M O N T H E R A P E D R O R I N G. Dr Tom Hartley UTAS HLS 2014

Transcription

1 T H E R A P E U T I C D R U G M O N I T O R I N G Dr Tom Hartley UTAS HLS 2014

2 TOPICS 1) Why we do TDM 2) What drugs do we monitor 3) How our data assists Clinical Pharmacists & Doctors 4) Bioavailability 5) Half Life and the kinetics of drug metabolism and elimination 6) Routes of elimination Renal and Hepatic 7) Completing the Picture : Absorption and Elimination as concurrent processes 8) Sample timing for TDM 9) Analytical Methods for TDM 10) Specialist TDM Labs the hunt for and importance of metabolites

3 ACB Price: 13.50

4 TDM LITERATURE Australian Presciber Journal Therapeutic Drug Monitoring Most major Hospitals have a Drug Information Centre and Clinical Pharmacists on the staff. Most GPs have Medical Director which is a Patient Management system and which has embedded in it a wealth of Pharmaceutical data.

5 TDM LITERATURE Australian Presciber

6 TDM LITERATURE Journal Therapeutic Drug Monitoring We also observed excellent correlation between the values obtained by the CLIA (x-axis) and the turbidimetric (y-axis) assay (y = , r = 0.99, n = 54). However, the slope of 1.10 was higher than the slope of 0.96 observed with the regression equation obtained by using values obtained by the FPIA and the turbidimetric assay. The positive bias obtained with the new turbidimetric assay compared with the CLIA assay resulted from lower cross reactivity of carbamazepine 10,11-epoxide, the active metabolite of carbamazepine, with CLIA

7 Most GPs have Medical Director which is a Patient Management system and which has embedded in it a wealth of Pharmaceutical data

8 WHY PROVIDE A TDM Hallworth and Capps : SERVICE? 1. Patient is not responding to therapy could this be due to inadequate plasma concentration? 2. Why is the plasma concentration inadequate? inappropriate dosage? poor compliance? malabsorption? rapid metabolism? 3. Could the patient s symptoms be caused by drug toxicity?

9 WHY PROVIDE A TDM SERVICE? Prof Birkett Clinical Pharmacology - Flinders Uni To individualise drug dosage by maintaining plasma or blood drug concentrations within a target range therapeutic range, therapeutic window. Not all drugs are suitable for TDM. TDM is helpful for those drugs where there is (i) Marked pharmacokinetic variability (ii) Concentration related therapeutic and adverse effects. (iii) A narrow therapeutic index (iv) Defined therapeutic concentration range (v) Desired therapeutic effect is difficult to monitor.

10 A DOCTOR THAT REQUESTS TDM EXPECTS You to recognise drug names You to know what the drugs are used for Some of them know the pharmacokinetics but if they don t then they expect you to know them! Expect you to know if your assay and/or therapeutic range is affected by other factors especially renal and liver function and co-medications Some will want you to perform the assay by a specific method eg same method as at the Hospital where the patient s kidney transplant was done. They are generally not interested in the analytical chemistry behind the assay but you have to know it well to be able to deal with their problem(s) with interpreting a patient s TDM result!

11 LET S ORGANISE OUR KNOWLEDGE ALONG CLINICAL PHARMACY LINES

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13 Drug Name Drug Use Dose (loading dose, maintenance dose) Therapeutic Range Toxic Range Carbamazepine Anticonvulsant, Neuropathic Pain and Bipolar disease Dose varies according to indication. Epilepsy: Adult 100mg bd increasing by mg over 2-4 weeks. Usual range g/day Trigeminal Neuralgia: up to mg daily (in 3-4 divided doses). Max 1.6g daily Neuropathic Pain: mg daily Mania and Bipolar: 400mg daily increasing to 1.6g daily Controlled release preparation available to minimise concentration-dependent adverse effects Epilepsy only: 17-50micromol/L (4-12 mg/l) > 34-50micromol/L (8-12mg/L) Bioavailability 85-90% Volume of Distribution Normal Half Life Half Life in End Stage Renal Disease Elimination Route Average Time to Steady State Serum Sampling Times Sampling Interval Other Comments/Considerations L/kg Variable: 12-17hrs (monotherapy) Unchanged Hepatic 2-4 weeks after initiation; 4-5 days after dose change (due to autoinduction) Trough (immediately before dose) Initially 2-4 weeks after initiation; 3-5 days after dose change or if signs and symptoms of toxicity Pharmacokinetic parameters (eg. Half life) affected by carbamazepine s metabolic enzyme autoinduction properties (usually takes 2 weeks to occur) Carbamazepine has an active metabolite (epoxide) - this may contribute to toxicity despite low or normal carbamazepine levels Drugs which may increase carbamazepine serum concentration: cimetidine, diltiazem, erythromycin, isoniazid, verapamil Drugs which may decrease carbamazepine serum concentration: phenytoin, phenobarbitone, primidone

14 ANALYTICAL METHODS 1. DRUG NAME 2. DRUG USE 3. DOSE loading dose, maintenance dose 4. THERAPEUTIC RANGE 5. TOXIC RANGE DRUG METABOLISM 6. BIOAVAILABILITY ie. What determines the circulating level 8. NORMAL HALF LIFE of a drug? ANALYTICAL METHODS 7. VOLUME OF DISTRIBUTION 9. HALF LIFE IN END STAGE RENAL DISEASE 10. ELIMINATION ROUTE 11. AVERAGE TIME TO STEADY STATE 12. SERUM SAMPLING TIMES 13. SAMPLING INTERVAL 14. OTHER CONSIDERATIONS RHH DRUG INFO CENTRE

15 1. CARBAMAZEPINE an anticonvulsant 2. CHLORPROMAZINE an antipsychotic 3. CYCLOSPORIN an immunosuppressant 4. DIGOXIN antiarrythmic 5. GENTAMICIN antiobiotic 6. HEPARIN anticoagulant 7. LITHIUM antidepressant 8. METHADONE pain reliever and heroin detoxification agent 9. METHOTREXATE cytotoxic 10. PARACETAMOL pain reliever and anti-inflammatory 11. PHENYTOIN (DILANTIN) anticonvulsant

16 11. PRIMIDONE anticonvulsant 12. ASPIRIN (SALICYLATE) pain reliever and antiinflammatory 13. SIROLIMUS an immunosuppressant 14. VALPROIC ACID (VALPROATE) anticonvulsant 15. TACROLIMUS an immunosuppressant 16. THEOPHYLLINE bronchodilator 17. THIOPENTONE anaesthetic agent 18. TOBRAMYCIN antibiotic 19. VANCOMYCIN antibiotic 20. VIGABACTRIN antibiotic 21. WARFARIN anticoagulant

17 Drug Name Drug Use Dose (loading dose, maintenance dose) Therapeutic Range Toxic Range Carbamazepine Anticonvulsant, Neuropathic Pain and Bipolar disease Dose varies according to indication. Epilepsy: Adult 100mg bd increasing by mg over 2-4 weeks. Usual range g/day Trigeminal Neuralgia: up to mg daily (in 3-4 divided doses). Max 1.6g daily Neuropathic Pain: mg daily Mania and Bipolar: 400mg daily increasing to 1.6g daily Controlled release preparation available to minimise concentration-dependent adverse effects Epilepsy only: 17-50micromol/L (4-12 mg/l) > 34-50micromol/L (8-12mg/L) Bioavailability 85-90% Volume of Distribution Normal Half Life Half Life in End Stage Renal Disease L/kg Variable: 12-17hrs (monotherapy) Unchanged Elimination Route Average Time to Steady State Serum Sampling Times Sampling Interval Other Comments/Considerations Hepatic 2-4 weeks after initiation; 4-5 days after dose change (due to autoinduction) Trough (immediately before dose) Initially 2-4 weeks after initiation; 3-5 days after dose change or if signs and symptoms of toxicity Pharmacokinetic parameters (eg. Half life) affected by carbamazepine s metabolic enzyme autoinduction properties (usually takes 2 weeks to occur) Carbamazepine has an active metabolite (epoxide) - this may contribute to toxicity despite low or normal carbamazepine levels Drugs which may increase carbamazepine serum concentration: cimetidine, diltiazem, erythromycin, isoniazid, verapamil Drugs which may decrease carbamazepine serum concentration: phenytoin, phenobarbitone, primidone

18 Carbamazepine : Bioavailability % Depends on : Dose Reaching the Circulation Dose Administered Dissolution properties of capsules and tablets Co-administration of foods and other drugs Integrity and function of the GI Tract esp. motility, gastric and intestinal ph IV Injections may get sequestered at the injection site

19 Carbamazepine : Normal Half Life = Variable 12-17hrs (monotherapy) Conc at time t=t = Conc at time t=now * Exp (-k d t ) k d = Elimination Rate Constant If we know k d and Conc now (ie t=now) we can solve this equation to predict what the drug concentration will be for any value of t in the future. How can we calculate k d? - Rule of thumb equation k d = / t half t half Is the time at which we observe that the concentration of the drug in the blood is exactly half what it was when we first measured it.

20 To get a better idea of drug dynamics we can use Excel to model what is happening in the stomach, blood, tissues or urine

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22 Carbamazepine ELIMINATION ROUTE : HEPATIC 1

23 Carbamazepine ELIMINATION ROUTE : HEPATIC 2

24 ELIMINATION ROUTE : RENAL

25 OXIDATION and HYDROXYLATION via the CYTOCHROME P450 SYSTEM (Cytochromes which absorb at 450nm in the presence of CO) Cytochrome P450 are classified into 4 major families I to IV and 6 major subfamilies indicated by letters and submembers indicated by a number eg IIC10. In humans there are 25 Cytochrome P450s.

26 N + -Glucuronidation, a Common Pathway in Human Metabolism of Drugs With a Tertiary Amine Group Edward M. Hawes Drug Metabolism and Drug Disposition Research Group, College of Pharmacy and Nutrition, University of Saskatchewan A= Aliphatic Glucuronides B = Aromatic Glucuronides

27 Phenytoin is virtually insoluble in water. Phase 1 metabolism involves hydoxylation by the cytochrome P450 isoenzymes (CYPs) followed by Phase 2 metabolism where uridine diphosphate-glucuronosyltransferase (UGT) enzymes produces a glucuronide metabolite that is highly water soluble and readily eliminated from the body. (UDP- GA = uridine 5'-diphosphoglucuronic acid ) Metabolism also terminates the biological activity of the drug. In the case of phenytoin, metabolism also increases the molecular weight of the compound, which allows it to be eliminated more efficiently in the bile.

28 A xenobiotic is a foreign chemical substance found within an organism

29 INTESTINAL METABOLISM Intestinal cells contain Cytochrome P450s Intestinal cells contain transmembrane drug Intestinal cells contain transmembrane drug transporters called P-Glycoprotein (P-gp) which can pump drugs especially chemotherapy agents back into the intestinal lumen!

30 Completing the Picture : Simultaneous Absorption and Elimination So far we have only talked about elimination But what about absorption For oral therapeutic drugs absorption and elimination are both going on at the same time So how does that affect the concentrations we measure in the blood? Does it mean that we have to choose when we measure concentrations in the blood?

31 AVERAGE TIME TO STEADY STATE 99% of TDM Samples are blood samples. Drug metabolism involves two competing processes on either side of the blood compartment. 1. Flow of the drug into the blood compartment 2. Flow of the drug out of the blood compartment

32 MODELS OF DRUG METABOLISM

33 MODELS OF ORAL DRUG METABOLISM

34 MODELS OF ORAL DRUG METABOLISM ALPHA could be 0.25 or 25% BETA could be 0.15 or 15%

35 DEMONSTRATION OF DRUG LEVEL RISING IN THE BLOOD : Alpha = 25%/hour

36 High value of Beta stops the drug accumulating in the blood

37 Lower value of Beta (1/4 of what it was in previous example) means the drug can accumulate in the blood

38 REACHING A PLATEAU Lower value of Beta plus more doses of the drug means that the drug level can approach a plateau.

39 SAMPLE TIMING FOR TDM 1 Now that we know what the pharamacokinetics look like we can suggest ideal TDM sampling times and intervals between samples for routine monitoring For Oral Medications this is usually this is just before the next dose the trough level. For Intravenous Medications this is usually 30 mins after the beginning or end of the infusion choose a time at which the drug has equilibrated across all body compartments

40 SAMPLE TIMING FOR TDM 2 Triggers for adjusting the interval between TDM routine monitoring samples Change in routine dose Appearance of unexpected symptoms Suspected poor patient compliance Additional drugs are being prescribed or withdrawn Deteriorating or Improving liver or renal function Deteriorating or Improving nutritional state Deteriorating or Improving Acid Base Status

41 ANALYTICAL METHODS USED IN TDM COLORIMETRIC / SPECTROPHOTOMETRIC EMIT IMMUNOTURBIDIMETRIC HPLC GC High Performance TLC GC MASS SPECTROMETRY LC MASS SPECTROMETRY

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46 SPECIALIST TDM LABS Specialist Therapeutic Drug Monitoring Labs use highly automated High Pressure Liquid Chromatography Systems often linked to Mass Spectrometers. The HPLC chromatogram enables you to detect metabolites and the presence of other unexpected medications or substances of abuse The Mass Spectrometer enables you to positively identify these unexpected compounds.

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50 DRUGS OF ABUSE TESTING

51 PHARMACOGENETICS Australian Prescriber Vol 32, No 3, June Pharmacogenetics of Warfarin - is testing clinically indicated? Jennifer H Martin, Royal Brisbane Hospital

52 Pharmacogenetics : Warfarin Metabolism Example

53 Consequences for the Patient

54 Where to get Reliable Pharmaceutical Information You will need to create an account on the Pacific(Hong Kong) site

55 TOPICS 1) Why we do TDM 2) What drugs do we monitor 3) How our data assists Clinical Pharmacists & Doctors 4) Bioavailability 5) Half Life and the kinetics of drug metabolism and elimination 6) Routes of elimination Renal and Hepatic 7) Completing the Picture : Absorption and Elimination as concurrent processes 8) Sample timing for TDM 9) Analytical Methods for TDM 10) Specialist TDM Labs the hunt for and importance of metabolites

56 THE END!