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1.
CPT Pharmacometrics Syst Pharmacol ; 9(12): 695-706, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33049120

RESUMO

Elevated serum creatinine (SCr ) caused by the inhibition of renal transporter(s) may be misinterpreted as kidney injury. The interpretation is more complicated in patients with chronic kidney disease (CKD) due to altered disposition of creatinine and renal transporter inhibitors. A clinical study was conducted in 17 patients with CKD (estimated glomerular filtration rate 15-59 mL/min/1.73 m2 ); changes in SCr were monitored during trimethoprim treatment (100-200 mg/day), administered to prevent recurrent urinary infection, relative to the baseline level. Additional SCr -interaction data with trimethoprim, cimetidine, and famotidine in patients with CKD were collated from the literature. Our published physiologically-based creatinine model was extended to predict the effect of the CKD on SCr and creatinine-drug interaction. The creatinine-CKD model incorporated age/sex-related differences in creatinine synthesis, CKD-related glomerular filtration deterioration; change in transporter activity either proportional or disproportional to glomerular filtration rate (GFR) decline were explored. Optimized models successfully recovered baseline SCr from 64 patients with CKD (geometric mean fold-error of 1.1). Combined with pharmacokinetic models of inhibitors, the creatinine model was used to simulate transporter-mediated creatinine-drug interactions. Use of inhibitor unbound plasma concentrations resulted in 66% of simulated SCr interaction data within the prediction limits, with cimetidine interaction significantly underestimated. Assuming that transporter activity deteriorates disproportional to GFR decline resulted in higher predicted sensitivity to transporter inhibition in patients with CKD relative to healthy patients, consistent with sparse clinical data. For the first time, this novel modelling approach enables quantitative prediction of SCr in CKD and delineation of the effect of disease and renal transporter inhibition in this patient population.


Assuntos
Creatinina/sangue , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Insuficiência Renal Crônica/sangue , Trimetoprima/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cimetidina/farmacocinética , Simulação por Computador , Inibidores do Citocromo P-450 CYP1A2/farmacocinética , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/uso terapêutico , Interações Medicamentosas , Famotidina/farmacocinética , Feminino , Taxa de Filtração Glomerular/fisiologia , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Trimetoprima/administração & dosagem , Trimetoprima/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/prevenção & controle
2.
Bioorg Med Chem Lett ; 30(21): 127571, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32980515

RESUMO

NLRP3 inflammasome mediated release of interleukin-1ß (IL-1ß) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1ß IC50 = 35 nM; IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.


Assuntos
Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Compostos de Sulfonilureia/farmacologia , Administração Oral , Animais , Betacoronavirus , COVID-19 , Linhagem Celular Tumoral , Infecções por Coronavirus , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/síntese química , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Inibidores do Citocromo P-450 CYP2C8/farmacologia , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Inibidores do Citocromo P-450 CYP2C9/síntese química , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Cães , Estabilidade de Medicamentos , Humanos , Interleucina-1beta/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pandemias , Pneumonia Viral , Ratos , SARS-CoV-2 , Relação Estrutura-Atividade , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacocinética
3.
Clin Pharmacol Drug Dev ; 9(2): 214-223, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31287236

RESUMO

In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Compostos Organofosforados/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Adulto , Idoso , Quinase do Linfoma Anaplásico/metabolismo , Área Sob a Curva , Estudos Cross-Over , Indutores do Citocromo P-450 CYP2B6/administração & dosagem , Indutores do Citocromo P-450 CYP2B6/farmacocinética , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Genfibrozila/administração & dosagem , Genfibrozila/farmacocinética , Voluntários Saudáveis , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Rifampina/administração & dosagem , Rifampina/farmacocinética
4.
Clin Pharmacol Ther ; 104(3): 495-504, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29171020

RESUMO

The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y12 inhibitors on montelukast pharmacokinetics. Clopidogrel (300 mg on day 1 and 75 mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC0-7h ratio to 45% of control (90% CI 40-50%, P < 0.001). Prasugrel (60 mg on day 1 and 10 mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.


Assuntos
Acetatos/farmacocinética , Clopidogrel/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/efeitos adversos , Citocromo P-450 CYP2C8/metabolismo , Antagonistas de Leucotrienos/farmacocinética , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Quinolinas/farmacocinética , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/sangue , Adulto , Clopidogrel/administração & dosagem , Simulação por Computador , Estudos Cross-Over , Ciclopropanos , Citocromo P-450 CYP2C8/genética , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Inativação Metabólica , Antagonistas de Leucotrienos/administração & dosagem , Antagonistas de Leucotrienos/efeitos adversos , Antagonistas de Leucotrienos/sangue , Masculino , Modelos Biológicos , Oxirredução , Farmacogenética , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/administração & dosagem , Cloridrato de Prasugrel/administração & dosagem , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/sangue , Medição de Risco , Especificidade por Substrato , Sulfetos , Adulto Jovem
5.
Biol Pharm Bull ; 40(7): 1078-1085, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28674251

RESUMO

Fluvastatin, which is one of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4 and CYP2C8. Predictions of drug-drug interactions (DDI) are important for the safety of combination therapies with statins, in particular drugs that are metabolized by CYP3A4. Little information is available regarding drug interactions with fluvastatin. Since CYP2C9 is a polymorphic enzyme, we investigated the effect of DDI via CYP2C9, CYP3A4, and CYP2C8 on fluvastatin pharmacokinetics by using a validated prediction method in relation to CYP2C9 variants. The predicted increases in the area under the concentration-time curve (AUC) ratios of fluvastatin in carriers with CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 versus that found in carriers with CYP2C9*1/*1 were 1.16, 1.35, 1.37, 1.65, and 2.06, respectively. Our in silico model predicted that administration of fluvastatin in conjunction with the potent inhibitors that completely inhibited CYP3A4 and CYP2C8 in carriers with the CYP2C9*3/*3 variant would cause a 3.23- and 2.60-fold increase in the AUC ratios, respectively, when compared to that for the carriers with the CYP2C9*1/*1 taking fluvastatin alone. We also predicted the effect of telmisartan when coadministered with fluvastatin. Our prediction results showed that the interaction between telmisartan and fluvastatin via CYP enzymes were negligible in clinical situations.


Assuntos
Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Citocromo P-450 CYP2C9/genética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Indóis/administração & dosagem , Mutação , Área Sob a Curva , Ácidos Graxos Monoinsaturados/farmacocinética , Fluvastatina , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Indóis/farmacocinética
6.
Br J Clin Pharmacol ; 83(12): 2778-2788, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28715853

RESUMO

AIMS: Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8. METHODS: The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects. RESULTS: Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (Cmax ) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the Cmax of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0-∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its Cmax 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0-∞ by half (90% CI 0.45, 0.59). CONCLUSION: Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged.


Assuntos
Acetamidas/farmacocinética , Acetatos/farmacocinética , Anti-Hipertensivos/farmacocinética , Indutores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Genfibrozila/administração & dosagem , Pró-Fármacos/farmacocinética , Pirazinas/farmacocinética , Rifampina/administração & dosagem , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Acetamidas/sangue , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/sangue , Ativação Metabólica , Adolescente , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP2C8/metabolismo , Indutores do Citocromo P-450 CYP2C8/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/efeitos adversos , Interações Medicamentosas , Genfibrozila/efeitos adversos , Alemanha , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/sangue , Rifampina/efeitos adversos , Medição de Risco , Adulto Jovem
7.
Basic Clin Pharmacol Toxicol ; 121(3): 169-174, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28374976

RESUMO

Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than those in wild-type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates.


Assuntos
Inibidores do Citocromo P-450 CYP2C8/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Genfibrozila/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , PPAR alfa/agonistas , Animais , Citocromo P-450 CYP2B1/química , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2B1/metabolismo , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/genética , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Genfibrozila/administração & dosagem , Hipolipemiantes/administração & dosagem , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/metabolismo
8.
Drug Metab Dispos ; 44(8): 1364-71, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27260150

RESUMO

The glucose-lowering drug pioglitazone undergoes hepatic CYP2C8-mediated biotransformation to its main metabolites. The antiplatelet drug clopidogrel is metabolized to clopidogrel acyl-ß-d-glucuronide, which was recently found to be a strong time-dependent inhibitor of CYP2C8 in humans. Therefore, we studied the effect of clopidogrel on the pharmacokinetics of pioglitazone. In a randomized crossover study, 10 healthy volunteers ingested either 300 mg of clopidogrel on day 1, and 75 mg on days 2 and 3, or placebo. Pioglitazone 15 mg was administered 1 hour after placebo and clopidogrel on day 1. Plasma concentrations of pioglitazone, clopidogrel, and their main metabolites were measured up to 72 hours. Clopidogrel increased the area under the plasma concentration-time curve (AUC0-∞) of pioglitazone 2.1-fold [P < 0.001, 90% confidence interval (CI) 1.8-2.6] and prolonged its half-life from 6.7 to 11 hours (P = 0.002). The peak concentration of pioglitazone was unaffected but the concentration at 24 hours was increased 4.5-fold (range 1.6-9.8; P < 0.001, 90% CI 3.17-6.45) by clopidogrel. The M-IV-to-pioglitazone AUC0-∞ ratio was 49% (P < 0.001, 90% CI 0.40-0.59) of that during the control phase, indicating that clopidogrel inhibited the CYP2C8-mediated biotransformation of pioglitazone. Clopidogrel increases the exposure to pioglitazone by inhibiting its CYP2C8-mediated biotransformation. In consequence, use of clopidogrel may increase the risk of fluid retention and other concentration-related adverse effects of pioglitazone.


Assuntos
Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Citocromo P-450 CYP2C8/metabolismo , Hipoglicemiantes/sangue , Inibidores da Agregação Plaquetária/administração & dosagem , Tiazolidinedionas/sangue , Ticlopidina/análogos & derivados , Administração Oral , Adulto , Área Sob a Curva , Biotransformação , Clopidogrel , Estudos Cross-Over , Citocromo P-450 CYP2C8/genética , Inibidores do Citocromo P-450 CYP2C8/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Feminino , Finlândia , Genótipo , Meia-Vida , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Masculino , Taxa de Depuração Metabólica , Variantes Farmacogenômicos , Fenótipo , Pioglitazona , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/sangue , Inibidores da Agregação Plaquetária/farmacocinética , Medição de Risco , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/farmacocinética , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/sangue , Ticlopidina/farmacocinética , Adulto Jovem
9.
Br J Clin Pharmacol ; 81(2): 313-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26446447

RESUMO

AIM: The aim of the present case report was to describe a novel pharmacokinetic drug­drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel. METHODS: The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-ß-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry. RESULTS: The patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176­726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 µM clopidogrel acyl-ß-D-glucuronide inhibited the depletion rate of 0.5 µM paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%. CONCLUSION: This is the first report of a clopidogrel­paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/sangue , Síndromes Neurotóxicas/etiologia , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/efeitos adversos , Ticlopidina/análogos & derivados , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/metabolismo , Clopidogrel , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Neurotóxicas/sangue , Neoplasias Ovarianas/sangue , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Paclitaxel/uso terapêutico , Ticlopidina/administração & dosagem , Ticlopidina/sangue , Ticlopidina/uso terapêutico
10.
Clin Pharmacokinet ; 54(10): 1057-69, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25929560

RESUMO

BACKGROUND AND OBJECTIVES: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). METHODS: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). RESULTS: Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. CONCLUSIONS: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.


Assuntos
Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Humanos , Masculino , Midazolam/farmacocinética , Pessoa de Meia-Idade , Nitrilas , Feniltioidantoína/administração & dosagem , Feniltioidantoína/farmacocinética , Neoplasias de Próstata Resistentes à Castração/enzimologia
11.
Clin Pharmacol Drug Dev ; 4(1): 56-62, 2015 01.
Artigo em Inglês | MEDLINE | ID: mdl-27128003

RESUMO

PURPOSE: To evaluate the potential effects of vorapaxar on the pharmacokinetics and safety of rosiglitazone. METHODS: This was an open-label, two-period, two-treatment, fixed-sequence study in 18 healthy subjects. On Day 1, Period 1, subjects received a single dose of rosiglitazone 8 mg. In Period 2, subjects received vorapaxar 40 mg on Day 1, vorapaxar 7.5 mg once-daily on Days 2-7, and a single dose of rosiglitazone 8 mg on Day 7. Rosiglitazone and N-desmethylrosiglitazone pharmacokinetics were assessed alone (Period 1) and after coadministration with vorapaxar (Period 2). Vorapaxar and its M20 metabolite pharmacokinetics were assessed on Day 7, Period 2. Safety and tolerability were assessed throughout the study. RESULTS: Coadministration of rosiglitazone with vorapaxar had no effect on rosiglitazone or N-desmethylrosiglitazone pharmacokinetics. The ratio of geometric means (GMR) and 90% confidence intervals (CI) of the coadministration versus monotherapy for Cmax (GMR 95; 90% CI 88, 103) and AUC0-24 h (GMR 103; 90% CI 98, 108) were within the 80-125% bioequivalence criteria. The metabolite-to-parent exposure ratio with and without vorapaxar was unaltered. Coadministration of vorapaxar with rosiglitazone was generally well tolerated. CONCLUSION: Coadministration of vorapaxar with rosiglitazone or drugs metabolized via CYP2C8 is unlikely to cause a significant pharmacokinetic interaction.


Assuntos
Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Hipoglicemiantes/farmacocinética , Lactonas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Piridinas/administração & dosagem , Receptor PAR-1/antagonistas & inibidores , Tiazolidinedionas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Biotransformação , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/efeitos adversos , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Lactonas/efeitos adversos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , North Dakota , Inibidores da Agregação Plaquetária/efeitos adversos , Piridinas/efeitos adversos , Receptor PAR-1/metabolismo , Rosiglitazona , Equivalência Terapêutica , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/sangue , Adulto Jovem
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