Incorporation and Performance Verification of Hepatic Portal Blood Flow Shunting in Minimal and Full PBPK Models of Liver Cirrhosis.

Patho-physiological changes in liver cirrhosis create portacaval shunts that allow blood flow to bypass the hepatic portal vein into the systemic circulation affecting drug pharmacokinetics (PKs). The objectives of this work were to implement a physiologically-based pharmacokinetic (PBPK) framework describing shunted blood flows in virtual patients with differing degrees of liver cirrhosis; and to assess the minimal and full PBPK model's performance using drugs with intermediate to high hepatic extraction. Single dose concentration-time profiles and PK parameters for oral ibrutinib, midazolam, propranolol, and buspirone were simulated in healthy volunteers (HVs) and subjects with cirrhosis (Child-Pugh severity score (CP-A, CP-B, or CP-C)). Model performance was verified by comparing predicted to observed fold-changes in PK parameters between HVs and cirrhotic subjects. The verified model was used to simulate the PK changes for simvastatin in patients with cirrhosis. The predicted area under the curve ratios (AUCCirr :AUCHV ) for ibrutinib were 3.38, 6.87, and 11.46 using the minimal PBPK model with shunt and 1.61, 2.58, and 4.33 without the shunt, these compared with observed values of 4.33, 8.14, and 9.04, respectively. For ibrutinib, propranolol, and buspirone, including a shunt in the PBPK model improved the prediction of the AUCCirr :AUCHV and maximum plasma concentration ratios (CmaxCirr :CmaxHV ). For midazolam, an intermediate extraction drug, the differences were less clear. Simulated simvastatin dose adjustments in cirrhosis suggested that 20 mg in CP-A and 10 mg in CP-B could be used clinically. A mechanistic model-informed understanding of the anatomic and pathophysiology of cirrhosis will facilitate improved dose prediction and adjustment in this vulnerable population.

Physiologically Based Pharmacokinetic Modelling to Predict Imatinib Exposures in Cancer Patients with Renal Dysfunction: A Case Study.

Imatinib is mainly metabolised by CYP3A4 and CYP2C8 and is extensively bound to α-acid glycoprotein (AAG). A physiologically based pharmacokinetic (PBPK) model for imatinib describing the CYP3A4-mediated autoinhibition during multiple dosing in gastrointestinal stromal tumor patients with normal renal function was previously reported. After performing additional verification, the PBPK model was applied to predict the exposure of imatinib after multiple dosing in cancer patients with varying degrees of renal impairment. In agreement with the clinical data, there was a positive correlation between AAG levels and imatinib exposure. A notable finding was that for recovery of the observed data in cancer patients with moderate RI (CrCL 20 to 39 mL/min), reductions of hepatic CYP3A4 and CYP2C8 abundances, which reflect the effects of RI, had to be included in the simulations. This was not the case for mild RI (CrCL 40 to 50 mL/min). The results support the finding of the clinical study, which demonstrated that both AAG levels and the degree of renal impairment are key components that contribute to the interpatient variability associated with imatinib exposure. As indicated in the 2020 FDA draft RI guidance, PBPK modelling could be used to support an expanded inclusion of patients with RI in clinical studies.

Another Step Toward Qualification of Pediatric Physiologically Based Pharmacokinetic Models to Facilitate Inclusivity and Diversity in Pediatric Clinical Studies.

Robust prediction of pharmacokinetics (PKs) in pediatric subjects of diverse ages, ethnicities, and morbidities is critical. Qualification of pediatric physiologically-based pharmacokinetic (P-PBPK) models is an essential step toward enabling precision dosing of these vulnerable groups. Twenty-two manuscripts involving P-PBPK predictions and corresponding observed PK data (e.g., area under the curve and clearance) for 22 small-molecule compounds metabolized by CYP (3A4, 1A2, and 2C9), UGT (1A9 and 2B7), FMO3, renal, non-renal, and complex routes were identified; ratios of mean predicted/observed (P/O) PK parameters were calculated. Seventy-eight of 115 mean predicted PK parameters were within 0.8 to 1.25-fold of observed data, 98 within 0.67 to 1.5-fold, 109 within 2-fold, and only 6 P/O ratios were outside of these bounds. A set of 12 CYP3A4-metabolized compounds and a set of 6 metabolized by other enzymes, CYP1A2 (1 compound), CYP2C9 (2 compounds), UGT1A9 (1 compound) and UGT2B7 (2 compounds) had 56 of 59 and 22 of 25 mean P/O ratios, respectively, that fell within the > 0.5 and < 2.0-fold boundaries. For compounds covering renal, non-renal, complex, and FM03 routes of elimination, 29 of 31 mean P/O ratios fell within the 0.67 to 1.5-fold bounds, including 4 of 5 P/O ratios from newborns. P-PBPK modeling and simulation is a strategic component of the complement of precision dosing methods and has a vital role to play in dose adjustment in vulnerable pediatric populations, such as those with disease or in different ethnic groups. Qualification of such models is an essential step toward acceptance of this methodology by regulators.

Development and application of a pediatric mechanistic kidney model.

Pediatric physiologically-based pharmacokinetic (P-PBPK) models have been used to predict age related changes in the pharmacokinetics (PKs) of renally cleared drugs mainly in relation to changes in glomerular filtration rate. With emerging data on ontogeny of renal transporters, mechanistic models of renal clearance accounting for the role of active and passive secretion should be developed and evaluated. Data on age-related physiological changes and ontogeny of renal transporters were applied into a mechanistic kidney within a P-PBPK model. Plasma concentration-time profile and PK parameters of cimetidine, ciprofloxacin, metformin, tenofovir, and zidovudine were predicted in subjects aged 1 day to 18 years. The predicted and observed plasma concentration-time profiles and PK parameters were compared. The predicted concentration-time profile means and 5th and 95th percent intervals generally captured the observed data and variability in various studies. Overall, based on drugs and age bands, predicted to observed clearance were all within two-fold and in 11 of 16 cases within 1.5-fold. Predicted to observed area under the curve (AUC) and maximum plasma concentration (Cmax ) were within two-fold in 12 of 14 and 12 of 15 cases, respectively. Predictions in neonates and early infants (up to 14 weeks postnatal age) were reasonable with 15-20 predicted PK parameters within two-fold of the observed. ciprofloxacin but not zidovudine PK predictions were sensitive to basal kidney uptake transporter ontogeny. The results indicate that a mechanistic kidney model accounting for physiology and ontogeny of renal processes and transporters can predict the PK of renally excreted drugs in children. Further data especially in neonates are required to verify the model and ontogeny profiles.

Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations.

There has been a significant increase in the use of physiologically based pharmacokinetic (PBPK) models during the past 20 years, especially for pediatrics. The aim of this study was to give a detailed overview of the growth and areas of application of pediatric PBPK (P-PBPK) models. A total of 181 publications and publicly available regulatory reviews were identified and categorized according to year, author affiliation, platform, and primary application of the P-PBPK model (in clinical settings, drug development or to advance pediatric model development in general). Secondary application areas, including dose selection, biologics, and drug interactions, were also assessed. The growth rate for P-PBPK modeling increased 33-fold between 2005 and 2020; this was mainly attributed to growth in clinical and drug development applications. For primary applications, 50% of articles were classified under clinical, 18% under drug development, and 33% under model development. The most common secondary applications were dose selection (75% drug development), pharmacokinetic prediction and covariate identification (47% clinical), and model parameter identification (68% model development), respectively. Although population PK modeling remains the mainstay of approaches supporting pediatric drug development, the data presented here demonstrate the widespread application of P-PBPK models in both drug development and clinical settings. Although applications for pharmacokinetic and drug-drug interaction predictions in pediatrics is advocated, this approach remains underused in areas such as assessment of pediatric formulations, toxicology, and trial design. The increasing number of publications supporting the development and refinement of the pediatric model parameters can only serve to enhance optimal use of P-PBPK models.

A best practice framework for applying physiologically-based pharmacokinetic modeling to pediatric drug development.

Pediatric physiologically-based pharmacokinetic (PBPK) models have broad application in the drug development process and are being used not only to project doses for clinical trials but increasingly to replace clinical studies. However, the approach has yet to become fully integrated in regulatory submissions. Emerging data support an expanded integration of the PBPK model informed approach in regulatory guidance on pediatrics. Best practice standards are presented for further development through interaction among regulators, industry, and model providers.

Integration of Omics Data Sources to Inform Mechanistic Modeling of Immune-Oncology Therapies: A Tutorial for Clinical Pharmacologists.

Application of contemporary molecular biology techniques to clinical samples in oncology resulted in the accumulation of unprecedented experimental data. These "omics" data are mined for discovery of therapeutic target combinations and diagnostic biomarkers. It is less appreciated that omics resources could also revolutionize development of the mechanistic models informing clinical pharmacology quantitative decisions about dose amount, timing, and sequence. We discuss the integration of omics data to inform mechanistic models supporting drug development in immuno-oncology. To illustrate our arguments, we present a minimal clinical model of the Cancer Immunity Cycle (CIC), calibrated for non-small cell lung carcinoma using tumor microenvironment composition inferred from transcriptomics of clinical samples. We review omics data resources, which can be integrated to parameterize mechanistic models of the CIC. We propose that virtual trial simulations with clinical Quantitative Systems Pharmacology platforms informed by omics data will be making increasing impact in the development of cancer immunotherapies.

Prediction of liver volume - a population-based approach to meta-analysis of paediatric, adult and geriatric populations - an update.

Liver volume is a critical scaling factor for predicting drug clearance in physiologically based pharmacokinetic modelling and for both donor/recipient graft size estimation in liver transplantation. The accurate and precise estimation of liver volume is therefore essential. The objective here was to extend an existing meta-analysis using a non-linear mixed effects modelling approach for the estimation of liver volume to other race groups and paediatric and geriatric populations. Interrogation of the PubMed® database was undertaken using a text string query to ensure as objective a retrieval of liver volume data for the modelling exercise as possible. Missing body size parameters were estimated using simulations from the Simcyp Simulator V13R1 for an age and ethnically appropriate population. Non-linear mixed effect modelling was undertaken in Phoenix 1.3 (Certara) utilizing backward deletion and forward inclusion of covariates from fully parameterized models. Existing liver volume models based on body surface area (BSA) and body weight and height were implemented for comparison. The extension of a structural model using a BSA equation and incorporating the Japanese race and age as covariates and exponents on LV0 (θBaseline ) and body surface area (θBSA ), respectively, delivered a comparatively low objective function value. Bootstrapping of the original dataset revealed that the confidence intervals (2.5-97.5%) for the fitted (theta) parameter estimates were bounded by the bootstrapped estimates of the same. In conclusion, extension and re-parameterization of the existing Johnson model adequately describes changes in liver volume using the body surface area in all investigated populations. Copyright © 2017 John Wiley & Sons, Ltd.

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept.

BACKGROUND AND PURPOSE: To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. EXPERIMENTAL APPROACH: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. RESULTS: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). CONCLUSION AND IMPLICATIONS: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.

Efficient discovery of anti-inflammatory small-molecule combinations using evolutionary computing.

The control of biochemical fluxes is distributed, and to perturb complex intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations leads to a combinatorial explosion in the number of experiments that would have to be performed in a complete analysis. We used a multiobjective evolutionary algorithm to optimize reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-1ß expression. The evolutionary algorithm converged on excellent solutions within 11 generations, during which we studied just 550 combinations out of the potential search space of ~9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the evolutionary algorithm were then optimized pairwise. A p38 MAPK inhibitor together with either an inhibitor of IκB kinase or a chelator of poorly liganded iron yielded synergistic inhibition of macrophage IL-1ß expression. Evolutionary searches provide a powerful and general approach to the discovery of new combinations of pharmacological agents with therapeutic indices potentially greater than those of single drugs.

Validation of a voltage-sensitive dye (di-4-ANEPPS)-based method for assessing drug-induced delayed repolarisation in beagle dog left ventricular midmyocardial myocytes.

INTRODUCTION: Evaluation of drug candidates in in-vitro assays of action potential duration (APD) is one component of preclinical safety assessment. Current assays are limited by technically-demanding, time-consuming electrophysiological methods. This study aimed to assess whether a voltage-sensitive dye-based assay could be used instead. METHODS: Optical APs were recorded using di-4-ANEPPS in electrically field stimulated beagle left ventricular midmyocardial myocytes (LVMMs). Pharmacological properties of di-4-ANEPPS on the main cardiac ion channels that shape the ventricular AP were investigated using IonWorks and conventional electrophysiology. Effects of 9 reference drugs (dofetilide, E4031, D-sotalol, ATXII, cisapride, terfenadine, alfuzosin, diltiazem and pinacidil) with known APD-modulating effects were assessed on optically measured APD at 1 Hz. RESULTS: Under optimum conditions, 0.1 microM di-4-ANEPPS could be used to monitor APs paced at 1 Hz during nine, 5 s exposures without altering APD. di-4-ANEPPS had no effect on either hI(ERG), hI(Na), hI(Ks) and hI(to) currents in transfected CHO cells (up to 10 microM) or I(Ca,L) current in LVMMs (at 16 microM). di-4-ANEPPS had no effect on APs recorded with microelectrodes at 1 or 0.5 Hz over a period of 30 min di-4-ANEPPS displayed the sensitivity to record changes in optically measured APD in response to altered pacing frequencies and sequential vehicle additions did not affect the optically measured APD. APD data obtained with 9 reference drugs were as expected except (i) D-sotalol-induced increases in duration were smaller than those caused by other I(Kr) blockers and (ii) increases in APD were not detected using low concentrations of terfenadine. DISCUSSION: Early in drug discovery, the di-4-ANEPPS-based method can reliably be used to assess drug effects on APD as part of a cardiac risk assessment strategy.

Gender differences in the slow delayed (IKs) but not in inward (IK1) rectifier K+ currents of canine Purkinje fibre cardiac action potential: key roles for IKs, beta-adrenoceptor stimulation, pacing rate and gender.

As the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarisation and Purkinje fibres have become an established in vitro preparation to assess the effects of these new drugs on action potential duration (APD), the main aim of this study was therefore to evaluate the relative contribution of the inward (I(K1)) and slow delayed (I(Ks)) rectifier cardiac K(+) currents to action potential repolarisation in beagle Purkinje fibres under three different experimental conditions: (i) selective block of I(K1) with BaCl(2), (ii) selective block of I(Ks) with (-) chromanol 293B under basal conditions and (iii) selective block of I(Ks) during beta-adrenoceptor stimulation. Furthermore, the dependence of this contribution on gender and pacing rate was investigated. Microelectrode techniques were employed to measure APD in Purkinje fibres from adult female and male dogs. At stimulation rates of 3.33, 1.0 and 0.2 Hz, the degree of prolongation of APD evoked by BaCl(2) (10 microM) was comparable in fibres from female and male dogs. At the same stimulation rates, 10 microM (-) chromanol 293B did not change the APD in fibres from female and male dogs. During beta-adrenoceptor stimulation with 0.1 microM isoproterenol, an APD prolonging effect of (-) chromanol 293B was detected. In the presence of isoproterenol, action potentials in fibres from male dogs get shorter when changing the stimulation rate from 1.0 to 0.2 Hz, while the opposite is seen in fibres from female dogs. This alteration was completely reversed by (-) chromanol 293B. In conclusion, our findings confirm that beta-adrenoceptor stimulation is one condition where there may be an increased role of I(Ks) in action potential repolarisation. Gender differences in the autonomic modulation of I(Ks) could be a contributing factor to the reported increased susceptibility of female hearts to arrhythmias.

Evidence for gender differences in electrophysiological properties of canine Purkinje fibres.

Women are more prone to develop torsades de pointes, a rare life-threatening polymorphic ventricular tachycardia, than are men during administration of medicines that have the potential to block I(Kr) (rapid delayed rectifier cardiac K(+) current) and to prolong the QT interval. Blockade of I(Kr), hypokalaemia and extreme bradycardia were used to evaluate whether there are gender differences in cardiac repolarisation in canine Purkinje fibres (PFs). Microelectrode techniques were employed to measure action potential (AP) parameters in PFs from adult female and male dogs. Under control conditions, fibres from female animals in normal or low K(+) conditions exhibited significantly longer AP durations at 50% (APD(50)) and 90% (APD(90)) of repolarisation as compared with APDs of fibres from male animals. Gender-related difference to rate adaptation was also present in APD(90) of fibres from female animals compared to males. At a stimulation rate of 0.2 Hz, but not at 1.0 Hz, dofetilide elicited a significantly higher increase in APD(90), incidence of early afterdepolarisations, triggered and sustained-triggered activities (TAs) in fibres from female animals compared to males in either normal or low K(+) conditions. The sustained TAs were reversed by raising the concentration of [K(+)](0) in Purkinje preparations from both male (one out of one) and female (12 out of 12) dogs. In conclusion, our data provide experimental evidence pointing to gender differences in canine AP repolarisation. PFs from female dogs can be used in safety pharmacology studies as a sensitive model for evaluating the potential proarrhythmic events in vitro of a new medicinal product.