Clinical Pharmacokinetics and Therapeutic Drug Monitoring

1. Clinical Pharmacokinetics and Therapeutic Drug Monitoring A.H. Thomson

2. Clinical Pharmacokinetics • Describe the profile of drug concentration in the body • Depends on: drug absorption, drug distribution, drug elimination • Aim: determine dosage regimens of drugs - how much? how often?

3. Drug Absorption Bioavailability • Proportion of the administered dose that reaches the systemic circulation. Absorption Rate • Rate of absorption from e.g. gut to the systemic circulation

4. Factors Influencing Bioavailability • Water/lipid solubility, polarity • Highly polar or water soluble drugs e.g. vancomycin (oral for gut infection, IV for systemic infection) • Highly lipid soluble drugs ciclosporin • First pass metabolism • Metabolism in the liver/gut wall: PGP; CyP3A • Drug interactions may alter bioavailability • Oral route may not be suitable: GTN, lidocaine • Potential drug error: IV dose <<< oral dose

5. Drugs With Low Bioavailability

6. Other Factors Affecting Bioavailability • Other drugs • Enzyme inducers (CYP 3A4) rifampicin, St John’s Wort • P-glycoprotein inducers St John’s Wort • Binding agents cholestyramine • Clinical factors • Hepatic disease: reduced first pass metabolism • Gastrointestinal disease: malabsorption syndromes • Vomiting, diarrhoea • Poor response may indicate poor absorption

7. Drug formulation can affect dosage regimen

8. Theophylline profile, Nuelin Liquid

9. Volume of distribution Relates the plasma concentration to the total amount of drug in the body Depends on • Plasma protein and tissue binding • Molecular weight • Lipid solubility Used to determine • Loading dose amount • Elimination half-life, dosage interval

10. Volumes of distribution Drug % plasma Lipid solubility/ Volume binding tissue binding (Lkg-1) Warfarin 99 low 0.14 Salicylic acid 80-95 low 0.1 Ceftazidime 15 low 0.25 Gentamicin <10 low 0.25 Amoxicillin 18 low 0.30 Theophylline 40 low/medium 0.48 Diazepam 99 high 1.1 Digoxin 25 high 7.0 Amitriptyline 95 high 15 Chloroquine 61 high 115

11. Volume and loading dose Loading dose (mg) = Target Conc (mg/L) x V (L)

12. Loading dose example - phenytoin • 65 year old male, 80 kg V = 0.7 L/kg = 56 L Target 20 mg/L x 56L = 1120 mg BNF 15 mg/kg = 1200 mg • 85 year old female, 40 kg, V= 0.7 L/kg = 28 L Target 20 mg/L x 28 L = 560 mg BNF 15 mg/kg = 600 mg • ...but if measured concentration = 10 mg/L “top up” dose = 300 mg

13. Drug elimination: clearance Volume of fluid (blood, serum, etc.) cleared of drug per unit time Depends on • Route of elimination (kidney, liver) • Clinical factors (age, weight, other disease) • Other drugs (interactions) Used to determine • Maintenance dose rate • Elimination half-life, dosage interval

14. Clearance and maintenance dose Dose rate = Target Cssav x Cl (mg/h) (mg/L) (L/h)

15. Maintenance dose examples - digoxin • 75 year old male, 82 kg, creatinine 72 mmol/L CL = 7.0 L/h Target 1.5 mg/L x 7.0L/hx 24 h = 255 mg (IV) = 425 mg (oral) • 85 year old female, 40 kg, creatinine 180 mmol/L CL = 1.55 L/h Target 1.5 mg/L x 1.55 L/h x 24 h = 56 mg (IV) = 93 mg (oral)

16. Elimination half-life Time for the concentration to fall to half Depends on • Clearance and Volume of distribution (-Ln 0.5 x V/CL) Used to determine • Time to eliminate drug from the body • Time to reach “steady state” • Dosage interval

17. 50% eliminated in 1 x t1/2 75% in 2 x t1/2 87.5% in 3 x t1/2 94 % in 4 x t1/2 97% in 5 x t1/2

18. Oral profile – accumulation to steady state

19. Examples of elimination half-lives digoxin: 40 - 80 hours (renal) gentamicin: 2 - 24 hours (renal) vancomycin: 3 - 72 hours (renal) theophylline: 6 - 12 hours (hepatic) amiodarone: 20 - 60 days (hepatic)

20. “Therapeutic Drug Monitoring” Toxic Target range Subtherapeutic Concentration

21. Which drugs are measured? • Antibiotics: gentamicin,tobramycin vancomycin, anti-TB (?) • Anticonvulsants: carbamazepine, phenytoin • Antiarrhythmics :digoxin • Immunosuppressants: ciclosporin, sirolimus, tacrolimus, mycophenolate • Other:theophylline, lithium, antiretroviral, methotrexate, antidepressants, antipsychotics…

22. Digoxin Case • JL, 79 year old male, weight 62 kg, creatinine conc 260 mol/L • Digoxin 250 micrograms daily • Patient admitted in uncontrolled atrial fibrillation • Digoxin concentration 0.5 nmol/L (Target range 1 - 2.6 nmol/L) Interpretation / action?

23. 79 year old male, weight 62 kg, creatinine 260 mol/L, digoxin 250 micrograms daily • Patient elderly, renal impairment • Ask the patient about side effects? • Digoxin conc: 0.5 nmol/L (1 - 2.6 nmol/L) • Concentration lower than expected • When was the last dose taken? • Compliance?

24. Digoxin sampling time

25. Action points • Admitted in uncontrolled AF • Treat the clinical problem - give a loading dose? - add another drug? • Future management - reduce the daily dose?

26. Digoxin Case • JL, 67 year old male, weight 82 kg, creatinine 75 mol/L, digoxin 250 micrograms daily • Patient admitted with nausea and vomiting • Digoxin concentration 3.6 nmol/L (target range 1 - 2.6 nmol/L) Interpretation / action?

27. JL, 67 years, weight 82 kg, creatinine 75 mol/L, digoxin 250 micrograms daily no renal problems, not elderly, dose seems reasonable • Patient admitted with nausea and vomiting suggests possible digoxin toxicity • Digoxin concentration 3.6 nmol/Lunexpectedly high • sampling time (>6 h post dose?), • compliance, drug interaction, • other explanation for clinical problem?

28. Sampling time after the dose: digoxin steady state profile

29. Digoxin TDM • Dosage regimen: renal function • Interactions: amiodarone, verapamil, spironolactone • Target Conc New dose = -------------------- x Old dose Measured Css • Sample time: >6 hours (distribution) t1/2 40 - 80 h (steady state

30. Gentamicin Case • 62 year old female, weight 65 kg, creatinine 75 mol/L • Gentamicin 140 mg twice daily • Day 1: peak 8.0 mg/L, trough 0.2 mg/Ltarget peak 5-12 mg/L, trough <2 mg/L • Day 2: peak 5.0 mg/L, trough 2.8 mg/L Interpretation / action?

31. Gentamicin case • Reasons for discrepancy • decline in renal function? • wrong dose? • dosage history? • sampling time? • accumulation to steady state?

32. Sampling time?

33. Aminoglycoside antibiotics • Aim for high peak - efficacy • Low trough - reduce toxicity • Dose/sampling time critical • Interpretation easier: • 12 - 24 hourly dosing • steady state, 1h peak, trough atend of dosage interval

34. Gentamicin Dose Requirements • 65 year old male, 80 kg, creatinine 70 mmol/L • Cl 4.6 L/h, V 20 L, T1/2 3 h 8 - 4 - 2 - 1-0.5 3h 6h 9h 12 h => 12 h peak 8 mg/L x 20 L = 160 mg => 160 mg 12 hourly • 85 year old female, 40 kg, creatinine 140 mmol/L • Cl 0.7 L/h, V 10 L, T1/2 12 h 8 - 4 - 2 - 1-0.5 12h 24h 36h48h => 48 h peak 8 mg/L x 10 L = 80 mg=> 80 mg 48 hourly

35. Dose adjustment - gentamicin • Higher peak: increase dose (proportional) • Lower trough: increase dosage interval • Increase peak, decrease trough: higher dose, less frequently

36. Phenytoin Case • 45 year old female, 60 kg, 300 mg daily • Admitted with status epilepticus • Phenytoin conc 16 mol/L (target range 40 - 80 mol/L) • Dose increased to 400 mg daily

37. Phenytoin Case • Controlled after 4 days, discharged home • Readmitted 10 days later with ataxia and increasing seizure frequency • Concentration 175 mol/L Interpretation / action?

38. Phenytoin: nonlinear ‘kinetics, Vmax = 450 mg Dose Css Time to ss (mg) (mol/L) (days) 200 15 3 250 24 4 300 40 7 350 75 17 400 220 106

39. Phenytoin: steady state conc vs daily dose

40. Phenytoin monitoring • Nonlinear kinetics – maintenance dose? • Cleared by metabolism in liver - hepatic disease? • Protein binding - increased free fraction: renal disease, hypoalbuminaemia, pregnancy? • Drug interactions -enzyme inducers, enzyme inhibitors?

41. Practical points - TDM • Starting dose: size of patient, drug route of elimination, renal, hepatic function? • Analysis of conc: clinical targets? • Interpretation: steady state? appropriate time after dose? • Dose adjustment: clinical targets, correct interpretation of concentration? • Other factors: drug interactions, protein binding, changing clinical condition