Neil Parrott

A Novel Strategy for Physiologically Based Predictions of Human Pharmacokinetics

BackgroundThe major aim of this study was to develop a strategy for predicting human pharmacokinetics using physiologically based pharmacokinetic (PBPK) modelling. This was compared with allometry (of plasma concentration-time profiles using the Dedrick approach), in order to determine the best approaches and strategies for the prediction of human pharmacokinetics.MethodsPBPK and Dedrick predictions were made for 19 F. Hoffmann-La Roche compounds. A strategy for the prediction of human pharmacokinetics using PBPK modelling was proposed in this study. Predicted values (pharmacokinetic parameters, plasma concentrations) were compared with observed values obtained after intravenous and oral administration in order to assess the accuracy of the prediction methods.ResultsBy following the proposed strategy for PBPK, a prediction would have been made prospectively for approximately 70% of the compounds. The prediction accuracy for these compounds in terms of the percentage of compounds with an average-fold error of <2-fold was 83%, 50%, 75%, 67%, 92% and 100% for apparent oral clearance (CL/F), apparent volume of distribution during terminal phase after oral administration (Vz/F), terminal elimination half-life (t½), peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) and time to reach Cmax (tmax), respectively. For the other 30% compounds, unacceptable prediction accuracy was obtained in animals; therefore, a prospective prediction of human pharmacokinetics would not have been made using PBPK. For these compounds, prediction accuracy was also poor using the Dedrick approach. In the majority of cases, PBPK gave more accurate predictions of pharmacokinetic parameters and plasma concentration-time profiles than the Dedrick approach.ConclusionsBased on the dataset evaluated in this study, PBPK gave reasonable predictions of human pharmacokinetics using preclinical data and is the recommended approach in the majority of cases. In addition, PBPK modelling is a useful tool to gain insights into the properties of a compound. Thus, PBPK can guide experimental efforts to obtain the relevant information necessary to understand the compound’s properties before entry into human, ultimately resulting in a higher level of prediction accuracy.

Physiologically based pharmacokinetic modeling in drug discovery and development: A pharmaceutical industry perspective

The application of physiologically based pharmacokinetic (PBPK) modeling has developed rapidly within the pharmaceutical industry and is becoming an integral part of drug discovery and development. In this study, we provide a cross pharmaceutical industry position on “how PBPK modeling can be applied in industry” focusing on the strategies for application of PBPK at different stages, an associated perspective on the confidence and challenges, as well as guidance on interacting with regulatory agencies and internal best practices.

Prediction of intestinal absorption: comparative assessment of gastroplus™ and idea™

We have assessed two commercial software tools employing physiologically based models for prediction of intestinal absorption in human. IDEA 2.0 and GASTROPLUS 3.1.0 were compared both in their ability to predict fraction absorbed for a set of 28 drugs and in terms of the functionality offered. The emphasis was placed on the practical usefulness to pharmaceutical drug discovery. Predictions were assessed for three levels of input data (i) pure in silico input, (ii) thermodynamic solubility and in silico permeability, (iii) thermodynamic solubility and human colon carcinoma cell line (CACO-2) permeability. We found the pure in silico prediction ability of the tools to be comparable with 70% correct classification rate. With measured input data the IDEA prediction rate improved to 79% while GASTROPLUS stayed at 70%. In terms of functionality GASTROPLUS is a powerful system for the trained user. Open access to model parameters, diagnostic tools and the ability to integrate data make it particularly suitable for the later stages of discovery and development. IDEA is web based and presents a simple interface suitable for widespread use with minimal training. However the limited functionality and inconvenient handling of multiple compound batches currently restrict the usefulness of version 2.0 for drug discovery.

Predicting pharmacokinetics of drugs using physiologically based modeling--application to food effects.

Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in development have distinctly sub-optimal biopharmaceutical properties, making the quantitative prediction of food effect for different formulations from in vitro data very challenging. If such drugs reach clinical development and show undesirable variability when dosed with food, improved formulation can help to reduce the food effect and carefully designed in vivo studies in dogs can be a useful guide to clinical formulation development. Even so, such in vivo studies provide limited throughput for screening, and food effects seen in dog cannot always be directly translated to human. This paper describes how physiologically based absorption modeling can play a role in the prediction of food effect by integrating the data generated during pre-clinical and clinical research and development. Such data include physicochemical and in vitro drug properties, biorelevant solubility and dissolution, and in vivo pre-clinical and clinical pharmacokinetic data. Some background to current physiological absorption models of human and dog is given, and refinements to models of in vivo drug solubility and dissolution are described. These are illustrated with examples using GastroPlus™ to simulate the food effect in dog and human for different formulations of two marketed drugs.

Predicting Pharmacokinetic Food Effects Using Biorelevant Solubility Media and Physiologically Based Modelling

AbstractBackground: Food-induced changes in gastric emptying time, gastric pH and/or intestinal fluid composition may have an impact on the pharmacokinetics of drugs. The aim of this work was to use mathematical models describing physiology in fed and fasted states together with biorelevant solubility and degradation data to simulate food effects for six compounds from recent Roche projects. Methods: The solubility of each compound was measured in different biorelevant media: simulated human gastric fluid for the fasted and fed state, simulated human intestinal fluid for the fasted, fed and high-fat state, and simulated human colonic fluid for the upper and the lower colon. A physiologically based absorption model was developed in GastroPlus™ for each compound using permeability, solubility, metabolism and distribution data. By incorporating the appropriate physiological parameters and solubility data into the model, the oral pharmacokinetics of each drug was simulated under fasted, fed and/or high-fat conditions. Predicted and observed plasma concentration-time profiles and food effects were compared for a range of doses to assess the accuracy of the simulations. Results: The models were able to distinguish between minor and significant food effects. The simulation captured well the magnitude of the food effects and for the six compounds correctly predicted the observed plasma exposure in fasted, fed and high-fat conditions. Conclusion: Biorelevant solubility tests can be used together with physiologically based absorption models to predict clinical food effects caused by solubility and/or dissolution rate limitations.

Applications of physiologically based absorption models in drug discovery and development.

This article describes the use of physiologically based models of intestinal drug absorption to guide the research and development of new drugs. Applications range from lead optimization in the drug discovery phase through clinical candidate selection and extrapolation to human to phase 2 formulation development. Early simulations in preclinical species integrate multiple screening data and add value by transforming these individual properties into a prediction of in vivo absorption. Comparison of simulations to plasma levels measured after oral dosing in animals highlights unexpected behavior, and parameter sensitivity analysis can explore the impact of uncertainties in key properties, point toward factors which are limiting absorption and contribute to assessment of compound developability. Physiological models provide reliable prediction of human absorption and with refinement based on phase 1 data are useful guides to further market formulation development. Improvements in the accuracy of simulations are expected as better in vitro methods generate more in vivo relevant solubility and permeability data, and modeling will play a central role in the development of more predictive methods for transporter-related effects on drug absorption.

Challenges and opportunities with modelling and simulation in drug discovery and drug development

The benefits of modelling and simulation at the pre-clinical stage of drug development can be realized through formal and realistic integration of data on physicochemical properties, pharmacokinetics, pharmacodynamics, formulation and safety. Such data integration and the powerful combination of physiologically based pharmacokinetic (PBPK) with pharmacokinetic–pharmacodynamic relationship (PK/PD) models provides the basis for quantitative outputs allowing comparisons across compounds and resulting in improved decision-making during the selection process. Such PBPK/PD evaluations provide crucial information on the potency and safety of drug candidates in vivo and the bridging of the PK/PD concept established during the pre-clinical phase to clinical studies. Modelling and simulation is required to address a number of key questions at the various stages of the drug-discovery and -development process. Such questions include the following. (1) What is the expected human PK profile for potential clinical candidate(s)? (2) Is this profile and its associated PD adequate for the given indication? (3) What is the optimal dosing schedule with respect to safety and efficacy? (4) Is a food effect expected? (5) How can formulation be improved and what is the potential benefit? (6) What is the expected variability and uncertainty in the predictions?

CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor

The metabotropic glutamate receptor 5 (mGlu5) is a glutamate-activated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinsons disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [3H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED50 equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30- to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.

Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants

Background: Physiologically based pharmacokinetic (PBPK) modelling can assist in the development of drug therapies and regimens suitable for challenging patient populations such as very young children. This study describes a strategy employing PBPK models to investigate the intravenous use of the neuraminidase inhibitor oseltamivir in infants and neonates with influenza.Methods: Models of marmoset monkeys and humans were constructed for oseltamivir and its active metabolite oseltamivir carboxylate (OC). These models incorporated physicochemical properties and in vitro metabolism data into mechanistic representations of pharmacokinetic processes. Modelled processes included absorption, whole-body distribution, renal clearance, metabolic conversion of the pro-drug, permeability-limited hepatic disposition of OC and age dependencies for all of these processes. Models were refined after comparison of simulations in monkeys with plasma and liver concentrations measured in adult and newborn marmosets after intravenous and oral dosing. Then simulations with a human model were compared with clinical data taken from intravenous and oral studies in healthy adults and oral studies in infants and neonates. Finally, exposures after intravenous dosing in neonates were predicted.Results: Good simulations in adult marmosets could be obtained after model optimizations for pro-drug conversion, hepatic disposition of OC and renal clearance. After adjustment for age dependencies, including reductions in liver enzyme expression and renal function, the model simulations matched the trend for increased exposures in newborn marmosets compared with those in adults. For adult humans, simulated and observed data after both intravenous and oral dosing showed good agreement and although the data are currently limited, simulations in 1-year-olds and neonates are in reasonable agreement with published results for oral doses. Simulated intravenous infusion plasma profiles in neonates deliver therapeutic concentrations of OC that closely mimic the oral profiles, with 3-fold higher exposures of oseltamivir than those observed with the same oral dose.Conclusions: This work exemplifies the utility of PBPK models in predicting pharmacokinetics in the very young. Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described.

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non–rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.