RESUMEN
In vivo studies of formulation performance with in vitro and/or in silico simulations are often limited by significant gaps in our knowledge of the interaction between administered dosage forms and the human gastrointestinal tract. This work presents a novel approach for the investigation of gastric motility influence on dosage form performance, by combining biopredictive dissolution tests in an innovative PhysioCell apparatus with mechanistic physiology-based pharmacokinetic modeling. The methodology was based on the pharmacokinetic data from a large (n = 118) cohort of healthy volunteers who ingested a capsule containing a highly soluble and rapidly absorbed drug under fasted conditions. The developed dissolution tests included biorelevant media, varied fluid flows, and mechanical stress events of physiological timing and intensity. The dissolution results were used as inputs for pharmacokinetic modeling that led to the deduction of five patterns of gastric motility and their prevalence in the studied population. As these patterns significantly influenced the observed pharmacokinetic profiles, the proposed methodology is potentially useful to other in vitro-in vivo predictions involving immediate-release oral dosage forms.
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Motilidad Gastrointestinal , Solubilidad , Humanos , Motilidad Gastrointestinal/fisiología , Adulto , Masculino , Femenino , Modelos Biológicos , Administración Oral , Adulto Joven , Voluntarios Sanos , Simulación por Computador , Liberación de Fármacos/fisiología , Persona de Mediana Edad , Ayuno/fisiología , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/fisiologíaRESUMEN
BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.
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Interacciones Farmacológicas , Pirimidinas , Sulfonamidas , Humanos , Femenino , Adulto , Adulto Joven , Pirimidinas/farmacocinética , Pirimidinas/administración & dosificación , Citocromo P-450 CYP1A2/metabolismo , Masculino , Etinilestradiol/farmacocinética , Voluntarios Sanos , Anticonceptivos Hormonales Orales/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Levonorgestrel/farmacocinética , Levonorgestrel/administración & dosificación , Anticonceptivos Orales Combinados/farmacocinética , Anticonceptivos Orales Combinados/administración & dosificación , Persona de Mediana Edad , Área Bajo la Curva , Combinación de MedicamentosRESUMEN
BACKGROUND AND OBJECTIVES: As drug development scientists strive to accelerate availability of therapies for patients, model-informed drug development (MIDD) plays an important role in contextualizing existing information and facilitating decision making. This paper describes an example of MIDD, where modeling and simulation informed decision making in the circumstance of a combined phase 2b and single pivotal study for ritlecitinib (JAK3/TEC family kinases inhibitor). METHODS: Longitudinal exposure-response (ER) modeling was conducted to describe ritlecitinib efficacy in alopecia areata patients. The Severity of Alopecia Tool (SALT) score (a continuous bounded outcome [CBO] score [0-100]) was used as the efficacy response. The average concentration during the time interval between two adjacent SALT scores was used as the exposure metric driving efficacy. RESULTS: The developed model well described the longitudinal SALT profile of ritlecitinib as well as the frequency of boundary data. The CBO model indicated tested doses in the phase 2b/3 clinical trial are in the ascending region of ER and contextualized a loading dose effect that impacted onset of efficacy without long-term benefit. It also identified disease severity as the only covariate impacting efficacy. The model-based simulation further informed impact of treatment interruption on the loss of efficacy in the absence of a dedicated treatment withdrawal study. Results indicated temporary treatment interruption ≤ 6 weeks is not expected to result in significant loss of efficacy. CONCLUSION: The CBO modeling approach and simulation supported the single pivotal trial strategy and guided dose selection in the accelerated drug development program of ritlecitinib, which can be applied to many indications where efficacy is measured on a bounded scale.
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Desarrollo de Medicamentos , Inhibidores de Proteínas Quinasas , Humanos , Simulación por Computador , Toma de DecisionesRESUMEN
Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.
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Alopecia Areata , Humanos , Equivalencia Terapéutica , Probabilidad , Inhibidores de Proteínas Quinasas , Medición de RiesgoRESUMEN
BACKGROUND: Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor undergoing parallel clinical development for alopecia areata, vitiligo, ulcerative colitis, Crohn's disease, and rheumatoid arthritis. OBJECTIVE: As studies read out simultaneously, strategic planning of population pharmacokinetic model development and evaluation is required to ensure timely decisions. METHODS: Data from healthy participants and patients from 12 clinical trials between December 2014 and July 2021 were included: seven phase I studies in healthy participants and organ impairment, five phase II/III studies in patients with rheumatoid arthritis, ulcerative colitis, alopecia areata, and vitiligo. Population pharmacokinetic models consisted of stepwise procedures to accommodate data availability and the model's application to answering clinical development questions. At each iteration of the model update, parameters of the next model were re-estimated by leveraging previous information and new data. RESULTS: Three model development lifecycle iterations of the ritlecitinib population pharmacokinetic model were conducted to support alopecia areata, vitiligo, and ulcerative colitis study readouts. Initial structural modeling based on healthy participant data (and some rheumatoid arthritis and alopecia areata data) in iteration 1 provided a platform for comprehensive covariate testing during iteration 2, and model evaluation and implementation of the frequentist prior approach in iteration 3. The final model was a two-compartment model with first-order absorption and direct-response non-stationary clearance and bioavailability driven by concentrations in the peripheral compartment. CONCLUSIONS: The present approach demonstrated the evolution of three population pharmacokinetic models with accumulating data, addressed clinical drug development questions related to systemic exposures of ritlecitinib, and informed the approved product label. CLINICAL TRIAL REGISTRATION: NCT02309827, NCT02684760, NCT02958865, NCT02969044, NCT03232905, NCT03732807, NCT04016077, NCT03715829, NCT04037865, NCT04004663, NCT04634565, NCT02974868.
Asunto(s)
Alopecia Areata , Artritis Reumatoide , Colitis Ulcerosa , Vitíligo , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Alopecia Areata/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Desarrollo de MedicamentosRESUMEN
PURPOSE: Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. METHODS: In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. RESULTS: In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. CONCLUSION: Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.
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Proteínas de Neoplasias , Transportadores de Anión Orgánico , Adulto , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Biomarcadores , Interacciones Farmacológicas , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/farmacologíaRESUMEN
Ritlecitinib is a selective, covalent, irreversible inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases. Pharmacokinetics and safety of ritlecitinib in participants with hepatic (Study 1) or renal (Study 2) impairment were to be characterized from two phase I studies. Due to a study pause caused by the COVID-19 pandemic, the study 2 healthy participant (HP) cohort was not recruited; however, the demography of the severe renal impairment cohort closely matched the study 1 HP cohort. We present results from each study and two innovative approaches to utilizing available HP data as reference data for study 2: a statistical approach using analysis of variance and an in silico simulation of an HP cohort created using a population pharmacokinetics (POPPK) model derived from several ritlecitinib studies. For study 1, the observed area under the curve for 24-h dosing interval and maximum plasma concentration for HPs and their observed geometric mean ratios (participants with moderate hepatic impairment vs HPs) were within 90% prediction intervals from the POPPK simulation-based approach, thereby validating the latter approach. When applied to study 2, both the statistical and POPPK simulation approaches demonstrated that patients with renal impairment would not require ritlecitinib dose modification. In both phase I studies, ritlecitinib was generally safe and well tolerated. These analyses represent a new methodology for generating reference HP cohorts in special population studies for drugs in development with well-characterized pharmacokinetics in HPs and adequate POPPK models. TRIAL REGISTRATION: ClinicalTrials.gov NCT04037865 , NCT04016077 , NCT02309827 , NCT02684760 , and NCT02969044 .
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COVID-19 , Carcinoma Hepatocelular , Hepatopatías , Neoplasias Hepáticas , Insuficiencia Renal , Humanos , Voluntarios Sanos , Pandemias , Inhibidores de Proteínas Quinasas/efectos adversos , Área Bajo la CurvaRESUMEN
Ritlecitinib, an inhibitor of Janus kinase 3 and hepatocellular carcinoma family kinases, is in development as potential treatment for several inflammatory diseases. In vitro studies presented ritlecitinib as an inhibitor of hepatic organic cation transporter (OCT) 1, renal transporters OCT2 and multidrug and toxin extrusion (MATE) proteins 1/2K using multiple substrates, and ritlecitinib's major inactive metabolite M2, as an inhibitor of OCT1. A clinical interaction study with an OCT1 drug probe (sumatriptan) and relevant probe biomarkers for OCT/MATE was conducted to assess the effect of ritlecitinib on these transporters in healthy adult participants. The selectivity of sumatriptan for OCT1 was confirmed through a series of in vitro uptake assays. A simple static model was used to help contextualize the observed changes in sumatriptan area under the plasma concentration-time curve (AUC). Coadministration of a single 400-mg dose of ritlecitinib increased sumatriptan AUC from time 0 to infinity (AUCinf ) by ≈30% relative to a single 25-mg sumatriptan administration alone. When administered 8 hours after a ritlecitinib dose, sumatriptan AUCinf increased by ≈50% relative to sumatriptan given alone. Consistent with OCT1 inhibition, the AUC from time 0 to 24 hours of isobutyryl-L-carnitine decreased by ≈15% after ritlecitinib. Based on the evaluation of the renal clearance of N1 -methylnicotinamide, ritlecitinib does not exert clinically meaningful inhibition on renal OCT2 or MATE1/2K. This study confirmed that ritlecitinib and M2 are inhibitors of OCT1 but not OCT2 or MATE1/2K in healthy adults.
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Proteínas de Transporte de Catión Orgánico , Sumatriptán , Adulto , Humanos , Transportador 1 de Catión Orgánico , Biomarcadores , Cationes/metabolismo , Células HEK293RESUMEN
AIMS: Since the first approval for transthyretin amyloid polyneuropathy patients, new formulations and different strength of tafamidis have been developed and tested in a different population (transthyretin amyloid cardiomyopathy). The objective of this analysis was to develop a unified population pharmacokinetic (PK) model of tafamidis, which can describe the PK of various different formulations in healthy subjects as well as patients with TTR amyloidosis, and to understand effects of intrinsic and extrinsic factors on the PK variability. METHODS: Pooled data from 23 clinical studies (17 Phase 1 and 6 Phase 2/3 studies) were used for the analysis. The plasma concentration-time data were analysed using a nonlinear mixed effects modelling methodology. Covariate analysis was performed using a stepwise covariate model building procedure. RESULTS: The final model was a 2-compartment model with first-order absorption and elimination coupled with an absorption lag time for nonsolution formations. Body weight, food and tafamidis formulations were incorporated as structural covariates on PK parameters. Covariate analysis further identified age ≥65 years (14.5% decrease) and moderate hepatic impairment effects (57.6% increase) on apparent clearance and transthyretin amyloid polyneuropathy effect (17.3% decrease) on F. However, model-based clinical trial simulation results indicated that tafamidis steady-state exposure changes were not clinically meaningful under the tested conditions. CONCLUSIONS: The unified population PK model of tafamidis was developed based on 23 studies. Subsequent clinical trial simulations indicated that no significant changes in tafamidis exposure necessitating a dose modification are expected due to either extrinsic or intrinsic factors. The model was used to support labelling statements for dose recommendations in special populations.
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Neuropatías Amiloides Familiares , Anciano , Neuropatías Amiloides Familiares/tratamiento farmacológico , Benzoxazoles , Voluntarios Sanos , HumanosRESUMEN
PF-05251749 is a dual inhibitor of casein kinase 1 δ/ε, key regulators of circadian rhythm. As a result of its mechanism of action, PF-05251749 may also change the heart rate corrected QT (QTc) circadian rhythm, which may confound detection of drug-induced QTc prolongation. In this analysis, a nonlinear mixed effect model including a multioscillator function was developed in addition to fitting the prespecified linear mixed effect concentration-QTc model, to identify QTc liability of PF-05251749 in the presence of potential circadian rhythm change. The modeling results suggested lack of clinically meaningful QTc prolongation (upper bound of 90% confidence interval for ∆∆QTc < 10 milliseconds) and that the drug-induced QTc circadian rhythm change was not present. However, simulation results indicated that inference of drug-induced QTc prolongation could be misleading if the drug effect on QTc circadian rhythm is not properly addressed. The modeling and simulation results suggest that prespecification of the concentration-QTc model should be reconsidered for drugs with circadian rhythm modulation potential.
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Ritmo Circadiano/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Caseína Cinasa 1 épsilon/antagonistas & inhibidores , Quinasa Idelta de la Caseína/antagonistas & inhibidores , Electrocardiografía , Humanos , Modelos Lineales , Dinámicas no LinealesRESUMEN
Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf) allows for analysis of the PK-QTc relationship using early Phase I data to assess QTc liability. In this paper, we compared the cardiac risk assessment based on the early Phase I analysis with that from a thorough QTc study across eleven drug candidate programs, and demonstrate that the conclusions are largely the same. The early Phase I analysis is based upon a linear mixed effect model with known covariance structure (Dosne et al. in Stat Med 36(24):3844-3857, 2017). The treatment effect was evaluated at the supratherapeutic Cmax as observed in the thorough QTc study using a non-parametric bootstrap analysis to generate 90% confidence intervals for the treatment effect, and implementation of the standardized methodology in R and SAS software yielded consistent results. The risk assessment based on the concentration-response analysis on the early Phase I data was concordant with that based on the standard analysis of the thorough QTc study for nine out of the eleven drug candidates. This retrospective analysis is consistent with and supportive of the conclusion of a previous prospective analysis by Darpo et al. (Clin Pharmacol Ther 97(4):326-335, 2015) to evaluate whether C-QTc analysis can detect QTc effects in a small study with healthy subjects.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Corazón/efectos de los fármacos , Preparaciones Farmacéuticas/administración & dosificación , Ensayos Clínicos Fase I como Asunto , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Medición de Riesgo/métodosRESUMEN
Parametric models used in time to event analyses are evaluated typically by survival-based visual predictive checks (VPC). Kaplan-Meier survival curves for the observed data are compared with those estimated using model-simulated data. Because the derivative of the log of the survival curve is related to the hazard--the typical quantity modeled in parametric analysis--isolation, interpretation and correction of deficiencies in the hazard model determined by inspection of survival-based VPC's is indirect and thus more difficult. The purpose of this study is to assess the performance of nonparametric hazard estimators of hazard functions to evaluate their viability as VPC diagnostics. Histogram-based and kernel-smoothing estimators were evaluated in terms of bias of estimating the hazard for Weibull and bathtub-shape hazard scenarios. After the evaluation of bias, these nonparametric estimators were assessed as a method for VPC evaluation of the hazard model. The results showed that nonparametric hazard estimators performed reasonably at the sample sizes studied with greater bias near the boundaries (time equal to 0 and last observation) as expected. Flexible bandwidth and boundary correction methods reduced these biases. All the nonparametric estimators indicated a misfit of the Weibull model when the true hazard was a bathtub shape. Overall, hazard-based VPC plots enabled more direct interpretation of the VPC results compared to survival-based VPC plots.
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Modelos de Riesgos Proporcionales , Algoritmos , Sesgo , Simulación por Computador , Humanos , Estimación de Kaplan-Meier , Valor Predictivo de las Pruebas , Tamaño de la Muestra , Análisis de SupervivenciaRESUMEN
BACKGROUND: Ixazomib is the first oral, proteasome inhibitor to reach phase III trials. Here, we present an integrated nonclinical and clinical assessment of ixazomib's effect on QTc intervals. METHODS: Nonclinical studies assessed (1) the in vitro binding of ixazomib to the hERG channel and (2) its effect on QT/QTc in dogs (N = 4) via telemetry. Pharmacokinetic-matched triplicate electrocardiograms were collected in four clinical phase I studies of intravenous (0.125-3.11 mg/m(2), N = 125, solid tumors/lymphoma) or oral (0.24-3.95 mg/m(2), N = 120, multiple myeloma) ixazomib. The relationship between ixazomib plasma concentration and heart rate (HR)-corrected QT using Fridericia (QTcF) or population (QTcP) methods was analyzed using linear mixed-effects models with fixed effects for day and time. RESULTS: In vitro binding potency for ixazomib to the hERG channel was weak (K i 24.9 µM; IC50 59.6 µM), and nonclinical telemetry studies showed no QT/QTc prolongation at doses up to 4.2 mg/m(2). In cancer patients, ixazomib, when evaluated at doses yielding various plasma concentrations (with 26 % of data greater than mean C max for the 4 mg phase 3 dose), had no meaningful effect on QTc based on model-predicted mean change in QTcF/QTcP from baseline. There was no relationship between ixazomib concentration and RR, suggesting no effect on HR. CONCLUSIONS: Ixazomib has no clinically meaningful effects on QTc or HR. Integrating preclinical data and concentration-QTc modeling of phase 1 data may obviate the need for a dedicated QTc study in oncology. A framework for QT assessment in oncology drug development is proposed.
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Compuestos de Boro/farmacología , Compuestos de Boro/uso terapéutico , Electrocardiografía/efectos de los fármacos , Glicina/análogos & derivados , Neoplasias/tratamiento farmacológico , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Animales , Compuestos de Boro/farmacocinética , Ensayos Clínicos Fase I como Asunto , Perros , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Glicina/farmacocinética , Glicina/farmacología , Glicina/uso terapéutico , Células HEK293 , Humanos , Masculino , Neoplasias/sangre , Inhibidores de Proteasoma/farmacocinética , Medición de RiesgoRESUMEN
The purpose of this study was to determine if the disposition of cefadroxil, an α-amino-containing ß-lactam antibiotic, changes during lipopolysaccharide (LPS)-induced acute inflammation. Six hours after LPS or saline treatment, mice received 1 nmol/g cefadroxil intravenously along with inulin for glomerular filtration rate (GFR) determination. Serial blood samples, along with tissue and urine samples, were collected at predetermined time points. In order to determine inflammation-induced changes in GFR, renal tubular secretion, and reabsorption, it was necessary to coadminister 70 mg/kg probenecid. Changes in the expression of the mRNA of transporters involved in cefadroxil disposition in the kidneys and choroid plexus were also investigated 6 h after LPS treatment. The results demonstrated marked increases in blood, cerebrospinal fluid, and tissue cefadroxil concentrations with LPS treatment. Tissue-to-blood concentration ratios were decreased by 4.6-fold in the choroid plexus and by 2.5-fold in the kidneys during LPS-induced inflammation. Renal, but not choroid plexus, mRNA expression of peptide transporter 2, organic-anion transporter 1 (OAT1), OAT3, and multidrug resistance-associated protein 4 was mildly reduced in LPS-treated mice. The renal clearance of cefadroxil was substantially decreased by LPS treatment (3-fold). GFR was also reduced by 3-fold in LPS-treated mice, but no significant differences in the fractional reabsorption of cefadroxil and renal secretion once normalized by GFR were observed. These findings demonstrated that LPS-induced inflammation has a dramatic effect on the renal excretion of cefadroxil. It appears that changes in transporter expression played a minor role during LPS treatment but that renal dysfunction, associated with GFR reduction, was responsible for the substantial increase in plasma cefadroxil concentration-time profiles.
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Antibacterianos/farmacocinética , Cefadroxilo/farmacocinética , Inflamación/metabolismo , Riñón/efectos de los fármacos , Adyuvantes Farmacéuticos/farmacología , Animales , Antibacterianos/sangre , Antibacterianos/líquido cefalorraquídeo , Antibacterianos/orina , Área Bajo la Curva , Cefadroxilo/sangre , Cefadroxilo/líquido cefalorraquídeo , Cefadroxilo/orina , Expresión Génica/efectos de los fármacos , Tasa de Filtración Glomerular , Inflamación/inducido químicamente , Inflamación/fisiopatología , Riñón/metabolismo , Riñón/fisiopatología , Lipopolisacáridos , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteína 1 de Transporte de Anión Orgánico/genética , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Probenecid/farmacologíaRESUMEN
PURPOSE: To develop a population pharmacokinetic model to quantitate the distribution kinetics of glycylsarcosine (GlySar), a substrate of peptide transporter 2 (PEPT2), in blood, CSF and kidney in wild-type and PEPT2 knockout mice. METHODS: A stepwise compartment modeling approach was performed to describe the concentration profiles of GlySar in blood, CSF, and kidney simultaneously using nonlinear mixed effects modeling (NONMEM). The final model was selected based on the likelihood ratio test and graphical goodness-of-fit. RESULTS: The profiles of GlySar in blood, CSF, and kidney were best described by a four-compartment model. The estimated systemic elimination clearance, volume of distribution in the central and peripheral compartments were 0.236 vs 0.449 ml/min, 3.79 vs 4.75 ml, and 5.75 vs 9.18 ml for wild-type versus knockout mice. Total CSF efflux clearance was 4.3 fold higher for wild-type compared to knockout mice. NONMEM parameter estimates indicated that 77% of CSF efflux clearance was mediated by PEPT2 and the remaining 23% was mediated by the diffusional and bulk clearances. CONCLUSIONS: Due to the availability of PEPT2 knockout mice, we were able to quantitatively determine the significance of PEPT2 in the efflux kinetics of GlySar at the blood-cerebrospinal fluid barrier.
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Dipéptidos/sangre , Dipéptidos/líquido cefalorraquídeo , Simportadores/metabolismo , Animales , Transporte Biológico , Dipéptidos/metabolismo , Femenino , Riñón/metabolismo , Cinética , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Simportadores/genéticaRESUMEN
Human clearance prediction for small- and macro-molecule drugs was evaluated and compared using various scaling methods and statistical analysis. Human clearance is generally well predicted using single or multiple species simple allometry for macro- and small-molecule drugs excreted renally. The prediction error is higher for hepatically eliminated small-molecules using single or multiple species simple allometry scaling, and it appears that the prediction error is mainly associated with drugs with low hepatic extraction ratio (Eh). The error in human clearance prediction for hepatically eliminated small-molecules was reduced using scaling methods with a correction of maximum life span (MLP) or brain weight (BRW). Human clearance of both small- and macro-molecule drugs is well predicted using the monkey liver blood flow method. Predictions using liver blood flow from other species did not work as well, especially for the small-molecule drugs.
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Sustancias Macromoleculares/farmacocinética , Preparaciones Farmacéuticas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacocinética , Animales , Humanos , Hígado/irrigación sanguínea , Peso Molecular , Flujo Sanguíneo Regional , Especificidad de la EspecieRESUMEN
Hyaluronic acid (HA)-based microspheres containing PEG 6000 and/or sodium taurocholate (NaTC) were prepared by the spray-drying method for nasal delivery of fexofenadine hydrochloride (HCl). Their physicochemical properties including particle size and drug contents were determined, while their morphology examined by a scanning electron microscope (SEM). The effects of the solubilizer (PEG 6000) and the permeation enhancer (NaTC) on the in vitro release characteristics of fexofenadine x HCl were observed. Moreover, the in vitro permeation of fexofenadine x HCl was determined using the human nasal cell (HNE) monolayers cultured on Transwell inserts. After nasal administration, fexofenadine x HCl in rabbit plasma was determined by the LC-MS/MS system. Fexofenadine x HCl-loaded microspheres were of spherical shape with 20-30 microm mean diameter. The loading efficiency was about 95%. In vitro release of fexofenadine x HCl from the microspheres was significantly increased with the addition of PEG 6000. Although NaTC did not alter the in vitro release of drug from the microspheres, its addition further increased the in vitro permeation of fexofenadine x HCl across the HNE cell monolayers. Moreover, the bioavailability of fexofenadine x HCl after nasal administration of the microsphere formulation to rabbits was increased up to about 48% while that of the control solution was only about 3%. These results indicated that the HA microsphere formulation could further be developed into a clinically useful nasal delivery system of fexofenadine x HCl.