Pharmacokinetics for Physicians Assoc Prof. Noel E. Cranswick Clinical Pharmacologist Royal Children s Hospital Melbourne
The Important Therapeutic Questions What drug? What dose? How long?
Drug Dosage Depends on: Pharmacokinetics Pharmacodynamics Therapeutic Window Idiosyncrasy
Kinetic Models: The LADME System L A D M E liberation (dissolution) absorption distribution (disposition) metabolism excretion
Pharmacokinetic Parameters AUC 0 t AUC 0 C max T max K V d Cl MRT t ½ τ
Pharmacokinetics: Volume
Pharmacokinetics: Clearance
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.
Pharmacokinetics
Bioavailability
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
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
Renal Elimination Filtration Passive Processes Active Processes Usually correlates with measures of renal function
Hepatic Elimination
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
CYP450
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
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
The pie chart below shows the % of clinically important drugs metabolized by the various CYP isozymes in liver
Hepatic Elimination
Hepatic Elimination
Isoniazid Distribution of AUC values based on genotype. 5 4 3 2 1-10 10 20 30 40
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
Valproate Metabolism Na Valproate CYP2C9 Major Metabolites 4-en-valproate
Valproate hepatotoxicity Na Valproate CYP2C9 Major Metabolites 4-en-valproate
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
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. 2008 October; 9(10): 1543 1546.
Carbamazepine SJS Pharmacogenomics. 2008 October; 9(10): 1543 1546.
Carbamazepine SJS Pharmacogenomics. 2008 October; 9(10): 1543 1546.
XXXXX. Gentamicin and Ototoxicity
Pharmacodynamics - How & Where Drugs Act? Receptor Systems Enzyme Systems Nuclear/Cytoplasmic Site Specificity
Pharmacodynamics
Pharmacodynamics
Pharmacodynamics
Pharmacodynamics
Pharmacodynamics
Satisfactory effect + Acceptable side-effects = Responder Prob(Satisfactory effect) Prob(Unacceptable side-effect) 1.2E+00 1.2E+00 1.0E+00 1.0E+00 Probability 8.0E-01 6.0E-01 4.0E-01 Probability 8.0E-01 6.0E-01 4.0E-01 2.0E-01 2.0E-01 0.0E+00 0 10 20 30 40 50 60 70 0.0E+00 0 10 20 30 40 50 60 70 Dose Dose
Serious poisonings/overdoses paracetamol antidepressants antipsychotic drugs alcohol amphetamines opioid drugs benzodiazepines anticholinesterases carbon monoxide iron envenomation.
Common and serious toxic syndromes digoxin toxicity lead and arsenic poisoning anticholinergic syndromes serotonergic syndrome neuroleptic malignant syndrome.
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
Paracetamol
Paracetamol - Oral Dosing Bioavailability: 60%-70% Tmax: 1-2 hours Cmax: ~25-35 mg/l (40mg/kg) Anderson, 1998
Paracetamol - PR Dosing Bioavailability: 30%-40% T max : 1-4 hours C max : ~15-25 mg/l (40mg/kg) Anderson, 1998
Paracetamol & pain - Dose effect Anderson & Holford, 1997
Pain and Fever - Paracetamol effects Anderson, 1988
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)
Metabolism Paracetamol CYP 2E1 CYP 1A2 Sulfate Glucuronide NAPQI