Saião A, Chan B, Isbister GK Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, NSW Emergency Department, Prince of Wales

Transcription

1 Saião A, Chan B, Isbister GK Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, NSW Emergency Department, Prince of Wales Hospital, Sydney, NSW, Australia

2 Paracetamol Poisoning No dramatic changes in treatment for decades Arguments about: Nomogram lines At risk patients Issues of interest: Massive ingestions are these different? Relationship between hepatotoxicity and increase t½ NAC infusion can we improve this? Predictors of outcomes

3 Massive Ingestion > 50g Clinical effects: Early onset of CNS depression, metabolic acidosis and cardiac effects Paracetamol concentrations remain higher much longer Massive dose: Useful setting to explore pharmacokinetics? saturation

4 t1/2 = 3.1 hr t1/2 = 6.7hr WHY???

5 NAC infusion protocol Conventional therapy (intravenous): Dose based on patient weight Complex 3 infusion protocol: Issues: Medication errors Not based on PK mismatch between NAC PK and paracetamol/napqi PK-PD Should NAC dose be based on paracetamol dose? Should NAC infusion match time-course of NAPQI?

6 Pharmacokinetics of NAC Brown M, et al. Eur J Clin Pharmacol 2004 Parameter description NAC parameters Value CV (%) Whole body clearance CL (L h -1 70kg -1 ) Intercompartmental clearance Q2(L h -1 70kg -1 ) Intercompartmental clearance Q3(L h -1 70kg -1 ) Central volume of distribution V1(L 70kg -1 ) Peripheral Vd V2(L 70kg -1 ) Peripheral Vd V3(L 70kg -1 ) [Q3] Dose [Q2] A3 k 13 k 31 A1 k 12 k 21 A2 k 10 CL

7 Conventional NAC infusion Constant production of NAPQI Time (hours)

8 Objective We aimed to investigate the pharmacokinetics of massive paracetamol overdose to explore the association between hepatotoxicity and increased half-life to investigate the outcomes in these patients

9 Methods Setting: Hunter Area Toxicology Service Prince of Wales Hospital Toxicology Unit Observational study Inclusion: Paracetamol overdose > 50g ingested Paracetamol concentrations/alt available

10 Methods Data extraction: Clinical database (HATS) 48 cases Medical record 4 cases Information: Demographics dose and time of ingestion serial paracetamol concentrations alanine transaminase (ALT) N-acetylcysteine administration

11 Data 51 overdoses median age of 32 yr (Range: 15-87y) 27 (53%) were female. median dose was 55g (IQR: 50-70g; Range:48-200g) Hepatotoxicity: 37 normal ALT 13 abnormal ALT 7 had ALT > 1000 NAC given in 48 patients

12 Data Analysis: population analysis Population is the EXPERIMENT UNIT Clinical Setting real-life USING sparse and unstructured data Determine typical PK and PKPD information for patients of the target population Identify and measure variability: Predictable: demographic, environmental or drugrelated factors that may influence PK or PKPD Estimate unexplained variation in the population Randomness or uncertainty eg. assay

13 Modelling Structural model: One and two compartment open models with linear and non-linear elimination kinetics were tried Priors: therapeutic study Error model Covariates: Phenotypic Hepatotoxicity Monolix TM used to model data

14 Time Concentration Data

15 Results Paracetamol concentration-versus-time data was best described with a one compartment model with firstorder input and first order elimination No evidence of non-linear elimination Population mean estimates: elimination rate constant (K), 0.232hr -1 volume of distribution (Vd), 14.9L absorption rate constant (Ka), 0.90hr -1 t 1/2 = 2.4h (IQR 1.6 to 4hr) Hepatotoxicity increased t 1/2

16 Using the population parameters Data theo. prctile Using the individual parameters y observations observations predictions predictions time

17 Hepatotoxicity and half-life 2.2hr 7.6hr 2.2hr 4hr

18 Hepatotoxicity and dose

19 Hepatotoxicity and NAC Abnormal ALT (13) ALT > 1000 I/U (7) NAC < 8 hours: 2.5 to 7.7hr delayed NAC: 11 to 38 hr not treated NAC < 8 hours: 3 and 5 hr delayed NAC: 14 to 38 hr not treated

20 Simulations 50g 75g 100g 200g Median with IQR

21 Simulations AT 8 hours: Concentration > 4 hour level AT 12hr 25% of patients still have concentration > 4 hour level SHIFT in time

22 NAC finished at hr 26 hours Concentration still above nomogram for an 18 hour level!

23 Conventional NAC infusion Constant production of NAPQI Time (hours)

24 Clinical considerations NAPQI likely to be produced for much longer How should we monitor massive overdoses? Serial paracetamol concentrations ALT, AST, INR NAC infusion Should we give more? Should we give longer? When do we stop? Are normal LFTs/INR after the completion of the 21hr protocol sufficient if paracetamol concentration still high

25 Conclusions Increased apparent t 1/2 in patients developing abnormal ALT, not explained by a larger ingested dose or non-linear elimination. Similar to Prescott data t 1/2 = 2.2hr in patients with normal ALT is similar to patients taking paracetamol therapeutically A proportion of patients ingesting > 50 g paracetamol developed abnormal ALT despite early NAC treatment

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