Pharmacokinetics PCTH 325. Dr. Shabbits September 12, C t = C 0 e -kt. Learning Objectives

Transcription

1 PCTH 325 Pharmacokinetics Dr. Shabbits September 12, 2013 Learning Objectives 1. Interpret Concentration vs graphs and use them to calculate half life and predict drug concentration 2. Describe the significance of steady state and how it is estimated 3. Describe the factors that contribute to variability in drug response between patients 4. Describe the key pharmacokinetic differences between neonates, the elderly and adults 5. Describe the main considerations related to pediatric drug dosing [Drug] in blood Concentration time relationships The ADME processes can be graphically represented on a concentration vs time graph used to determine or predict the plasma concentration of free drug A D IV any other route M + E Administer drug Take blood samples at various times Measure [drug] in blood Plot data The concentration-time equation iv Concentration C t = C 0 e -kt C 0 C t C t = drug conc at time t C 0 = drug conc at time 0 k = elimination rate constant the fraction of drug eliminated per unit time 0 0 t 1

2 lnc 0 Linearizing the concentration-time equation Exponential: C t = C 0 e -kt Logarithm: lnc t = -k t + lnc 0 ln Concentration (ln C t ) (t) Y = m X + b Slope = -k Application of k: Half-life Elimination half-life (t ½ ): the amount of time required for drug concentration to decrease by one half t ½ = k Sample Calculation: The first order elimination rate constant for acetaminophen (Tylenol ) is 0.23 hr -1. What is its t ½? t ½ = = = 3 hours k 0.23 hr -1 * Note the units ~ k: time -1 vs t ½ : time Application of k: Drug elimination Application of the conc - time equation # Elimination half-lives % Drug Remaining % Drug Eliminated Application: Estimating drug washout prior to surgery, following a drug overdose etc. ~5 half-lives for drug to be completely eliminated If the initial plasma concentration of Tylenol is found to be 20 μg/ml, what will the plasma concentration be after 8 hours? Use C t = C 0 e -kt or lnc t = -k t + lnc 0 Step 1: lnc 8h = -kt + lnc 0 Step 2: lnc 8h = -(0.23hr -1 )(8hr) + ln(20μg/ml) Step 3: lnc 8h = 1.16 Step 4: C 8h = 3.2 μg/ml 2

3 Drug accumulation steady state Repeated drug administration results in drug accumulation that eventually reaches a steady state plateau. Drug accumulation steady state The time to steady state depends on the drug s t ½ Rule of Thumb: it takes ~5 half-lives to achieve a steady state drug concentration (C SS ) Drug input Drug output Concentration Multiple Doses Steady State Absorption = Elimination (rate in = rate out) Single Dose # Elimination half-lives % C SS Reached Therapeutic range The goal of drug therapy is to ensure that C SS falls within the therapeutic range Summary Administration of agonist or antagonist Toxic Level THERAPEUTIC RANGE po, sl, im iv protein binding, V d Concentration Therapeutic Level phase I and II, induction, inhibition k, t ½ Free drug binds receptor Response solubility, ph, ionization undesirable desirable 3

4 Variability in drug response Why do some drugs work for some people and not others? Why do people experience side effects differently? Should everyone take the same medication dose? Patient compliance Did the patient take the right amount of drug at the right time? was the Rx filled? (97% acute vs 40% long term prevention) forgetfulness / dementia complicated regimen / instructions not understood physical disability (ex: arthritis) lack of insight (schizophrenia, depression) side effects (optimized dosing?) economic factors (generic alternative?) Colour matters A survey of 600 people showed that medication colour affects compliance ~ International Journal of Biotechnology women prefer red men prefer pink pink = sweet yellow = salty white and blue = bitter orange = sour Patient compliance Did the patient take the right amount of drug at the right time? was the Rx filled? (97% acute vs 40% long term prevention) forgetfulness / dementia complicated regimen / instructions not understood physical disability (ex: arthritis) lack of insight (schizophrenia, depression) side effects (optimized dosing?) economic factors (generic alternative?) 4

5 Drug interactions Was the medication affected by other drugs or diet? P450 enzymes grapefruit juice alcohol Tums Genetics and Race : Pharmacogenomics t½ = poor response t½ = toxicity Genetics and Race: Acetaldehyde dehydrogenase involved in ethanol metabolism reduced or absent activity in Asians Age Are there differences between age groups? clinically important differences in both the young and old many relate to the ADME processes # of Subjects Drug conc (g/ml) 5

6 Age the elderly It s all downhill after fold in drug toxicity as one ages from (3% in group vs 21% in group) Definitions of Old young old: old old: years 85 years age-based estimates complicated by: limited clinical trial data physiological age chronological age multiple illnesses & medications interactions altered PK processes % Function Remaining Age (years) Absorption Distribution Oral delivery: gastric ph (geriatric = 4 vs adults = 2) how might this affect drug absorption in the stomach? (*consider both acids and bases) how will this affect drugs that are normally degraded by stomach acid? Notable differences in body composition: adipose tissue lipophilic drugs have a lower plasma concentration for equivalent dose TBW hydrophilic drugs have a higher plasma concentration for equivalent dose serum albumin fraction of free drugs that normally bind plasma proteins 6

7 Metabolism Notable differences in liver mass and function: liver mass liver blood flow Phase I enzyme activity in drug half-life (geriatric vs adult) need to dose or dosing frequency Phase II reactions (conjugation) are largely unchanged with advanced age Excretion Overall decrease in kidney function: 20% reduction in kidney size 30% fewer functioning glomeruli 35% fewer nephrons 40-50% reduction in blood flow in drug half-life (geriatric vs adult) need to dose or dosing frequency Age the young Neonatal pharmacokinetics Perinate: Neonate: Infant: Child: Adolescent: Adult: 20 weeks gestation 27 days birth 27 days 28 days 11 months 1 11 years years > 17 years Pediatrics does not deal with miniature men and women, with the same disease and reduced doses in smaller bodies Dr. Abraham Jacobi Key PK differences between neonates and adults body composition and the ADME processes Little clinical data on drug safety in infants and children Most drugs used off label with dosages based on experience and observation not experimental evidence 7

8 Absorption Oral delivery: gastric ph (pediatric = 4 vs adults = 2) how will this affect drug absorption in the stomach? (*consider both acids and bases) how will this affect drugs that are normally degraded by stomach acid? Distribution Body Composition (as % body weight) Total body water Neonate Adult Protein Vd of hydrophilic drugs in neonate free fraction of protein bound drugs in neonate Fat 10 (term) 1-3 (preterm) 20 How would the [plasma] of a drug with Vd = 200 L change in the neonate? Metabolism Decrease in drug metabolism due to immaturity of some Phase I & II enzymes need to dose or dosing frequency Enzyme System Expression Excretion Elimination of renally excreted drugs decreased in the neonate due to reduced GFR and renal tubular secretion (only ~20% that of adult for 1 st year) t ½ (neonate vs adult) Phase I Cyp 3A7 & 4A1 Cyp 2D6 & 2E1 Cyp 3A4 & 2C family at birth hours after birth first few weeks Ampicillin Gentamicin 4 hr vs 1-2 hr 18 hr vs 2 hr need to dose or frequency Phase II Cyp 1A2 Glucuronyl transferase ~ 3 months several months premature infants << renal function vs full-term 8

9 Pediatric drug dosing Medication errors in neonates can have severe consequences the most pharmacologically vulnerable stage of life Optimal dosing based on: plasma [drug] > body surface area > weight > age but NOT adult dose corrected for weight Summary factors affecting drug response Compliance Drug interactions Disease Ethnicity Age young and old all ADME processes potentially affected Start low and go slow When in doubt check it out 9