RESUMEN
This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for C max, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for C max, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied intravenous microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic drug-drug interaction understanding.
Asunto(s)
Ciclosporina/farmacocinética , Ácidos Indolacéticos/farmacocinética , Piridinas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Administración Intravenosa , Administración Oral , Adolescente , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Ciclosporina/administración & dosificación , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Ácidos Indolacéticos/administración & dosificación , Masculino , Persona de Mediana Edad , Piridinas/administración & dosificación , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Adulto JovenRESUMEN
Fevipiprant, a prostaglandin D2 receptor 2 antagonist, is in clinical development as a treatment for asthma. The goal of this study was to assess the potential of fevipiprant to cause drug-drug interactions (DDI) as a perpetrator, that is, by altering the pharmacokinetics (PK) of co-medications. In vitro drug interaction studies of clinically relevant drug metabolizing enzymes and transporters were conducted for fevipiprant and its acyl glucuronide (AG) metabolite. Comparison of Ki values with unbound systemic or portal vein steady-state plasma exposure of fevipiprant and its AG metabolite revealed the potential for inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) transporters (R-value of 5.99), while other targets including cytochrome P450 enzymes were not, or only marginally, inhibited. Consequently, an open-label, two-part, two-period, single-sequence clinical study assessed the effect of fevipiprant 450â¯mg QD on the pharmacokinetics of simvastatin 20â¯mg and rosuvastatin 20â¯mg, two statins with different dependency in OATP1B1-mediated hepatic uptake, in healthy adult volunteers. The study also assessed the pharmacogenetics of the SLCO1B1 gene, which encodes OATP1B1. Clinically, fevipiprant 450â¯mg QD showed a low potential for interaction and increased the peak concentrations of simvastatin acid and rosuvastatin by 2.23- and 1.87-fold, respectively, with little or no impact on total exposure. Genotype analysis confirmed that SLCO1B1 genotype influences statin pharmacokinetics to a similar extent either with or without fevipiprant co-administration. In summary, fevipiprant at 450â¯mg QD has only minor liabilities as a perpetrator for DDI.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Ácidos Indolacéticos/farmacología , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Piridinas/farmacología , Rosuvastatina Cálcica/farmacocinética , Simvastatina/farmacocinética , Adulto , Interacciones Farmacológicas , Femenino , Genotipo , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico , Farmacogenética , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidoresRESUMEN
We evaluated the pharmacokinetics (PK), safety, and tolerability of a novel oral CRTh2 antagonist, fevipiprant (QAW039), in healthy subjects. Peak concentrations of fevipiprant in plasma were observed 1-3 hours postdosing. Concentrations declined in a multiexponential manner, followed by an apparent terminal phase (t1/2 , â¼20 hours). Steady state was achieved in 4 days with <2-fold accumulation. Elimination was partly by renal excretion (≤30% of the dose) and glucuronidation. Food had minimal impact on the PK of fevipiprant, and it was well tolerated at single and multiple oral doses up to 500 mg/day. No dose-dependent adverse events were observed, and all the events were mild or moderate in severity. Systemic concentrations were sufficiently high to achieve relevant target occupancy, considering in vitro pharmacology data. In summary, the data support further development as a once-daily oral therapy for allergic diseases.
Asunto(s)
Interacciones Alimento-Droga , Ácidos Indolacéticos/administración & dosificación , Piridinas/administración & dosificación , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Humanos , Ácidos Indolacéticos/efectos adversos , Ácidos Indolacéticos/farmacocinética , Masculino , Persona de Mediana Edad , Piridinas/efectos adversos , Piridinas/farmacocinéticaRESUMEN
For antibody drug conjugates (ADCs), the fate of the cytotoxic payload in vivo needs to be well understood to mitigate toxicity risks and properly design the first in-patient studies. Therefore, a distribution, metabolism, and excretion (DME) study with a radiolabeled rat cross-reactive ADC ([(3)H]DM1-LNL897) targeting the P-cadherin receptor was conducted in female tumor-bearing nude rats. Although multiple components [total radioactivity, conjugated ADC, total ADC, emtansine (DM1) payload, and catabolites] needed to be monitored with different technologies (liquid scintillation counting, liquid chromatography/mass spectrometry, enzyme-linked immunosorbent assay, and size exclusion chromatography), the pharmacokinetic data were nearly superimposable with the various techniques. [(3)H]DM1-LNL897 was cleared with half-lives of 51-62 hours and LNL897-related radioactivity showed a minor extent of tissue distribution. The highest tissue concentrations of [(3)H]DM1-LNL897-related radioactivity were measured in tumor. Complimentary liquid extraction surface analysis coupled to micro-liquid chromatography-tandem mass spectrometry data proved that the lysine (LYS)-4(maleimidylmethyl) cyclohexane-1-carboxylate-DM1 (LYS-MCC-DM1) catabolite was the only detectable component distributed evenly in the tumor and liver tissue. The mass balance was complete with up to 13.8% ± 0.482% of the administered radioactivity remaining in carcass 168 hours postdose. LNL897-derived radioactivity was mainly excreted via feces (84.5% ± 3.12%) and through urine only to a minor extent (4.15% ± 0.462%). In serum, the major part of radioactivity could be attributed to ADC, while small molecule disposition products were the predominant species in excreta. We show that there is a difference in metabolite profiles depending on which derivatization methods for DM1 were applied. Besides previously published results on LYS-MCC-DM1 and MCC-DM1, maysine and a cysteine conjugate of DM1 could be identified in serum and excreta.
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Anticuerpos/metabolismo , Antineoplásicos Fitogénicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Inmunoconjugados/farmacocinética , Maitansina/farmacocinética , Administración Intravenosa , Animales , Anticuerpos/administración & dosificación , Anticuerpos/sangre , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Biotransformación , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Cadherinas/inmunología , Cadherinas/metabolismo , Línea Celular Tumoral , Heces/química , Femenino , Semivida , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/sangre , Maitansina/administración & dosificación , Maitansina/sangre , Tasa de Depuración Metabólica , Ratas Desnudas , Distribución TisularRESUMEN
RATIONALE: Antibody-drug conjugates (ADCs) are some of the most promising antibody-related therapeutics. The fate of the cytotoxic moiety of ADCs in vivo after proteolytic degradation of the antibody needs to be well understood in order to mitigate toxicity risks and design proper first in patient studies. METHODS: The feasibility of liquid extraction surface analysis micro-capillary liquid chromatography/tandem mass spectrometry (LESA-µLC/MS/MS) was tested for direct surface sampling of two possible ADC catabolites composed of synthetically modified maytansinoid (DM1) and 4-[N-maleimidomethyl]cyclohexane-1-carbonyl (MCC) from rat liver and tumor tissue. Moreover, the iMatrixSpray was incorporated to prepare calibration standards (Cs) and quality control (QC) samples by spraying analyte solution at different concentrations directly on blank tissue. RESULTS: Lys-MCC-DM1 sprayed on blank liver tissue was homogeneously distributed (12.3% variability). The assay was selective (inference ≤20%) and linear from 50.0 to 1000 ng/mL without any carry-over. Inter-run accuracy and precision were ≤2.3% and ≤25.9% meeting acceptance. Lys-MCC-DM1 was the only catabolite detected in liver and tumor tissue and was most likely responsible for the total radioactivity signal in liver tissue 72 h post-dose measured by quantitative whole body autoradiography (QWBA). CONCLUSIONS: Both analytical assays (LESA-µLC/MS/MS and QWBA) are complementary to each other and provide useful quantitative and qualitative information in spatial tissue distribution of ADCs and their related catabolites. Copyright © 2016 John Wiley & Sons, Ltd.
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Antineoplásicos/análisis , Inmunoconjugados/análisis , Extracción Líquido-Líquido/métodos , Hígado/química , Neoplasias/química , Espectrometría de Masas en Tándem/métodos , Animales , Antineoplásicos/metabolismo , Cromatografía Liquida/métodos , Inmunoconjugados/metabolismo , Modelos Lineales , Maleimidas , Maitansina , Modelos Biológicos , Imagen Molecular , Ratas , Reproducibilidad de los ResultadosRESUMEN
Adequate monitoring of internal standard (IS) response across an analytical run and identification of anomalies is now a common expectation. However, the means to conduct this assessment in an appropriate manner is unclear and differs widely between laboratories. A European Bioanalysis Forum (EBF) topic team was formed to survey current practices within European Bioanalysis Forum member companies and to recommend a best practice approach for dealing with IS response variability.
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Proyectos de Investigación , Europa (Continente) , HumanosRESUMEN
Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (l-Dopa)-induced dyskinesias (LID). This study investigated the novel selective α7 nAChR partial agonist (R)-3-(6-ρ-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo(2.2.2)octane (AQW051) for its antidyskinetic activity in l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus monkeys. Six MPTP monkeys were repeatedly treated with l-Dopa to develop reproducible dyskinesias. AQW051 (2, 8, and 15 mg/kg) administered 1 h before l-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the l-Dopa antiparkinsonian response, by 30 min at the highest AQW051 dose (15 mg/kg). Dyskinesias were significantly reduced for the total period of l-Dopa effect following treatment with 15 mg/kg; achieving a reduction of 60% in median values. Significant reductions in 1 h peak dyskinesia scores and maximal dyskinesias were also observed with AQW051 (15 mg/kg). To understand the exposure-effect relationship and guide dose selection in clinical trials, plasma concentration-time data for the 15 mg/kg AQW051 dose were collected from three of the MPTP monkeys in a separate pharmacokinetic experiment. No abnormal behavioral or physiological effects were reported following AQW051 treatment. Our results show that AQW051 at a high dose can reduce LID without compromising the benefits of l-Dopa and extend the duration of the l-Dopa antiparkinsonian response in MPTP monkeys. This supports the clinical testing of α7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of l-Dopa.
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Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Intoxicación por MPTP/tratamiento farmacológico , Agonistas Nicotínicos/uso terapéutico , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/etiología , Femenino , Macaca fascicularis , Actividad Motora/efectos de los fármacos , Ovariectomía , Factores de TiempoRESUMEN
A sensitive and ultra-fast method utilizing the laser diode thermal desorption ion source using atmospheric pressure chemical ionization coupled to tandem mass spectrometry (LDTD-APCI-MS/MS) was developed for the quantitative analysis of BKM120, an investigational anticancer drug in human plasma. Samples originating from protein precipitation (PP) followed by salting-out assisted liquid-liquid extraction (SALLE) were spotted onto the LazWell™ plate prior to their thermal desorption and detection by tandem mass spectrometry in positive mode. The validated method described in this paper presents a high absolute extraction recovery (>90 %) for BKM120 and its internal standard (ISTD) [D8]BKM120, with precision and accuracy meeting the acceptance criteria. Standard curves were linear over the range of 5.00 to 2000 ng mL(-1) with a coefficient of determination (R (2)) >0.995. The method specificity was demonstrated in six different batches of human plasma. Intra- and inter-run precision as well as accuracy within ±20 % at the lower limit of quantification (LLOQ) and ±15 % (other levels) were achieved during a three-run validation for quality control (QC) samples. The post-preparative stability on the LazWell™ plate at room temperature was 72 h and a 200-fold dilution of spiked samples was demonstrated. The method was applied successfully to three clinical studies (n = 847) and cross-checked with the validated LC-ESI-MS/MS reference method. The sample analysis run time was 10 s as compared to 4.5 min for the current validated LC-ESI-MS/MS method. The resultant data were in agreement with the results obtained using the validated reference LC-ESI-MS/MS assay and the same pharmacokinetic (PK) parameters were calculated for both analytical assays. This work demonstrates that LDTD-APCI-MS/MS is a reliable method for the ultra-fast quantitative analysis of BKM120 which can be used to speed-up and support its bioanalysis in the frame of the clinical trials.
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Aminopiridinas/sangre , Rayos Láser , Extracción Líquido-Líquido/métodos , Morfolinas/sangre , Plasma/química , Espectrometría de Masas en Tándem/métodos , Atmósfera , Presión Atmosférica , Calibración , Química Farmacéutica/métodos , Cromatografía Liquida , Humanos , Modelos Lineales , Control de Calidad , Valores de Referencia , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray , Temperatura , Factores de TiempoRESUMEN
An improved extraction procedure and a new RP-HPLC method were developed for selective and rapid analysis of caffeine and 14 of its metabolites in urine. Analytes were isolated by solid-phase extraction and separated on an Eclipse XDB-C18 column. Recoveries ranged between 83 and 99%. Precision, linearity and accuracy of the chromatographic method were found to be within required limits. Using this procedure, caffeine metabolic ratios were determined in 20 subjects with characteristic CYP1A2 activities, relatively to smoking habit and contraceptives intake. The method might be useful to point out induction and inhibition of CYP1A2 activity.