influence physiological function if located within or near a gene. Example: SNPs in the F5 gene causing factor V Leiden disorder, increasing thrombosis risk under certain conditions. Balanced Polymorphism: When gene variants confer both advantages and disadvantages, maintaining a stable presence in the population (e.g., G6PD deficiency and malaria resistance). Prevalence and Impact of SNPs: About 10 million SNPs in the human genome. Affect drug response, disease susceptibility, and interaction with environmental factors. Single gene pharmacokinetic disorders Classical Mendelian Model: Applies to single-gene (monogenic) disorders. Mutation in a single gene is the primary or sole cause of the disorder. Typically, rare disorders with high genetic penetrance. inheritance patterns are predictable in a Mendelian fashion Complex Disease Paradigm: Involves multiple genes and environmental factors. Genetic variants have lower penetrance and more complex inheritance patterns. Historical Context: Early 20th century: Archibald Garrod identified "inborn errors of metabolism. Example: Albinism, where lack of an enzyme disrupts melanin synthesis. Contribution to Molecular Pathology: Investigation of rare diseases has advanced understanding of molecular pathology. Example: Familial hypercholesterolaemia and the mechanism of statins. Further Examples: Several single-gene disorders illustrate the classical Mendelian model.  Plasma cholinesterase deficiency Walter Kalow’s Discovery: 1950’s Suxamethonium sensitivity due to genetic variation of drug metabolism Autosomal recessive trait affects rate of metabolism Suxamethonium is a short acting neuromuscular blocking drug in anaesthesia Normally hydrolysed rapidly by plasma cholinesterase Genetic variation: around 1 in 3000 individuals cannot rapidly inactivate suxamethonium and recessive genes results in abnormal plasma cholinesterase with modified substrate and inhibitor specificity Detection: Blood test measures effect of dibucaine, which inhibits abnormal enzyme less effectively and Heterozygotes reduced dibucaine sensitivity, intermediate between normal and homozygotes Impact on homozygotes: Appear healthy unless exposed to suxamethonium or mivacurium and experience prolonged neuromuscular block if exposed Case example: middle-aged man with hypertension and depression experienced prolonged paralysis after ECT using suxamethonium. This found to be homozygous for ineffective plasma cholinesterase Other abnormal responses: Malignant hyperpyrexia: genetically determined adverse reaction involving the ryanodine receptor Family history and testing are important but routine screening is impractical due to rarity Acute intermittent Polyphria Hepatic polyphyria: it is an inherited disorder affecting porphyrin haem biosynthesis pathway. Prototypic pharmacogenetic disorders Patients may be symptomatic even without drug exposure Acute Intermittent Porphyria: Most common and sever form, autosomal dominant inheritance w/ mutations in porphobilinogen deaminase gene (PBGD) and reduced enzyme activity leads to accumulation of haem precursors and porphyrins Environmental factors: Interplay with drugs, hormones and chemicals alongside, sedatives, anticonvulsants and other drugs can trigger severe attacks Clinical Management: Supportive measures can lead to complete recovery and life expectancy declined with the advent of sedative and anticonvulsant drugs Drug induced precipitation: Drugs inducing CYP enzymes (e.g. barbiturates, carbamazepine, Griseofulvin) can trigger acute attacks and barbiturates induce ALA synthase, increasing ALA production and porphyrin accumulation Gender disparity: disease is 5 times more common in women due to hormonal fluctuations precipitating attacks Treatment advances: Givosiran, a small interfering RNA, reduces ALA synthase mRNA, alleviating neurotoxin build-up implicated in polyphyria attacks and expensive but effective treatment option Therapeutic Drugs and Clinically Available Pharmacogenomic Tests Challenges in pharmacogenetic testing adoption: Various barriers hinder widespread implementation in routine clinical practice Reimbursement is contingent on evidence of cost-effectiveness Randomised control trials are increasingly assessing pharmacogenomics-informed prescribing strategies Complex multifactorial traits: Drug response influenced by multiple genes, genetic variants and environmental factors. Probability of drug benefit and harm often a continuum with wide variation across individuals Reliance on a single predictive genetic biomarker may lack precision in guiding treatment Clinical setting considerations: Research predominantly conducted in resource-rich areas with predominantly white populations, applicability to diverse non-White population and primary care settings uncertain and evaluation requires interpretation alongside full medical history and other biomarkers Key steps in evaluating pharmacogenetic markers: Confirmation of analytic and clinical validity Demonstration of clinical utility through improved efficacy or safety Health economic considerations regarding frequency of genetic markers in patient population Pharmacogenetic evaluation tests: Variants of human leukocyte antigens (HLAs) linked to severe harmful drug reactions and gene controlling drug metabolism Genes encoding drug targets for rational drug selection (Companion diagnostics) Example Warfarin testing combing genetic information about metabolism and target  Incorporating Pharmacogenetic Data Into Daily Clinical Workflows Challenges in Pharmacogenetic translation: Scientific discovery marker to tailored treatment plan delivery faces multiple hurdles Large throughput studies and electronic patient databases facilitate detection of genetic associations Uncertain clinical relevance due to multiple influential physiological and environmental factors Lack of consensus on the correct clinical action and treatment pathways Key questions for clinicians: Is this situation appropriate for requesting a genetic test? How should the genetic data be interpreted? Is there a universally agreed recommended course of action? Indications Trastuzumab (Herceptin) for Breast Cancer: It is a monoclonal antibody targeting HER2 receptor in breast cancer patients, treat patients with HER2 receptor mutation Dasatinib and Imatinib for Haematological Malignancies: First-line tyrosine kinase inhibitors for chronic myeloid leukaemia (CML) and some adults with acute lymphocytic leukaemia (ALL) Effective in patients with Philadelphia chromosome, but mutation T315I in BCR/ABL confers resistance to dasatinib Drug treatment for cystic fibrosis includes channel potentiators and correctors and efficacious for patients with specific genetic mutations Small-molecule treatments for inherited conditions: Givosiran for acute intermittent porphyria and Eteplersen for Duchenne/Becker muscular dystrophy with specific mutations Dose adjustment Based on genetic predictors of drug metabolism Thiopurine Drugs (Tioguanine, Mercaptopurine, Azathioprine): Used to treat leukaemia and immunosuppression in inflammatory disorders Detoxified by thiopurine S methyltransferase (TPMT) and xanthine oxidase Reduced starting doses recommended for patients with genotypes associated with reduced metabolism Genetic testing helps guide dosing, but careful monitoring of WBC count is still necessary 5-FU related compounds (Capecitabine and Tegafur): Used to treat solid tumours but have narrow therapeutic window and serious toxicity Approximately 80% detoxified by dihydropyrimidine dehydrogenase (DPYD) 4 main clinically important genetic variants of DPYD account for 20-30% of cases with life- threatening toxicity Identification of variants guides dose adjustments, gradual dose increments, and even choice of alternative chemotherapy Screening patients who are highly susceptible to serious adverse reactions Abacavir: Effective in treating HIV infection but limited by severe rashes Susceptibility to adverse effects linked to HLA variant HLA-B*5701 Testing for this variant is considered standard of care supported by prospective randomised trials Carbamazepine: Can cause severe rashes including Stevens-Johnson syndrome & toxic epidermal necrolysis Associated with HLA allele HLA-B*1502, more common in certain ethnic groups in Thailand, Malaysia and Taiwan Screening for this allele before treatment is potentially valuable in populations with high allele frequency Communicating the Presence or Absence of Risk Lacosamide: Used in treatment of epilepsy Product information indicates no clinically relevant difference in lacosamide exposure between extensive metabolizers and poor metabolizers based on CYP2C19 status Conclusions Twin studies and single gene disorders: Twin studies and well documented single gene disorders demonstrate that susceptibility to adverse effects can be genetically determined Single-gene disorders include autosomal recessive, autosomal dominant, X- linked and maternally inherited mitochondrial disorders Pharmacogenomic testing: Offers the potential for more precise personalized therapeutics for various drugs and disorders Still requires high-quality trial evidence of clinical utility, particularly in cases where drug response is influenced by complex multifactorial traits Research activity and progress: Pharmacogenomic testing is an area of intense research activity and rapid progress Expectations are high, but the key goal remains to consistently demonstrate that these tests improve outcomes and add to present best practice