Current Issues of Therapeutic Drug Monitoring (TDM) in Children in Hong Kong

Transcription

1 Current Issues of Therapeutic Drug Monitoring (TDM) in Children in Hong Kong Dr Albert Chan, MD Consultant Chemical Pathologist, PMH Director, HA Toxicology Reference Lab HATS Conference 5 Mar 2011

2 Dinner Dinner meeting. March 2010 (3 ppt slides in 3 mins) Q: What next logical thing(s) ) to do in pharmacovigilance/ / toxicology in HK? A: Poisoning Prevention Drug Safety and Efficacy Personalized medicine

3 A Bold Interpretation of the HK Successfully bottle - up the problem! Experience Bottle - neck! INFECTION DRUG SAFETY Etc. Development of Tertiary Laboratory Services Research Labs Service Labs DH Labs Etc. Relative Lack of Development in Lab Services: Safety & efficacy monitoring Quality control / assurance New biomarkers Support new drug / CM development

4 To Address the Gaps in the Loop of Drug Safety 1. Quality of medicines in the market (eg( DH programs) 2. Safety in the administration of medicines (eg( HA Medication Safety Committee) 3. Dx / Management of poisonings (eg( HA initiatives on poisoning such as the TRL project) 4. Upstream intervention Quality of prescription / usage of drugs Monitoring of efficacy / safety / adverse reactions especially for f special drugs 5. Personalized medicine Application of molecular genetics etc to identify the best medicines ines for each patients, for optimal therapy and least toxicity. Evolving from poisoning, to safety, to personalized medicine Item 4 & 5 are the weak links. Likewise, the collaboration between en units /team members, and the need to enhance the lab

5 Case 1 Newborn Known family history of congenital heart septal defect Previous sibling with PS + ASD Unremarkable antenatal history with normal echo findings Presented in utero with fetal tachycardia of 200 /min requiring emergency C/S BW 3.14 kg Apgar score: 8 at 1 min, 9 at 5 min ECG: atrial flutter with 2:1 block Rx: iv ATP and digoxin

6 Serial digoxin levels Reference interval for digoxin: nmol/l for atrial fibrillation (adult)

7 Relationship between serum digoxin level and time Conversion factor from ng/ml to nmol/l: x 1.26

8 Relationship between serum digoxin level and time (oral digoxin)

9 Digoxin-like immunoreactive substances (DLIS) Paediatric Research 1984;18:

10 Effect on digoxin level after antidote Total digoxin level Administration of antidote Free digoxin level

11 Monitoring after giving antidote Free digoxin level Free :: unbound, bioactive portion Could be separated from digibind-bound bound digoxin by ultrafiltration Manual procedure Special arrangement with the laboratory

12 Factors affecting digoxin assay Interfered by drugs - spironolactone, canrenone (metabolite of spironolactone) Interfered by cardiac glycosides in herbal medications Danshen,, Lu Shen Wan, Chan Su, Kyushin,, Siberian Ginseng, Uzara root Interfered by digoxin-like immunoreactive substances (DLIS) mild to clinically significant Reported in renal, hepatic failure, newborn infants, pregnant women

13 The Issue A simple test: most labs provide digoxin assay However, results could be compromised by: Inappropriate collection / sampling time Interfering substances eg DLIS, antidote (digibind( digibind), digitalis-containing plants herbal medications Not eradicated by newer assay designs/versions Interpretation / Toxicity could be further affected by: Electrolyte disturbances, acid-base status

14 Case 2

15 Case 2 A consultation concerning spurious serial phenytoin levels F/41 Known case of epilepsy on Rx since age of 3 Oct 7 Nov 16 Nov 19 Nov 30 Dec 12 Phenytoin in µmol/l (RR: 40-79) H 150 H 116 H 118 H

16 Case 2 Oct 7 Nov 16 Nov 19 Nov 30 Dec 12 Phenytoin conc (µmol/l) H 150 H 116 H 118 H Drug history 100 mg bd and nocte 130 mg bd and 100 mg nocte 100 mg bd and nocte 100 mg bd and nocte 100 mg bd and 130 mg nocte

17 Further info No toxic symptoms/signs Lab error therefore suspected Follow up All lab results were analytically verified Further Further exploration of drug history revealed

18 Detailed drug hx traced Aug 25 Oct 10 Oct 16 Nov 18 Dec 9 Phenytoin 100 mg bd + N to 160 mg bd mg N to 130 mg bd + 100mg N to 100 mg bd + N 100 mg bd + to 130 mg nocte Na valproate 400 mg tds 200 mg N Nocte dose (200mg 400mg) Ditto Ditto Ditto

19 Wide inter-individual individual differences between dosages and plasma conc

20 Interpretation of drug levels Wide inter-individual individual differences in pharmacokinetics (pk( pk) The same therapeutic dose can give rise to very different levels in individuals Drug compliance: invalid drug level if patient non-compliant Drug-drug interaction: affect protein binding induction/inhibition of drug metabolizing enzymes (cytochrome P450 family) Assay performance: adequate laboratory quality control system

21 Phenytoin toxicity: acute vs chronic

22 Other issues identified Dose Dose escalation / changes Gentle stepwise approach not followed Blood sampling before steady state reached Frequency of prescription Once daily preferred (for phenytoin) Drug Drug interaction between phenytoin and valproic acid not recognized

23 To Address the Gaps in the Loop of Drug Safety 1. Quality of medicines in the market (eg( DH programs) 2. Safety in the administration of medicines (eg( HA Medication Safety Committee) 3. Dx / Management of poisonings (eg( HA initiatives on poisoning such as the TRL project) 4. Upstream intervention Quality of prescription / usage of drugs Monitoring of efficacy / safety / adverse reactions especially for f special drugs 5. Personalized medicine Application of molecular genetics etc to identify the best medicines ines for each patients, for optimal therapy and least toxicity. Evolving from poisoning, to safety, to personalized medicine Item 4 & 5 are the weak links. Likewise, the collaboration between en units / team members, and the need to enhance the lab

24 Concept of TDM Pharmacokinetics Pharmacodynamics Distribution Dosage Regimen Absorption Plasma Conc Site of Action Effects Metabolism Distribution The TDM concept is simple but it is not that easy to implement, especially in paediatrics

25 New formulation / brand of drugs (eg( patent vs generic) Why TDM? Higher than standard dosage required Therapeutic dose close to toxic dose Wide inter-individual individual variation in metabolism Modified from Eur Arch Psychiatric Clin Neurosci 2008;258:21-27

26 The Need to Acquire / Promote a TDM Culture TDM as Therapeutic Drug Monitoring Traditional meaning/indications TDM as Therapeutic Drug Management TDM Program multi-disciplinary team work Soldin OP & Soldin SJ. Ther Drug Monit 2002;24:1-8

27 For sustainable improvement / impact a TDM culture is required To promote awareness / best practice on therapeutics and quality prescription To improve communication / team work / breach boundary between groups To improve infra-structure / drug monitoring service To establish TDM program / TDM teams at the front line To address special needs / groups eg paediatrics

28 Snapshot Routine TDM Lab Service in HA * Test available

29 Limitations of routine TDM service in HK Samples: serum/plasma, blood volume not paediatric friendly Reference ranges: lack of RR for paediatric groups Relative lag / lack on the coverage of less frequently prescribed drugs Immunoassay-based >>> chromatography-based platforms ie assay kits dependent, implication to logistics and services availability / analytical performance / automation / cost / TAT / staffing

30 Non-plasma based analysis Dried blood spot: to be explored Easier and more convenient to collect Fewer blood volume required, especially for repeated blood taking Saliva: Non-invasive/painless free (non-protein bound/bioactive) drug level Allow repeated monitoring Potential substitute of TDM for voriconazole, phenytoin, carbamazepine,, etc.

31 Important Drugs Not Yet Covered Anti-fungals fungals: voriconazole, itraconazole, flucytosine,, etc Anti-viral (eg( HIV): atazanavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir, efavirenz, nevirapine Anti-bacterials / anti-tb : daptomycin etc Psychiatric meds: clozapine, olanzapine, quetiapine,, etc Anti-epileptic: topiramate,, etc Chemotherapeutic agents: 5-fluorouracil, 5 bulsulfan, mitotane

32 Global Issues of Paediatric TDM TDM starts with the availability of good drugs for clinical use, but this is a global weak link, especially in paediatrics Efficacy / safety not properly tested in paediatrics,, especially in neonates / infant --- therapeutic orphans Lack of incentives to re-study old drugs in market Lack of reference intervals targeted for paediatric age groups Lack of drug safety and effectiveness information specifically for f different age groups by FDA (newborn, infants, children, adolescents) ents) Drug labeling inadequate while no lack of disclaimers Very often extrapolation from adults, even though it is universally accepted that kids are not small adults Problem of many paediatric preparations (eg( oral, IM/IV, rectal etc) Complicate monitoring issue further MacLeod S. Ther Drug Monit 2010;32: Steinbrook R. NEJM 2002;347: Soldin OP & Soldin SJ. Ther Drug Monit 2002;24:1-8

33 MacLeod S. Ther Drug Monit 2010;32:

34 Paediatric TDM MacLeod S. Ther Drug Monit 2010;32:

35 Soldin OP & Soldin SJ. Ther Drug Monit 2002;24:1-8

36 Blood volume: required vs allowed Digoxin Carbamazepine Amikacin Plasma vol 150 µl 150 µl 50 µl Dead vol Total plasma vol Min. bld volume (assume HCT 50%) For 4 kg neonate, estimated TBV 81 µl 231 µl 462 µl 44 µl 194 µl 388 µl 320 ml 20 µl 70 µl 140 µl Ref: Dried blood spot: ~ 70 µl L collected

37 Paediatric TDM in HK / Areas for Improvement Dedicated paediatric TDM services Pooling of services, central lab, For better efficiency and TAT Paediatric friendly lab service Adequate coverage Antiepileptic, antibacterials, antifungals,, anti-hiv drugs Sample volume requirement Small volume, covering multiple drugs Set up dried blood spot (DBS) / saliva-based analysis Better technology platform and logistics (chromatography / mass spec) Development of better and non-invasive biomarkers

38 TDM and Beyond From blood levels to: Biomarkers of efficacy / toxicity, in blood / body fluids / tissues or non-invasive means Routine pharmacogenetic services / personalized medicine

39 Conclusion Promote / develop the TDM culture Formation of multi-disciplinary TDM teams and implementation of TDM program Improvement in the infra-structure of lab service - extended TDM, pharmacogenetics/ / biomarkers Development of a paediatric friendly TDM service. From poisoning, to prevention, safety / efficacy to personalized medicine

40 THANK YOU