Pharmacokinetics for Physicians. Assoc Prof. Noel E. Cranswick Clinical Pharmacologist Royal Children s Hospital Melbourne

Transcription

1 Pharmacokinetics for Physicians Assoc Prof. Noel E. Cranswick Clinical Pharmacologist Royal Children s Hospital Melbourne

2 The Important Therapeutic Questions What drug? What dose? How long?

3 Drug Dosage Depends on: Pharmacokinetics Pharmacodynamics Therapeutic Window Idiosyncrasy

4

5 Kinetic Models: The LADME System L A D M E liberation (dissolution) absorption distribution (disposition) metabolism excretion

6 Pharmacokinetic Parameters AUC 0 t AUC 0 C max T max K V d Cl MRT t ½ τ

7 Pharmacokinetics: Volume

8

9

10 Pharmacokinetics: Clearance

11 Pharmacokinetics: Clearance Hepatic: Metabolism, does not correlate well with liver function tests. Renal: Passive/Active, correlates to renal function (but not shown with egfr) Bile: Parent compound or metabolites Total clearance = Add all clearances.

12

13 Pharmacokinetics

14

15

16

17

18

19

20

21 Bioavailability

22 Calculation of Bioequivalence Usually Model Independent Calculations Parametric approach: 90% CI (equivalent to the rejection of 2 one sided H o at 5% level) Log transformation of concentration & concentration dependent variables

23 Calculation of Bioequivalence Deviation Allowed for bioequivalence is usually +/- 20% = 80% - 125% for both AUC and Cmax Sufficient washout period between treatments Sequence Effects Sampling covers at least 80% of the AUC Steady-state sampling over full 24 hours

24 Renal Elimination Filtration Passive Processes Active Processes Usually correlates with measures of renal function

25

26 Hepatic Elimination

27 Hepatic Elimination Partially documented for the Cytochromes P450 Group of related isoenzymes Hydroxylation of hundreds of structurally diverse drugs. The reaction involves NADPH co-factor: NADPH + H(+) + O(2) + RH NADP(+) + H(2)O + ROH In addition, cytochrome P450 catalyses N-, O- and S- dealkylation via an initial hydroxylation stage and may catalyse N-oxidation. Enzyme activity varies with age, sex, race and isoform

28 CYP450

29 Hepatic Elimination Implications for altered Biotransformation : Therapeutic Failure: Cyclosporin and graft rejection Increased Pharmacologic Effects: CYP2D6 substrate in the first 1-2 weeks Increased risk of toxicity: Valproate hepatotoxicity : CYP2C9 and 4-en-VPA

30 Cytochromes P450 (CYP450) Isoforms Substrates Inducers Inhibitors 1A2 Paracetamol 3-methyl- Erythromycin Theophylline cholanthrene Fluvoxamine Caffeine 2D6 Codeine Fluoxetine Paroxetine Quinidine 3A3,4 Cyclosporin Tacrolimus (FK506) 3A4 and 2C9 Viagra Cimetidine Erythromycin

31 The pie chart below shows the % of clinically important drugs metabolized by the various CYP isozymes in liver

32

33 Hepatic Elimination

34 Hepatic Elimination

35

36 Isoniazid Distribution of AUC values based on genotype

37 Valproate hepatotoxicity Major Pathways of Metabolism: Glucuronidation beta-oxidation Minor Pathway of Metabolism: omega-oxidation (via CYP2C9): Metabolite: 4-en-VPA microvesicular cholestasis Secondary carnitine deficiency coenzyme A free radical scavengers

38 Valproate Metabolism Na Valproate CYP2C9 Major Metabolites 4-en-valproate

39 Valproate hepatotoxicity Na Valproate CYP2C9 Major Metabolites 4-en-valproate

40 Pharmacogenomics - Long Term Aims Individualised Doses: Simple testing (genotype / phenotype) Drug and dose: Classical & Population PK methods Genotyping & Phenotyping Prediction of adverse events: Who will have reactions before they have them Decreased risk of toxicity: Define therapeutic ranges for individuals

41 Carbamazepine SJS 0.25% incidence of carbamazepine-sjs/ten in Taiwan 3% false-positive rate for HLA-B*1502, 98.3% sensitivity, 97% specificity, 7.7% positive predictive value and 100% negative predictive value. 98.3% of the one case in every 400 people, the number needed to screen is 407 people, with subsequent carbamazepine avoidance, to prevent one case of SJS/TEN. Pharmacogenomics October; 9(10):

42 Carbamazepine SJS Pharmacogenomics October; 9(10):

43 Carbamazepine SJS Pharmacogenomics October; 9(10):

44 XXXXX. Gentamicin and Ototoxicity

45 Pharmacodynamics - How & Where Drugs Act? Receptor Systems Enzyme Systems Nuclear/Cytoplasmic Site Specificity

46

47

48

49 Pharmacodynamics

50

51

52 Pharmacodynamics

53 Pharmacodynamics

54 Pharmacodynamics

55 Pharmacodynamics

56 Satisfactory effect + Acceptable side-effects = Responder Prob(Satisfactory effect) Prob(Unacceptable side-effect) 1.2E E E E+00 Probability 8.0E E E-01 Probability 8.0E E E E E E E Dose Dose

57

58 Serious poisonings/overdoses paracetamol antidepressants antipsychotic drugs alcohol amphetamines opioid drugs benzodiazepines anticholinesterases carbon monoxide iron envenomation.

59 Common and serious toxic syndromes digoxin toxicity lead and arsenic poisoning anticholinergic syndromes serotonergic syndrome neuroleptic malignant syndrome.

60 All areas should be covered. Pay special attention to: Anticonvulsants Psychopharmacology Cancer Drugs Rheumatology Drugs Antibiotics Pain Drugs Drugs that are monitored Drug ADRs: Cardiac Disease Liver Disease Pharmacogenomics Drug Areas

61 Paracetamol

62 Paracetamol - Oral Dosing Bioavailability: 60%-70% Tmax: 1-2 hours Cmax: ~25-35 mg/l (40mg/kg) Anderson, 1998

63 Paracetamol - PR Dosing Bioavailability: 30%-40% T max : 1-4 hours C max : ~15-25 mg/l (40mg/kg) Anderson, 1998

64 Paracetamol & pain - Dose effect Anderson & Holford, 1997

65 Pain and Fever - Paracetamol effects Anderson, 1988

66 Paracetamol - Metabolism Paracetamol is metabolised in the Liver: -via glucuronidation and sulfate conjugation (~90-95%) (excreted in the urine as glucuronide and sulfate conjugates). Children: Adults: sulfate predominates glucuronide predominates -via CYP 2E1 and CYP 1A2 to form N-acetyl-parabenzoquinoneimine - NAPQI (which is hepatotoxic) (~5%) then glutathione to cysteine and mercapturic acid conjugates (CYP 2E1 may also metabolise paracetamol in the kidney)

67 Metabolism Paracetamol CYP 2E1 CYP 1A2 Sulfate Glucuronide NAPQI

68

69

70

71

72