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Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data.
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Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Cardiotoxicidade/etiologia , Coração/efeitos dos fármacos , Torsades de Pointes/induzido quimicamente , Tuberculose/tratamento farmacológico , Adulto , Algoritmos , Diarilquinolinas/efeitos adversos , Diarilquinolinas/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Eletrocardiografia/métodos , Feminino , Humanos , Masculino , Moxifloxacina/efeitos adversos , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
Mechanistic modeling of in vitro data generated from metabolic enzyme systems (viz., liver microsomes, hepatocytes, rCYP enzymes, etc.) facilitates in vitro-in vivo extrapolation (IVIV_E) of metabolic clearance which plays a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modeling. A similar concept can be applied to solubility and dissolution experiments whereby mechanistic modeling can be used to estimate intrinsic parameters required for mechanistic oral absorption simulation in vivo. However, this approach has not widely been applied within an integrated workflow. We present a stepwise modeling approach where relevant biopharmaceutics parameters for ketoconazole (KTZ) are determined and/or confirmed from the modeling of in vitro experiments before being directly used within a PBPK model. Modeling was applied to various in vitro experiments, namely: (a) aqueous solubility profiles to determine intrinsic solubility, salt limiting solubility factors and to verify pKa; (b) biorelevant solubility measurements to estimate bile-micelle partition coefficients; (c) fasted state simulated gastric fluid (FaSSGF) dissolution for formulation disintegration profiling; and (d) transfer experiments to estimate supersaturation and precipitation parameters. These parameters were then used within a PBPK model to predict the dissolved and total (i.e., including the precipitated fraction) concentrations of KTZ in the duodenum of a virtual population and compared against observed clinical data. The developed model well characterized the intraluminal dissolution, supersaturation, and precipitation behavior of KTZ. The mean simulated AUC0-t of the total and dissolved concentrations of KTZ were comparable to (within 2-fold of) the corresponding observed profile. Moreover, the developed PBPK model of KTZ successfully described the impact of supersaturation and precipitation on the systemic plasma concentration profiles of KTZ for 200, 300, and 400 mg doses. These results demonstrate that IVIV_E applied to biopharmaceutical experiments can be used to understand and build confidence in the quality of the input parameters and mechanistic models used for mechanistic oral absorption simulations in vivo, thereby improving the prediction performance of PBPK models. Moreover, this approach can inform the selection and design of in vitro experiments, potentially eliminating redundant experiments and thus helping to reduce the cost and time of drug product development.
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Liberação Controlada de Fármacos , Absorção Intestinal/fisiologia , Cetoconazol/farmacocinética , Modelos Biológicos , Absorção Fisiológica , Administração Oral , Biofarmácia/métodos , Química Farmacêutica , Simulação por Computador , Humanos , Modelos Químicos , Permeabilidade , SolubilidadeRESUMO
The aim of this study was to evaluate gastrointestinal (GI) dissolution, supersaturation, and precipitation of posaconazole, formulated as an acidified (pH 1.6) and neutral (pH 7.1) suspension. A physiologically based pharmacokinetic (PBPK) modeling and simulation tool was applied to simulate GI and systemic concentration-time profiles of posaconazole, which were directly compared with intraluminal and systemic data measured in humans. The Advanced Dissolution Absorption and Metabolism (ADAM) model of the Simcyp Simulator correctly simulated incomplete gastric dissolution and saturated duodenal concentrations of posaconazole in the duodenal fluids following administration of the neutral suspension. In contrast, gastric dissolution was approximately 2-fold higher after administration of the acidified suspension, which resulted in supersaturated concentrations of posaconazole upon transfer to the upper small intestine. The precipitation kinetics of posaconazole were described by two precipitation rate constants, extracted by semimechanistic modeling of a two-stage medium change in vitro dissolution test. The 2-fold difference in exposure in the duodenal compartment for the two formulations corresponded with a 2-fold difference in systemic exposure. This study demonstrated for the first time predictive in silico simulations of GI dissolution, supersaturation, and precipitation for a weakly basic compound in part informed by modeling of in vitro dissolution experiments and validated via clinical measurements in both GI fluids and plasma. Sensitivity analysis with the PBPK model indicated that the critical supersaturation ratio (CSR) and second precipitation rate constant (sPRC) are important parameters of the model. Due to the limitations of the two-stage medium change experiment the CSR was extracted directly from the clinical data. However, in vitro experiments with the BioGIT transfer system performed after completion of the in silico modeling provided an almost identical CSR to the clinical study value; this had no significant impact on the PBPK model predictions.
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Simulação por Computador , Liberação Controlada de Fármacos , Trato Gastrointestinal/fisiologia , Modelos Biológicos , Triazóis/farmacocinética , Administração Oral , Biofarmácia/métodos , Química Farmacêutica , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal/fisiologia , Modelos Químicos , SolubilidadeRESUMO
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.
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Potenciais de Ação/efeitos dos fármacos , Arritmias Cardíacas/induzido quimicamente , Simulação por Computador , Drogas em Investigação/efeitos adversos , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , HumanosRESUMO
Residual renal function confers a survival benefit among dialysis patients thought to be related to greater volume removal and solute clearance. Whether the presence of residual renal function is protective or merely a marker for better health is not clear. The basic mechanisms governing the decline or persistence of residual renal function are poorly understood and few studies have examined the role of medical therapy in its preservation. Dialysis modality, inflammatory processes often associated with comorbid diseases (including diabetes mellitus and obesity), volume dysregulation, and vitamin D deficiency are predictive of residual renal function decline. We review potential mechanisms for preservation of remaining glomerular filtration rate among chronic dialysis patients.
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Falência Renal Crônica/terapia , Rim/fisiologia , Diálise Renal/métodos , Taxa de Filtração Glomerular , HumanosRESUMO
Sparsentan is a dual endothelin/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. In vitro data indicate that sparsentan is likely to inhibit or induce various CYP enzymes at therapeutic concentrations. Sparsentan as a victim and perpetrator of CYP3A4 mediated drug-drug interactions (DDIs) has been assessed clinically. A mechanistic, bottom-up, physiologically-based pharmacokinetic (PK) model for sparsentan was developed based on in vitro data of drug solubility, formulation dissolution and particle size, drug permeability, inhibition and induction of metabolic enzymes, and P-glycoprotein (P-gp) driven efflux. The model was verified using clinical PK data from healthy adult volunteers administered single and multiple doses in the fasted and fed states for a wide range of sparsentan doses. The model was also verified by simulation of clinically observed DDIs. The verified model was then used to test various DDI simulations of sparsentan as a perpetrator and victim of CYP3A4 using an expanded set of inducers and inhibitors with varying potency. Additional perpetrator and victim DDI simulations were performed using probes for CYP2C9 and CYP2C19. Simulations were conducted to predict the effect of complete inhibition of P-gp inhibition on sparsentan absorption and clearance. The predictive simulations indicated that exposure of sparsentan could increase greater than two-fold if co-administered with a strong CYP3A4 inhibitor, such as itraconazole. Other potential DDI interactions as victim or perpetrator were all within two-fold of control. The effect of complete P-gp inhibition on sparsentan PK was negligible.
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Citocromo P-450 CYP3A , Modelos Biológicos , Compostos de Espiro , Sulfonamidas , Adulto , Humanos , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações MedicamentosasRESUMO
BACKGROUND: There are two main reasons for drug withdrawals at the various levels of the development path - hepatic and cardiac toxicity. The latter one is mainly connected with the proarrhythmic potency and according to the present practice is supposed to be recognized at the pre-clinical (in vitro and animal in vivo) or clinical level (human in vivo studies). There are, although, some limitations to all the above mentioned methods which have led to novel in vitro - in vivo extrapolation methods being introduced. With the use of in silico implemented mathematical and statistical modelling it is possible to translate the in vitro findings into the human in vivo situation at the population level. Human physiology is influenced by many parameters and one of them which needs to be properly accounted for is a heart rate which follows the circadian rhythm. We described such phenomenon statistically which enabled the improved assessment of the drug proarrhythmic potency. METHODS: A publicly available data set describing the circadian changes of the heart rate of 18 healthy subjects, 5 males (average age 36, range 26-45) and 13 females (average age 34, range 20-50) was used for the heart rate model development. External validation was done with the use of a clinical research database containing heart rate measurements derived from 67 healthy subjects, 34 males and 33 females (average age 33, range 17-72). The developed heart rate model was then incorporated into the ToxComp platform to simulate the impact of circadian variation in the heart rate on QTc interval. The usability of the combined models was assessed with moxifloxacin (MOXI) as a model drug. RESULTS: The developed heart rate model fitted well, both to the training data set (RMSE = 128 ms and MAPE = 12.3%) and the validation data set (RMSE = 165 ms and MAPE = 17.1%). Simulations performed at the population level proved that the combination of the IVIVE platform and the population variability description allows for the precise prediction of the circadian variation of drugs proarrhythmic effect. CONCLUSIONS: It can be concluded that a flexible and practically useful model describing the heart rate circadian variation has been developed and its performance was verified.
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Envelhecimento/fisiologia , Arritmias Cardíacas/fisiopatologia , Compostos Aza/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Modelos Biológicos , Quinolinas/farmacologia , Caracteres Sexuais , Adulto , Idoso , Envelhecimento/efeitos dos fármacos , Animais , Feminino , Fluoroquinolonas , Humanos , Concentração Inibidora 50 , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Adulto JovemRESUMO
The bioequivalence of bempedoic acid oral suspension and commercial immediate release (IR) tablet formulations were assessed using a physiologically based pharmacokinetic (PBPK) model. The mechanistic model, developed from clinical mass balance results and in vitro intrinsic solubility, permeability, and dissolution data, was verified against observed clinical pharmacokinetics (PK) results. Model inputs included a fraction of a dose in solution (0.01%), viscosity (118.8 cps), and median particle diameter (50 µm) for the suspension and particle diameter (36.4 µm) for IR tablets. Dissolution was determined in the relevant media (pH 1.2-6.8) in vitro. Model simulations of bioequivalence predicted oral suspension (test) to IR tablet (reference) geometric mean ratio estimates of 96.9% (90% confidence interval [CI]: 92.6-101) for maximum concentration and 98.2% (90% CI: 87.3-111) for the area under the concentration-time curve. Sensitivity analyses showed gastric transit time had a minor impact on model predictions. Oral suspension biopharmaceutical safe space was defined by extremes of particle size and the percent of bempedoic acid in solution. PBPK model simulations predicted that the rate and extent of bempedoic acid absorption are unlikely to exhibit clinically meaningful differences when dosed as an oral suspension compared with an IR tablet without requiring a clinical bioequivalence study in adults.
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While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract.
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Modelos Biológicos , Projetos de Pesquisa , Triazóis/administração & dosagem , Adolescente , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Preparações de Ação Retardada , Trato Gastrointestinal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Equivalência Terapêutica , Triazóis/farmacocinética , Adulto JovemRESUMO
Physiologically-based pharmacokinetic models combine knowledge about physiology, drug product properties, such as physicochemical parameters, absorption, distribution, metabolism, excretion characteristics, formulation attributes, and trial design or dosing regimen to mechanistically simulate drug pharmacokinetics (PK). The current work describes the development of a multiphase, multilayer mechanistic dermal absorption (MPML MechDermA) model within the Simcyp Simulator capable of simulating uptake and permeation of drugs through human skin following application of drug products to the skin. The model was designed to account for formulation characteristics as well as body site- and sex- population variability to predict local and systemic bioavailability. The present report outlines the structure and assumptions of the MPML MechDermA model and includes results from simulations comparing absorption at multiple body sites for two compounds, caffeine and benzoic acid, formulated as solutions. Finally, a model of the Feldene (piroxicam) topical gel, 0.5% was developed and assessed for its ability to predict both plasma and local skin concentrations when compared to in vivo PK data.
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Modelos Biológicos , Disponibilidade Biológica , Transporte Biológico , HumanosRESUMO
In this study, we aimed to develop and qualify a PBPK model for scalp application using two drugs with marked differences in physicochemical properties and PK profiles. The parameters related to scalp physiology, drug PK, and formulations were incorporated into a Multi-Phase and Multi-Layer (MPML) Mechanistic Dermal Absorption (MechDermA) model within the Simcyp® Simulator V17. The finasteride PBPK model was linked to its effect on dihydrotestosterone (DHT) levels in plasma and scalp using an indirect response model. Predicted PK (and PD for finasteride) profiles and parameters were compared against the clinically reported data and justified by visual predictive checks and two-fold error criteria for model verification. The PBPK/PD model for finasteride reasonably demonstrated an ability to predict its respective PK and PD profiles, and parameters following scalp application under various clinical scenarios. Using the same scalp physiological input parameters, the minoxidil PBPK model was then developed and satisfactorily qualified with independent clinical datasets. Collectively, these results suggested that the established PBPK model may have broader utility for other topical formulations intended for scalp application.
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Finasterida , Minoxidil , Modelos Biológicos , Couro CabeludoRESUMO
BACKGROUND: Our understanding of the severe acute respiratory syndrome coronavirus 2 has evolved since the first reported cases in December 2019, and a greater emphasis has been placed on the hyper-inflammatory response in severely ill patients. The purpose of this study was to determine risk factors for mortality and the impact of anti-inflammatory therapies on survival. AIM: To determine the impact of various therapies on outcomes in severe coronavirus disease 2019 patients with a focus on anti-inflammatory and immune-modulating agents. METHODS: A retrospective analysis was conducted on 261 patients admitted or transferred to the intensive care unit in two community hospitals between March 12, 2020 and June 17, 2020. Totally 167 patients received glucocorticoid (GC) therapy. Seventy-three patients received GC alone, 94 received GC and tocilizumab, 28 received tocilizumab monotherapy, and 66 received no anti-inflammatory therapy. RESULTS: Patient survival was associated with GC use, either alone or with tocilizumab, and decreased vasopressor requirements. Delayed administration of GC was found to decrease the survival benefit of GC therapy. No difference in survival was found with varying anticoagulant doses, convalescent plasma, tocilizumab monotherapy; prone ventilation, hydroxychloroquine, azithromycin, or intravenous ascorbic acid use. CONCLUSION: This analysis demonstrated the survival benefit associated with anti-inflammatory therapy of GC, with or without tocilizumab, with the combination providing the most benefit. More studies are needed to assess the optimal timing of anti-inflammatory therapy initiation.
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This workshop report summarizes the proceedings of Day 2 of a three-day workshop on "Current State and Future Expectations of Translational Modeling Strategies toSupportDrug Product Development, Manufacturing Changes and Controls". From a drug product quality perspective, physiologically based biopharmaceutics modeling (PBBM) is a tool to link variations in the drug product quality attributes to in vivo outcomes enabling the establishment of clinically relevant drug product specifications (CRDPS). Day 2 of the workshop focused on best practices in developing, verifying and validating PBBM. This manuscript gives an overview of podium presentations and summarizes breakout (BO) session discussions related to (1) challenges and opportunities for using PBBM to assess the clinical impact of formulation and manufacturing changes on the in vivo performance of a drug product, (2) best practices to account for parameter uncertainty and variability during model development, (3) best practices in the development, verification and validation of PBBM and (4) opportunities and knowledge gaps related to leveraging PBBM for virtual bioequivalence simulations.
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Biofarmácia , Relatório de Pesquisa , Modelos Biológicos , Solubilidade , Equivalência TerapêuticaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), an ongoing pandemic that started as an outbreak in China. The clinical picture varies from asymptomatic or mild cases to critically ill patients. Most of the critically ill patients present with hypoxia due to acute respiratory distress syndrome. These patients have a poor prognosis, especially in people with underlying co-morbidities. We present a case report of a 78-year-old male with multiple co-morbidities initially presenting with cardiac arrest and COVID-19 who showed drastic clinical improvement after he was administered a packed red blood cell transfusion. The patient was initially intubated for acute respiratory failure but was extubated on the second day as the patient's respiratory status improved. Although this patient had multiple comorbidities, he did extremely well after he received a packed red blood cell transfusion. Recently, there is some evidence showing the effect of the novel coronavirus on hemoglobin levels. Poor clinical outcomes of critically ill patients are most likely due to the impaired gaseous exchange in the lungs in addition to the decreased oxygen-carrying capacity caused by the destruction of red blood cells. Currently, there is limited evidence available in this area and further research may help in developing effective treatment strategies.
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In the present study, an in vitro-in vivo extrapolation of dissolution integrated to a physiologically based pharmacokinetics modeling approach, considering a product-specific particle size distribution and a self-buffering effect of the drug, is introduced and appears to be a promising translational modeling strategy to support drug product development, manufacturing changes and setting clinically relevant specifications for immediate release formulations containing ibuprofen and other weak acids with similar properties.
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Trato Gastrointestinal/efeitos dos fármacos , Ibuprofeno/administração & dosagem , Ibuprofeno/química , Administração Oral , Adulto , Química Farmacêutica/métodos , Desenvolvimento de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Humanos , Modelos Biológicos , Tamanho da Partícula , Solubilidade/efeitos dos fármacosRESUMO
INTRODUCTION: When developing bio-enabling formulations, innovative tools are required to understand and predict in vivo performance and may facilitate approval by regulatory authorities. EMEND® is an example of such a formulation, in which the active pharmaceutical ingredient, aprepitant, is nano-sized. The aims of this study were 1) to characterize the 80â¯mg and 125â¯mg EMEND® capsules in vitro using biorelevant tools, 2) to develop and parameterize a physiologically based pharmacokinetic (PBPK) model to simulate and better understand the in vivo performance of EMEND® capsules and 3) to assess which parameters primarily influence the in vivo performance of this formulation across the therapeutic dose range. METHODS: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp Simulator, informed by the in vitro results and data available from the literature. RESULTS: In vitro experiments indicated a large effect of native surfactants on the solubility of aprepitant. Coupling the in vitro results with the PBPK model led to an appropriate simulation of aprepitant plasma concentrations after administration of 80â¯mg and 125â¯mg EMEND® capsules in both the fasted and fed states. Parameter Sensitivity Analysis (PSA) was conducted to investigate the effect of several parameters on the in vivo performance of EMEND®. While nano-sizing aprepitant improves its in vivo performance, intestinal solubility remains a barrier to its bioavailability and thus aprepitant should be classified as DCS IIb. CONCLUSIONS: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to understand and predict the absorption of this poorly soluble compound from an enabling formulation. The approach can be applied to other poorly soluble compounds to support rational formulation design and to facilitate regulatory assessment of the bio-performance of enabling formulations.
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Aprepitanto/farmacocinética , Jejum/metabolismo , Nanopartículas/metabolismo , Adolescente , Adulto , Química Farmacêutica/métodos , Simulação por Computador , Estudos Cross-Over , Trato Gastrointestinal/metabolismo , Humanos , Absorção Intestinal/fisiologia , Modelos Biológicos , Tamanho da Partícula , Solubilidade/efeitos dos fármacos , Tensoativos/química , Adulto JovemRESUMO
This publication summarizes the proceedings of day 2 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material.
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Produtos Biológicos/farmacocinética , Biofarmácia/métodos , Desenvolvimento de Medicamentos/métodos , Modelos Biológicos , Absorção Fisiológica , Biofarmácia/normas , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Congressos como Assunto , Desenvolvimento de Medicamentos/normas , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Rotulagem de Medicamentos/normas , Liberação Controlada de Fármacos , Humanos , Solubilidade , Equivalência TerapêuticaRESUMO
QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine. The impact of bio-relevant concentration in plasma versus estimated heart tissue exposure on predictions was also assessed. Tolterodine and its therapeutically equipotent metabolite formed via CYP2D6 pathway, 5-HMT, inhibit multiple cardiac ion currents (IKr, INa, ICaL). The QSTS model was able to accurately simulate the QT prolongation at therapeutic and supra-therapeutic dose levels of tolterodine well within 95% confidence interval limits of observed data. The model was able to predict the QT prolongation difference between CYP2D6 extensive and poor metaboliser subject groups at both dose levels thus confirming the ability of the model to account for electrophysiologically active metabolite. The QSTS model was able to simulate the negligible QT prolongation observed with fesoterodine establishing that the 5-HMT does not prolong QT interval even though it is a blocker of hERG channel. With examples of TOL and FESO, we demonstrated the utility of the QSTS approaches to simulate virtual TQT trials, which in turn could complement and reduce the clinical studies or help optimise clinical trial designs.
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Compostos Benzidrílicos/toxicidade , Simulação por Computador , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Modelos Cardiovasculares , Antagonistas Muscarínicos/toxicidade , Tartarato de Tolterodina/toxicidade , Torsades de Pointes/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Compostos Benzidrílicos/farmacocinética , Biotransformação , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Relação Dose-Resposta a Droga , Genótipo , Ventrículos do Coração/fisiopatologia , Humanos , Síndrome do QT Longo/fisiopatologia , Antagonistas Muscarínicos/farmacocinética , Variantes Farmacogenômicos , Fenótipo , Medição de Risco , Tartarato de Tolterodina/farmacocinética , Torsades de Pointes/fisiopatologiaRESUMO
Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical "safe space" for post-approval risk management to identify high-risk clinical scenarios.