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Title: Population pharmacokinetic and pharmacodynamic modelling to describe the effects of APAP overdose on novel biomarkers in UK patients
Author: Turkistani, Areej
ISNI:       0000 0004 7656 9711
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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Paracetamol (APAP) overdose is a major medical problem in the UK and the leading cause of drug-induced liver injury (DILI) and acute liver failure. It is involved in 48% of poisoning admissions to hospital resulting in at least 200 deaths per year. Stratification of risk and the use of N-acetyl-cysteine (NAC) antidote therapy is sub-optimal and based on a timed determination of plasma APAP concentration. The current assessment of drug-induced liver injury or dysfunction in clinical practice is through liver function tests (LFT) obtained from a blood sample. These tests include serum concentration of total bilirubin (TBL), activity assessment of liver enzymes (alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT)) and coagulation profile. However, the change in these enzymes' activity is not specific to DILI and changes are confounded with different diseases of the liver such as viral hepatitis, fatty liver disease and liver cancer. Novel mechanistic biomarkers have been demonstrated to provide added value for the early prediction of APAP-induced hepatotoxicity. These biomarkers are more specific to activity within the liver, such as Glutamate Dehydrogenase (GLDH) which reflects mitochondrial dysfunction, Keratin-18 (K18) as a monitor for apoptotic-necrotic dynamics, high mobility group box-1 (HMGB1) that increases as a result of immune inflammatory system activation and lastly, serum microRNA (miR-122), which is a highly liver-specific mRNA. The primary objective of this thesis is to translate these novel biomarkers from mouse animal models into human models, and then to assess their potential use in clinical practice via simulation, examining the sensitivity of these biomarkers and their effectiveness in detecting liver injury. Population Pharmacokinetic and Pharmacodynamic (Pop-PKPD) modelling of the available data can enable greater understanding of APAP-induced liver injury and newly identified biomarkers, and was applied to estimate mean population PK parameters of APAP and PD parameters of each biomarker, taking into account inter and intra subject variability. The final population PK model for APAP following overdose is a one-compartment disposition model with first-order absorption, with an exponential residual error model, and alcoholism as a categorical covariate on CL, with alcoholic patients having a 14% increase in APAP clearance compared to non-alcoholic patients. The sequential combined effect compartment/indirect response model for PKPD models was implemented to describe the time course effect of APAP overdose on current and novel biomarkers. In the BIOPAR study, measured biomarker levels in most patients tended to fall within normal ranges, with time-courses relatively flat in shape, and the PKPD models yielded parameter estimates reflecting these trends in the data. These parameters estimate were used to simulate the individual time course of effect quantified by each biomarker post-dose administration with a richer sampling timecourse than feasible clinically. PKPD parameters and simulated biomarker levels at various timepoints were explored with an ROC analysis to characterise their potential to predict DILI outcome as assessed by ALT, and hence their potential utility in a clinical setting. It showed good potential predictivity for HMGB1 and AK18 biomarkers measured at any timepoint across a 72h timecourse following overdose.
Supervisor: Jorgensen, Andrea ; Pertinez, Henry Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral