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BACKGROUND AND OBJECTIVE: Physiologically based pharmacokinetic (PBPK) models are valuable for translating in vitro absorption, distribution, metabolism, and excretion (ADME) data to predict clinical pharmacokinetics, and can enable discovery and early clinical stages of pharmaceutical research. However, in predicting pharmacokinetics of organic anion transporting polypeptide (OATP) 1B substrates based on in vitro transport and metabolism data, PBPK models typically require additional empirical in vitro-to-in vivo scaling factors (ESFs) in order to accurately recapitulate observed clinical profiles. As model simulation is very sensitive to ESFs, a critical evaluation of ESF estimation is prudent. Previously studies have applied classic 'two-stage' and 'naïve pooled data' approaches in identifying a set of compound independent ESFs. However, the 'two-stage' approach has the parameter identification issue in separately fitting data for individual compounds, while the 'naïve pooled data' approach ignores interstudy variability, leading to potentially biased ESF estimates. METHODS: In this study, we have applied a nonlinear mixed-effect approach in estimating ESF of the PBPK model and incorporated additional data from 86 runs of in vitro uptake assay and 49 clinical studies of 12 training compounds in model development to further enhance the translation of in vitro data to predict the pharmacokinetics of OATP1B substrate drugs. To test predication accuracy of the model, a 'leave-one-out' analysis has been performed. RESULTS: The established model can reasonably describe the clinical observations, with both mean values and interstudy variabilities quantified for ESF and volume of distribution parameters. The mean estimates are largely consistent with values in the previous reports. The interstudy variabilities of these parameters are estimated to be at least 50% (as coefficient of variation). Most compounds can be reasonably predicted in the 'leave-one-out' analysis. CONCLUSION: This study improves the confidence in predicting the pharmacokinetics of OATP1B substrates in individual studies of small sample sizes, and quantifies the variability associated with the prediction.
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Transportador 1 de Anión Orgánico Específico del Hígado , Modelos Biológicos , Dinámicas no Lineales , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Simulación por ComputadorRESUMEN
Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors ("Dustats"), which are typically low MW (300-400 daltons) aliphatic carboxylic acids. Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells. Neutral compound, molidustat, was not a substrate to OATP1B1/1B3. None of the dustats showed transport by other hepatic uptake transporters, including NTCP, OAT2 and OAT7. In the primary human hepatocytes, uptake of all acids was significantly reduced by rifampin (OATP1B inhibitor); with an estimated fraction transported by OATP1B (ft ,OATP1B) of up to >80% (daprodustat). Molidustat uptake was minimally inhibited by rifampin; and low permeability acids (desidustat and enarodustat) also showed biliary efflux in sandwich culture human hepatocytes. In vivo, intravenous pharmacokinetics of all 5 acids was significantly altered by a single-dose rifampin (30 mg/kg) in Cynomolgus monkey. Hepatic clearance (non-renal) was about 4-fold (vadadustat) to >11-fod (daprodustat and roxadustat) higher in control group compared to rifampin-treated subjects. In vivo ft ,OATP1B was estimated to be ~70-90%. In the case of molidustat, rifampin had a minimal effect on overall clearance. Rifampin also considerably reduced volume of distribution of daprodustat and roxadustat. Overall, OATP1B significantly contribute to the hepatic clearance and pharmacokinetics of several dustats, which are low MW carboxylic acids. OATP1B activity should therefore by evaluated in this property space. Significance Statement Our in vitro and in vivo results suggest that OATP1B-mediated hepatic uptake play a significant role in the pharmacokinetics of low MW acidic dustats, which are being developed or approved for the treatment of anemia in chronic kidney disease. Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids.
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Daprodustat is the first oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically-based PK (PBPK) modeling of its drug-drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single-dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable 9.9 ± 1.2-fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady-state was also reduced by 5.0 ± 1.1-fold, whereas the half-life change was minimal (1.5-fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B-CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18-fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well-captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate-to-strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation.
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Citocromo P-450 CYP2C8 , Interacciones Farmacológicas , Hepatocitos , Transportador 1 de Anión Orgánico Específico del Hígado , Insuficiencia Renal Crónica , Rifampin , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Adulto , Animales , Femenino , Humanos , Masculino , Citocromo P-450 CYP2C8/metabolismo , Inhibidores del Citocromo P-450 CYP2C8/farmacocinética , Glicina/análogos & derivados , Glicina/farmacocinética , Células HEK293 , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Hepatopatías/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Macaca fascicularis , Insuficiencia Renal Crónica/metabolismo , Rifampin/farmacología , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/antagonistas & inhibidoresRESUMEN
The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions.
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Proteínas de Transporte de Membrana , Medicina de Precisión , Humanos , Interacciones Farmacológicas , Desarrollo de MedicamentosRESUMEN
Creatinine, a clinical marker for kidney function, is predominantly cleared by glomerular filtration, with active tubular secretion contributing to about 30% of its renal clearance. Recent studies suggested the potential involvement of organic anion transporter (OAT)2, in addition to the previously known organic cation transporter (OCT)2-mediated basolateral uptake, in creatinine active secretion. Here we characterized the transport mechanisms of creatinine using transfected human embryonic kidney (HEK)293 cells and freshly prepared human primary renal proximal tubule epithelial cells (hPTCs). Creatinine showed transport by OAT2 in transfected HEK293 cells. In addition, both creatinine and metformin showed transport by OCT2 and multidrug and toxin extrusion pump (MATE)1 and MATE2K, while penciclovir was selective for OAT2. Time-dependent cell accumulation was observed for creatinine and metformin in hPTCs. Their accumulation was increased by pyrimethamine but inhibited by decynium-22, likely due to differential inhibition of OCT2 versus MATEs. Additionally, indomethacin (an OAT2 inhibitor) reduced penciclovir uptake (â¼75%) in hPTCs illustrating functional OAT2 activity. However, no modulation of creatinine and metformin cell accumulation was apparent with indomethacin. Creatinine transport characteristics in the presence of inhibitors approached those of metformin, an OCT2/MATE substrate, but were distinct from those of penciclovir, an OAT2-selective substrate. Moreover, indomethacin showed no significant effect on the basolateral-to-apical transport and net secretion of creatinine across hPTC monolayers. Collectively, the functional studies suggest OCT2 as the primary basolateral uptake mechanism and that OAT2 has a minimal role, in creatinine renal secretion. Our results highlight the utility of hPTCs to enable the functional assessment of renal transport mechanisms. SIGNIFICANCE STATEMENT: Our results obtained with primary hPTCs indicate that OCT2/MATE (vs. OAT2) play a major role in the active renal secretion of creatinine. Quantitative pharmacokinetic models should therefore focus on OCT2/MATE when describing serum creatinine and creatinine clearance modulation by inhibitor drugs and genotype- or disease-related activity changes. The present study highlights the utility of freshly isolated hPTCs to support solute carrier phenotyping to enable the functional assessment of renal transport mechanisms.
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Metformina , Transportadores de Anión Orgánico , Humanos , Transportador 2 de Cátion Orgánico , Creatinina , Proteínas de Transporte de Catión Orgánico , Células HEK293 , Riñón , Metformina/farmacología , IndometacinaRESUMEN
The effect of food on oral drug absorption is determined by the complex interplay among gut physiological factors and drug properties. The currently used dissolution testing and classification systems (biopharmaceutics classification system, BCS or biopharmaceutics drug disposition classification system, BDDCS) do not account for dynamic changes in gastrointestinal physiology caused by food intake. This study aimed to identify key drug properties that influence food effect (FE) using supervised machine learning approaches. The analysis showed that drugs with high logP, dose number, and extraction ratio have a higher probability of positive FE, while drugs with low permeability and high efflux saturation index have a greater likelihood of negative FE. Weakly acidic drugs also showed a greater probability of positive FE, particularly at pKa >4.3. The importance of drug properties in predicting FE was ranked as logP, dose number, extraction ratio, pKa, and permeability. The accuracy of FE prediction using the models was compared with BCS and extended clearance classification system (ECCS). Overall, the likelihood or magnitude of FE depends on physiological changes to food intake such as altered bile acid secretion rate, intestinal metabolism, transport kinetics, and gastric emptying time, which should be considered along with drug properties (e.g., solubility, logP, and ionization) in predicting FE of orally administered drugs.
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Biofarmacia , Interacciones Alimento-Droga , Transporte Biológico , Solubilidad , Permeabilidad , Ingestión de Alimentos , Preparaciones Farmacéuticas , Absorción IntestinalRESUMEN
Drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptides 1B1/1B3 (OATP1B) can be substantial, however, challenges remain for predicting interaction risk. Emerging evidence suggests that endogenous biomarkers, particularly coproporphyrin-I (CP-I), can be used to assess in vivo OATP1B activity. The present work under the International Consortium for Innovation and Quality in Pharmaceutical Development was aimed primarily at assessing CP-I as a biomarker for informing OATP1B DDI risk. Literature and unpublished CP-I data along with pertinent in vitro and clinical DDI information were collected to identify DDIs primarily involving OATP1B inhibition and assess the relationship between OATP1B substrate drug and CP-I exposure changes. Static models to predict changes in exposure of CP-I, as a selective OATP1B substrate, were also evaluated. Significant correlations were observed between CP-I area under the curve ratio (AUCR) or maximum concentration ratio (Cmax R) and AUCR of substrate drugs. In general, the CP-I Cmax R was equal to or greater than the CP-I AUCR. CP-I Cmax R < 1.25 was associated with absence of OATP1B-mediated DDIs (AUCR < 1.25) with no false negative predictions. CP-I Cmax R < 2 was associated with weak OATP1B-mediated DDIs (AUCR < 2). A correlation was identified between CP-I exposure changes and OATP1B1 static DDI predictions. Recommendations for collecting and interpreting CP-I data are discussed, including a decision tree for guiding DDI risk assessment. In conclusion, measurement of CP-I is recommended to inform OATP1B inhibition potential. The current analysis identified changes in CP-I exposure that may be used to prioritize, delay, or replace clinical DDI studies.
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Coproporfirinas , Transportadores de Anión Orgánico , Humanos , Coproporfirinas/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado , Interacciones Farmacológicas , Biomarcadores , Industria FarmacéuticaRESUMEN
INTRODUCTION: Membrane transporters are now widely recognized for their role in the absorption, distribution, clearance, and elimination of drugs. The organic cation transporters (OCTs, SLC22A) are expressed in the intestine, liver, and kidneys and are of importance in determining systemic pharmacokinetics (PK) and tissue-specific exposure of drugs and metabolites. AREAS COVERED: An overview of the role of OCTs in drug disposition is presented. Genetic variation in OCTs and the effects on PK and drug response were discussed. EXPERT OPINION: Clinical studies demonstrated significance of OCT1 and OCT2 in the hepatic uptake and renal secretion of drug, respectively. These mechanisms are important in determining the systemic PK and tissue exposure and thus pharmacodynamics of several drugs (e.g. metformin, morphine, sumatriptan). Emerging pharmacogenomic data also suggests multidrug and toxin extrusion pump (MATE1, SLC47A1) contribution to PK and response of drugs like metformin and cisplatin. Considerations to genotyping of functional and common variants of OCTs should be given, particularly for cationic drugs with hepatic elimination or renal secretion being major clearance pathways, in the clinical development. While the current evidence indicate that pharmacokinetic variability associated with known genotypes of OCTs/MATEs is relatively small, they may be of relevance in the tissue-specific effects and for drugs with low therapeutic index.
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Metformina , Proteínas de Transporte de Catión Orgánico , Humanos , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Cisplatino , Metformina/farmacocinética , Desarrollo de Medicamentos , Variación Genética , Transportador 2 de Cátion Orgánico/genética , Transportador 2 de Cátion Orgánico/metabolismoRESUMEN
P-glycoprotein (P-gp) may limit oral drug absorption of substrate drugs due to intestinal efflux. Therefore, regulatory agencies require investigation of new chemical entities as possible inhibitors of P-gp in vitro. Unfortunately, inter-laboratory and inter-assay variability have hindered the translatability of in vitro P-gp inhibition data to predict clinical drug interaction risk. The current study was designed to evaluate the impact of potential IC50 discrepancies between two commonly utilized assays, i.e., bi-directional Madin-Darby Canine Kidney-MDR1 cell-based and MDR1 membrane vesicle-based assays. When comparing vesicle- to cell-based IC50 values (n = 28 inhibitors), non-P-gp substrates presented good correlation between assay formats, whereas IC50s of P-gp substrates were similar or lower in the vesicle assays. The IC50s obtained with a cell line expressing relatively low P-gp aligned more closely to those obtained from the vesicle assay, but passive permeability of the inhibitors did not appear to influence the correlation of IC50s, suggesting that efflux activity reduces intracellular inhibitor concentrations. IC50s obtained between two independent laboratories using the same assay type showed good correlation. Using the G-value (i.e., ratio of estimated gut concentration-to-inhibition potency) >10 cutoff recommended by regulatory agencies resulted in minimal differences in predictive performance, suggesting this cutoff is appropriate for either assay format.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Animales , Perros , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Interacciones Farmacológicas , Transporte Biológico , Línea CelularRESUMEN
Hepatic impairment (HI) is known to modulate drug disposition and may lead to elevated plasma exposure. The aim of this study was to quantitate the in vivo OATP1B-mediated hepatic uptake activity in populations with varying degrees of HI. First, we measured baseline levels of plasma coproporphyrin-I, an endogenous OATP1B biomarker, in an open-label, parallel cohort study in adult subjects with normal liver function and mild, moderate, and severe HI (n = 24, 6/cohort). The geometric mean plasma concentrations of coproporphyrin-I were 1.66-fold, 2.81-fold (P < 0.05), and 7.78-fold (P < 0.0001) higher in mild, moderate, and severe impairment than those healthy controls. Second, we developed a dataset of 21 OATP1B substrate drugs with HI data extracted from literature. Median disease-to-healthy plasma area under the curve (AUC) ratios for substrate drugs were ~ 1.4, 3.0, and 6.4 for mild, moderate, and severe HI, respectively. Additionally, significant linear relationship was noted between AUC ratios of substrate drugs without and with co-administration of rifampin, a prototypic OATP1B inhibitor, and AUC ratios in moderate (P < 0.01) and severe (P < 0.001) HI. Third, a physiologically-based pharmacokinetic model analysis was conducted with 10 substrate drugs following estimation of relative OATP1B functional activity in virtual disease population models using coproporphyrin-I data and verification of substrate models with rifampin drug-drug interaction data. This approach adequately predicted plasma AUC change particularly in moderate (9 of 10 within 2-fold) and severe (5 of 5 within 2-fold) HI. Collective findings indicate progressive reduction, by as much as 90-92%, in OATP1B activity in the HI population.
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Hepatopatías , Rifampin , Adulto , Humanos , Coproporfirinas , Preparaciones Farmacéuticas , Estudios de Cohortes , Biomarcadores , Interacciones Farmacológicas , Área Bajo la CurvaRESUMEN
Organic anion transporter 2 (OAT2 or SLC22A7) plays an important role in the hepatic uptake and renal secretion of several endogenous compounds and drugs. The goal of this work is to understand the structure activity of OAT2 inhibition and assess clinical drug interaction risk. A single-point inhibition assay using OAT2-transfected HEK293 cells was employed to screen about 150 compounds; and concentration-dependent inhibition potency (IC50) was measured for the identified "inhibitors". Acids represented about 65% of all inhibitors, and the frequency of bases-plus-zwitterions approximately doubled for "non-inhibitors". Interestingly, 9 of 10 most potent inhibitors (low IC50) are acids (pKa â¼ 3-5). Additionally, inhibitors are significantly larger and lipophilic than non-inhibitors. In silico (binary) models were developed to identify inhibitors and non-inhibitors. Finally, in vivo risk assessed via static drug-drug interaction models identified several inhibitors with potential for renal and hepatic OAT2 inhibition at clinical doses. This is the first study assessing the global pattern of OAT2-ligand interactions.
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Hígado , Transportadores de Anión Orgánico Sodio-Independiente , Humanos , Células HEK293 , Interacciones Farmacológicas , Medición de RiesgoRESUMEN
Excess dietary fructose consumption promotes metabolic dysfunction thereby increasing the risk of obesity, type 2 diabetes, non-alcoholic steatohepatitis (NASH), and related comorbidities. PF-06835919, a first-in-class ketohexokinase (KHK) inhibitor, showed reversal of such metabolic disorders in preclinical models and clinical studies, and is under clinical development for the potential treatment of NASH. In this study, we evaluated the transport and metabolic pathways of PF-06835919 disposition and assessed pharmacokinetics in preclinical models. PF-06835919 showed active uptake in cultured primary human hepatocytes, and substrate activity to organic anion transporter (OAT)2 and organic anion transporting-polypeptide (OATP)1B1 in transfected cells. "SLC-phenotyping" studies in human hepatocytes suggested contribution of passive uptake, OAT2- and OATP1B-mediated transport to the overall uptake to be about 15%, 60% and 25%, respectively. PF-06835919 showed low intrinsic metabolic clearance in vitro, and was found to be metabolized via both oxidative pathways (58%) and acyl glucuronidation (42%) by CYP3A, CYP2C8, CYP2C9 and UGT2B7. Following intravenous dosing, PF-06835919 showed low clearance (0.4-1.3 mL/min/kg) and volume of distribution (0.17-0.38 L/kg) in rat, dog and monkey. Human oral pharmacokinetics are predicted within 20% error when considering transporter-enzyme interplay in a PBPK model. Finally, unbound liver-to-plasma ratio (Kpuu) measured in vitro using rat, NHP and human hepatocytes was found to be approximately 4, 25 and 10, respectively. Similarly, liver Kpuu in rat and monkey following intravenous dosing of PF-06835919 was found to be 2.5 and 15, respectively, and notably higher than the muscle and brain Kpuu, consistent with the active uptake mechanisms observed in vitro. Significance Statement This work characterizes the transport/metabolic pathways in the hepatic disposition of PF-06835919, a first-in-class KHK inhibitor for the treatment of metabolic disorders and NASH. Phenotyping studies using transfected systems, human hepatocytes and liver microsomes signifies the role of OAT2 and OATP1B1 in the hepatic uptake and multiple enzymes in the metabolism of PF-06835919. Data presented suggest hepatic transporter-enzyme interplay in determining its systemic concentrations and potential enrichment in liver, a target site for KHK inhibition.
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During its fourth transporter workshop in 2021, the International Transporter Consortium (ITC) provided updates on emerging clinically relevant transporters for drug development. Previously highlighted and new transporters were considered based on up-to-date clinical evidence of their importance in drug-drug interactions and potential for altered drug efficacy and safety, including drug-nutrient interactions leading to nutrient deficiencies. For the first time, folate transport pathways (PCFT, RFC, and FRα) were examined in-depth as a potential mechanism of drug-induced folate deficiency and related toxicities (e.g., neural tube defects and megaloblastic anemia). However, routine toxicology studies conducted in support of drug development appear sufficient to flag such folate deficiency toxicities, whereas prospective prediction from in vitro folate metabolism and transport inhibition is not well enough established to inform drug development. Previous suggestion of a retrospective study of intestinal OATP2B1 inhibition to explain unexpected decreases in drug exposure were updated. Furthermore, when the absorption of a new molecular entity is more rapid and extensive than can be explained by passive permeability, evaluation of the OATP2B1 transport may be considered. Emerging research on hepatic and renal OAT2 is summarized, but current understanding of the importance of OAT2 was deemed insufficient to justify specific consideration for drug development. Hepatic, renal, and intestinal MRPs (MRP2, MRP3, and MRP4) were revisited. MRPs may be considered when they are suspected to be the major determinant of drug disposition (e.g., direct glucuronide conjugates); MRP2 inhibition as a mechanistic explanation for drug-induced hyperbilirubinemia remains justified. There were no major changes in recommendations from previous ITC whitepapers.
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Glucurónidos , Proteínas de Transporte de Membrana , Transporte Biológico , Ácido Fólico/metabolismo , Glucurónidos/metabolismo , Humanos , Proteínas de Transporte de Membrana/metabolismo , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
The role of membrane transporters on pharmacokinetics (PKs), drug-drug interactions (DDIs), pharmacodynamics (PDs), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in the diseased patient population or specific populations, such as pediatrics or pregnancy, is still emerging. This white paper highlights recent advances in studying the changes in transporter expression and activity in various diseases (i.e., renal and hepatic impairment and cancer) and some specific populations (i.e., pediatrics and pregnancy) with the focus on clinical implications. Proposed alterations in transporter abundance and/or activity in diseased and specific populations are based on (i) quantitative transporter proteomic data and relative abundance in specific populations vs. healthy adults, (ii) clinical PKs, and emerging transporter biomarker and/or pharmacogenomic data, and (iii) physiologically-based pharmacokinetic modeling and simulation. The potential for altered PK, PD, and toxicity in these populations needs to be considered for drugs and their active metabolites in which transporter-mediated uptake/efflux is a major contributor to their absorption, distribution, and elimination pathways and/or associated DDI risk. In addition to best practices, this white paper discusses current challenges and knowledge gaps to study and quantitatively predict the effects of modulation in transporter activity in these populations, together with the perspectives from the International Transporter Consortium (ITC) on future directions.
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Modelos Biológicos , Proteómica , Adulto , Transporte Biológico , Niño , Interacciones Farmacológicas , Humanos , Proteínas de Transporte de Membrana/metabolismoRESUMEN
PF-06835919 is a first-in-class ketohexokinase inhibitor (KHKi), recently under development for the treatment of metabolic and fatty liver diseases, which inhibited organic anion transporting polypeptide (OATP)1B1 in vitro and presented drug-drug interaction (DDI) risk. This study aims to investigate the dose-dependent effect of KHKi on OATP1B in vivo activity. We performed an open-label study comparing pharmacokinetics of atorvastatin (OATP1B probe) dosed alone (20 mg single dose) and coadministered with two dose strengths of KHKi (50 and 280 mg once daily) in 12 healthy participants. Additionally, changes in exposure of coproporphyrin-I (CP-I), an endogenous biomarker for OATP1B, were assessed in the atorvastatin study (1.12-fold and 1.49-fold increase in area under the plasma concentration-time profile (AUC) with once-daily 50 and 280 mg, respectively), and a separate single oral dose study of KHKi alone (100-600 mg, n = 6 healthy participants; up to a 1.80-fold increase in AUC). Geometric mean ratios (90% confidence interval) of atorvastatin AUC following 50 and 280 mg KHKi were 1.14 (1.00-1.30) and 1.54 (1.37-1.74), respectively. Physiologically-based pharmacokinetic modeling of CP-I plasma exposure following a single dose of KHKi predicted in vivo OATP1B inhibition from about 13% to 70% over the 100 to 600 mg dose range, while using the in vitro inhibition potency (1.9 µM). Model-based analysis correctly predicted "no-effect" (AUC ratio < 1.25) at the low dose range and "weak" effect (AUC ratio < 2) on atorvastatin pharmacokinetics at the high dose range of KHKi. This study exemplified the utility of biomarker-informed model-based approach in discerning even small effects on OATP1B activity in vivo, and to project DDI risk at the clinically relevant doses.
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Fructoquinasas , Atorvastatina , Biomarcadores , Interacciones Farmacológicas , Fructoquinasas/metabolismo , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Medición de RiesgoRESUMEN
Quantitative prediction of drug-drug interactions (DDIs) involving organic anion transporting polypeptide (OATP)1B1/1B3 inhibition is limited by uncertainty in the translatability of experimentally determined in vitro inhibition potency (half-maximal inhibitory concentration (IC50 )). This study used an OATP1B endogenous biomarker-informed physiologically-based pharmacokinetic (PBPK) modeling approach to predict the effect of inhibitor drugs on the pharmacokinetics (PKs) of OATP1B substrates. Initial static analysis with about 42 inhibitor drugs, using in vitro IC50 values and unbound liver inlet concentrations (Iin,max,u ), suggested in vivo OATP1B inhibition risk for drugs with R-value (1+ Iin,max,u /IC50 ) above 1.5. A full-PBPK model accounting for transporter-mediated hepatic disposition was developed for coproporphyrin I (CP-I), an endogenous OATP1B biomarker. For several inhibitors (cyclosporine, diltiazem, fenebrutinib, GDC-0810, itraconazole, probenecid, and rifampicin at 3 different doses), PBPK models were developed and verified against available CP-I plasma exposure data to obtain in vivo OATP1B inhibition potency-which tend to be lower than the experimentally measured in vitro IC50 by about 2-fold (probenecid and rifampicin) to 37-fold (GDC-0810). Models verified with CP-I data are subsequently used to predict DDIs with OATP1B probe drugs, rosuvastatin and pitavastatin. The predicted and observed area under the plasma concentration-time curve ratios are within 20% error in 55% cases, and within 30% error in 89% cases. Collectively, this comprehensive study illustrates the adequacy and utility of endogenous biomarker-informed PBPK modeling in mechanistic understanding and quantitative predictions of OATP1B-mediated DDIs in drug development.
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Atorvastatina/farmacocinética , Coproporfirinas/sangre , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Hígado/efectos de los fármacos , Moduladores del Transporte de Membrana/farmacología , Modelos Biológicos , Rosuvastatina Cálcica/farmacocinética , Biomarcadores/sangre , Simulación por Computador , Interacciones Farmacológicas , Células HEK293 , Humanos , Hígado/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Medición de Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: Herbal medicine represents a significant component of disease prevention and therapy in most African countries. Herb-drug interactions (HDI) can arise from the co-administration of herbal and orthodox medicines. OBJECTIVE: This study assessed the potential for HDI of V. amygdalina, O. gratissimum, M. oleifera, A. indica, and P. nitida extracts using in vitro assays. Little is known about these medicinal plants' potential for drug interaction despite their extensive use in Nigeria for several disease conditions. METHOD: The medicinal plant crude extracts were evaluated for Cytochrome P450 (CYP) enzyme induction using cryopreserved human hepatocytes. Enzyme activity was determined by quantifying probe substrate metabolism and metabolite formation using liquid chromatography-mass spectrometry/mass spectrometry. The extracts were evaluated for the potential to inhibit P-glycoprotein (P-gp) activity using human embryonic kidney membrane vesicles over-expressing human P-gp. The herbal extracts in vivo drug interaction potential was predicted based on the USFDA drug interaction guidance. RESULT: O. gratissimum and P. nitida methanol extracts induced CYP1A2 enzyme activity by greater than 3-fold. P. nitida methanol extracts showed over 2-fold induction of CYP1A2 mRNA expression. O. gratissimum methanol extract induced CYP2B6 mRNA expression over 2-fold. P. nitida and A. indica methanol extracts showed potent inhibition of P-gp activity (IC50: 3.8 and 5.4 µg/mL), respectively, while V. amygdalina and M. oleifera methanol extracts showed moderate P-gp inhibition (IC50: 12.1 and 37.2 µg/mL, respectively). CONCLUSION: Our studies suggested that the medicinal plants' extracts can modulate CYP enzymes and P-gp activity with the potential to cause herb-drug interaction in vivo.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Inductores de las Enzimas del Citocromo P-450/farmacología , Extractos Vegetales/farmacología , Plantas Medicinales/química , Células Cultivadas , Cromatografía Liquida/métodos , Inductores de las Enzimas del Citocromo P-450/aislamiento & purificación , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Interacciones de Hierba-Droga , Humanos , Concentración 50 Inhibidora , Riñón/efectos de los fármacos , Riñón/metabolismo , Medicinas Tradicionales Africanas , Nigeria , Extractos Vegetales/administración & dosificación , Espectrometría de Masas en Tándem/métodosRESUMEN
Quantitative assessment of drug-drug interactions (DDIs) involving breast cancer resistance protein (BCRP) inhibition is challenged by overlapping substrate/inhibitor specificity. This study used physiologically-based pharmacokinetic (PBPK) modeling to delineate the effects of inhibitor drugs on BCRP- and organic anion transporting polypeptide (OATP)1B-mediated disposition of rosuvastatin, which is a recommended BCRP clinical probe. Initial static model analysis using in vitro inhibition data suggested BCRP/OATP1B DDI risk while considering regulatory cutoff criteria for a majority of inhibitors assessed (25 of 27), which increased rosuvastatin plasma exposure to varying degree (~ 0-600%). However, rosuvastatin area under plasma concentration-time curve (AUC) was minimally impacted by BCRP inhibitors with calculated G-value (= gut concentration/inhibition potency) below 100. A comprehensive PBPK model accounting for intestinal (OATP2B1 and BCRP), hepatic (OATP1B, BCRP, and MRP4), and renal (OAT3) transport mechanisms was developed for rosuvastatin. Adopting in vitro inhibition data, rosuvastatin plasma AUC changes were predicted within 25% error for 9 of 12 inhibitors evaluated via PBPK modeling. This study illustrates the adequacy and utility of a mechanistic model-informed approach in quantitatively assessing BCRP-mediated DDIs.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Rosuvastatina Cálcica/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Área Bajo la Curva , Interacciones Farmacológicas , Femenino , Células HEK293 , Humanos , Intestinos/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Transportadores de Anión Orgánico/antagonistas & inhibidores , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: The use of herbal medicines is common in Africa, and patients often use a combination of herbs and drugs. Concurrent herbal and pharmaceuticals treatments can cause adverse effects through herb-drug interactions (HDI). This study evaluated the potential risk of HDI for five medicinal plants, Vernonia amygdalina, Ocimum gratissimum, Moringa oleifera, Azadirachta indica, and Picralima nitida, using in vitro assays. Patients with diabetes and some other disease conditions commonly use these medicinal plants in Nigeria, and little is known regarding their potential for drug interaction, despite their enormous use. METHODS: Crude extracts of the medicinal plants were evaluated for reversible and time-dependent inhibition (TDI) activity of six cytochrome P450 (CYP) enzymes using pooled human liver microsomes and cocktail probe-based assays. Enzyme activity was determined by quantifying marker metabolites' formation using liquid chromatography-mass spectrometry/mass spectrometry. The drug interaction potential was predicted for each herbal extract using the in vitro half-maximal inhibitory concentration (IC50) values and the percentage yield. RESULTS: O. gratissimum methanol extracts reversibly inhibited CYP 1A2, 2C8, 2C9 and 2C19 enzymes (IC50: 6.21 µg/ml, 2.96 µg/ml, 3.33 µg/ml and 1.37 µg/ml, respectively). Additionally, V. amygdalina methanol extract inhibited CYP2C8 activity (IC50: 5.71 µg/ml); P. nitida methanol and aqueous extracts inhibited CYP2D6 activity (IC50: 1.99 µg/ml and 2.36 µg/ml, respectively) while A. indica methanol extract inhibited CYP 3A4/5, 2C8 and 2C9 activity (IC50: 7.31 µg/ml, 9.97 µg/ml and 9.20 µg/ml, respectively). The extracts showed a potential for TDI of the enzymes when incubated at 200 µg/ml; V. amygdalina and A. indica methanol extracts exhibited TDI potential for all the major CYPs. CONCLUSIONS: The medicinal plants inhibited CYP activity in vitro, with the potential to cause in vivo HDI. Clinical risk assessment and proactive monitoring are recommended for patients who use these medicinal plants concurrently with drugs that are cleared through CYP metabolism.