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Research activities

The overall aim of CAPKR is to provide an academic centre of excellence for research and training in drug metabolism and pharmacokinetics (DMPK) and to engage in problems of generic interest to the Pharmaceutical Industry.  We develop methodologies that will help accelerate the discovery and development of better and safer drugs and are primarily concerned with mechanism-based prediction of human pharmacokinetics.  There are 4 research themes in CAPKR.

Prediction of Hepatic Drug Clearance

Aims: to explore systems and strategies to improve the utility of in vitro methodologies, in particular to address the issues of systematic human metabolic underprediction, interindividual variability between livers, role of the intestine and transport-mediated uptake and complexities.

Ongoing Work:

• Development of an empirical scaling method based on in vitro/in vivo databases as a means of eliminating the underprediction which currently results from the physiological approach.
• Experimental assessment of variability and the quantitative uncertainties of intrinsic clearance determined using human hepatocytes.
• Development of a PBPK model for intestinal first pass clearance by CYP and UGT.
• Determination of effect of BSA on Glucuronidation clearance and fm_UGT estimates.
• Comparison of microsomes and hepatocytes for the prediction of clearance for compounds cleared by parallel CYP and UGT elimination pathways.
• Characterisation of compounds with high intestinal extraction (P450 mediated) and transporter issues in intestinal microsomes and transporter cell lines.
• Further evaluation of the F_G in vitro approach – assess the impact of fu(gut), permeability and metabolism clearance data generated in house.
• Validation of the “transporter/media loss” and oil-separation methods with a range of model drugs and incubations in the presence of transporter inhibitor (rifampicin) in rat hepatocytes.

Planned Work:

• Experimental assessment of loss of CYP incurred in the preparation of liver samples for in vitro systems and in their use; assessment of the impact of this in determination of intrinsic clearance.
• Experimental assessment of non-CYP and parallel elimination pathways (CYP, SULT & UGT) in substrate clearance prediction.
• Assessment of inter-individual variability in the intestinal P450 clearance and impact on F_G prediction.  Further characterise sulphotransferases (SULTs) in human intestinal liver cytosol.
• Explore the use of reference drugs as calibrators to rationalise empirical scaling and overcome systematic underprediction of hepatic clearance.
• Assess the use of human cryopreserved hepatocytes in uptake studies.

Prediction of Drug-Drug Interactions

Aims: to establish a generic framework that uses microsomal kinetic data, together with other perpetrator PK characteristics, to qualitatively zone and quantitatively predict the likely severity of a DDI involving CYP enzymes and transporters.

Ongoing Work:

• Extend our existing database analysis for time-dependent inhibition (37 CYP3A4 clinical studies) assessing the impact of the active metabolite and reversible inhibition on the AUC ratio prediction.
• Extend our general DDI prediction strategy for reversible interactions (based on 146 clinical studies) by examining further case studies with inhibitors with active uptake issues (e.g. gemfibrozil-mediated drug-drug interactions).
• Further evaluation of the fraction of the drug transported (ft) and its impact on prediction of transporter-mediated DDIs.
• Evaluation of the maximal F_G ratio as a pragmatic indicator of the extent of intestinal interactions and its utility for both reversible and time-dependent inhibition interactions (in particular for BDDCS Class 2 compounds).
• Critical evaluation of in vitro experimental design for time-dependent inhibition studies in various in vitro systems (recombinant, HLM, hepatocytes) using mibefradil as a CYP3A4 exemplar.  (IC₅₀ shift and Progress Curve Analysis).
• Sensitivity analysis – investigate the relative importance of in vitro parameters (k_inact, K_I) and information on substrate (fm_CYP), enzyme (k_deg) and inhibitor on the magnitude of drug-drug interactions.
• Investigate the impact of the time course of inhibitor, hepatic uptake and contribution of active metabolites on the DDI prediction.

Planned Work:

• Characterisation of OATP1B1 inhibitors and substrates in expression cells.
• Explore physiologically-based approaches to the prediction of hepatic uptake transporter (OATP1B1) drug-drug interactions.
• Analysis of the prediction of rifampicin induction DDIs from in vitro data and use as a calibrating inducer.

Whole Body PBPK Modelling

Aims: to develop and evaluate whole body PBPK models as a systems approach to the prediction of pharmacokinetic behaviour.  Particular attention is placed on model development, and use of drug specific physicochemical, in vitro and nonclinical data, together with physiological data, incorporating variability and uncertainty.

Ongoing Work:

• Assess the temporal tissue distribution of the enantiomers of eight β-blockers in 12 rat tissues following iv bolus cassette dose administration, where compounds were administered as racemates (one exception) and are currently being quantified using enantiospecific assays.
• Determine the CL_int for the selected β-blocker enantiomers using hepatocytes.
• Develop WBPBPK models to describe the pharmacokinetic behaviour of the selected β-blocker enantiomers and norfloxacin in rats.  Explore the non-linear pharmacokinetics of the latter.
• Further explore the mechanistic equations that were recently developed to predict tissue-to-plasma water partition coefficients, and their application to volume of distribution predictions and WBPBPK modelling.
• Evaluation of PBPK model for the prediction of the intestinal first-pass metabolism involving both metabolite (CYP, UGT) and efflux transporters (pGP).
• Develop PBPK models that incorporate active transport and metabolism within the liver.
• Develop PBPK models describing CNS disposition that utilise data obtained from both cell-based in vitro studies and in vivo experimentation.

Planned Work:

• Attempt to predict the human pharmacokinetic behaviour of the selected β-blockers, if human plasma concentration data can be located, using the WBPBPK models developed in rats.
• Complete the analysis of lipid (neutral lipid, neutral phospholipid and acidic phospholipid) content of drug tissues and apply the mechanistic equations to the prediction of Kpu values of individual tissues, and Vuss (and Vss) for a series of compounds obtained from both consortium members and elsewhere with comparison to both observed values in dog and those obtained in rat and human.
• Further qualify and improve the mechanistic equations for the prediction of tissue Kpu values by attempting to generate a combined equation for bases as an improvement to the current utilisation of one equation for bases of pKa≥7 and a second bases of pKa<7.
• Perform closed loop whole body PBPK modelling for the β-blockers using NONMEM.

Modelling and Simulation

Aims: to develop methodology and to apply that methodology to the optimal design of pharmacokinetic and pharmacodynamic experiments, with the aim to maximize information from these experiments.

Ongoing Work:

• Development of software (PopDes) for optimal design of multiresponse individual and population pharmacokinetic experiments.  Updating with recent methodological developments specifically on sampling windows.
• Development of methodologies for sample size/power calculations for repeated ordinal and count measurements in population pharmacodynamic experiments.
• Computational and methodological work on Bayesian optimal design for fixed and mixed effects pk and pd models.
• Analysis of population pk/pd data with missingness.
• Development of a physiologically based model for the PK/PD of Strontium.
• Application of the CAPKR developed model reduction lumping algorithm to a published, nonlinear, empirical model for the PK of Strontium, in collaboration with colleagues at Queens University Belfast.
• Structural identifiability analysis and reparameterisation of PK/PD models.
• Development of a physiologically based PK/PD obesity model for placebo data.

Planned Work:

• Optimal design of paediatric population pk experiments using adult data.
• Model reduction for complicated mechanistic pk/pd models.
• Optimal design of categorical population pd experiments.
• Extend the sample size calculation methods for responses involving categorical variables to continuous variables in population pharmacokinetic experiments.
• Application of the methodologies for sample size/power calculation to prospective population PK and PD experiments.
• Release another version of PopDes that is based on the new methodological developments with an up to date manual.