Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug-drug interaction study in patients with ALK + advanced tumors.

PURPOSE: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. METHODS: This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. RESULTS: Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. CONCLUSION: Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

[Metabolism of Sesamin and Drug-Sesamin Interaction].

　Sesamin, derived from sesame seeds, is known to have various biological effects. Since some of these effects appear to be derived from its metabolites, the elucidation of sesamin metabolism is essential to understanding the molecular mechanism of its effects. In addition, it is important to clarify drug-sesamin interactions in order to address safety concerns, as some food factors are known to affect drug metabolism. Our previous studies revealed that sesamin was sequentially metabolized by cytochrome P450 (CYP) and UDP-glucuronosyltransferase or sulfotransferase. Whereas sesamin metabolism is mainly mediated by CYP2C9 in human liver, sesamin causes a mechanism-based inhibition (MBI) of CYP2C9. However, we found that the metabolite-intermediate complex between CYP2C9 and sesamin was unstable, and the effects of sesamin appeared to be minimal. To confirm this assumption, in vivo studies using rats were conducted. After the administration of sesamin to rats for 3 d, diclofenac (an NSAID) was administered to measure the time course of plasma concentration of diclofenac. No significant differences were observed in the diclofenac Cmax, Tmax, and AUC0-24 h between the group that was administered sesamin and the group that was not. Based on these results, it could be concluded that no significant interaction occurs in people who take sesamin supplements at a standard dose.

Function of 38 variants CYP2C9 polymorphism on ketamine metabolism in vitro.

BACKGROUND: Cytochrome P450 proteins (CYP 450) is the most important enzyme system of drug phase I metabolism in liver. In previous reports, reduced efficiency or increased risk of adverse events can be affected by primary sequence mutation in CYP450. AIM: To investigate the effect of gene polymorphism on the metabolism of ketamine in vitro, including the new alleles: 2C9*58, *59 and *60. METHOD: Incubation system which was contained insect microsome, b5, NADPH and 1M PBS incubated 10 µM-1000 µM ketamine in 37 °C for 40 min concentration of norketamine was analyzed by ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS). RESULT: Catalytic activity of thirty-eight CYP2C9 alleles on ketamine metabolism to norketamine was surveyed. Compared with 2C9*1, three alleles (2C9*40, *49 and *51) was demonstrated dramatically increased intrinsic clearance (1.2-fold-3.75-fold); four subtypes (2C9*27, *31, *41 and *56) exhibited no significantly change on enzyme activity. The resting 31 alleles expressed different degrees of reduction compared with wild type. CONCLUSION: The result of research warns that attention should be more paid on individual who carry on the special 2C9 alleles under the situation of administrating ketamine.

Adverse event due to a likely interaction between sodium aescinate and ginkgo biloba extract: a case report.

WHAT IS KNOWN AND OBJECTIVE: Drug-induced nephrotoxicity is potentially lethal. When sodium aescinate is given to surgical inpatients to treat postoperative inflammation and oedema, adverse drug reactions and drug-drug interactions must be closely monitored. CASE DESCRIPTION: We report a case of a 58-year-old man with phalangeal fractures who suffered from acute kidney injury that was most likely induced by the drug interaction between sodium aescinate and ginkgo biloba extract due to the protein-binding and metabolic characteristics of these drugs. WHAT IS NEW AND CONCLUSION: Close monitoring and the prompt discontinuation of drugs that have high protein-binding capacity and hepatic metabolism are necessary to avoid drug-drug interactions in patients who are treated with sodium aescinate.

The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review.

WHAT IS KNOWN AND OBJECTIVES: Voriconazole is a triazole antifungal agent and is extensively metabolized via cytochrome P450 (CYP450); therefore, special precautions need to be taken when co-administered with a known CYP450 inducer, which may lead to treatment failure. The influence of some CYP450 inducers on the pharmacokinetics of voriconazole has been described in previous studies, but a systematic review was lacking. In this study, we carried out a systematic review to assess the influence of CYP450 inducers on the pharmacokinetic (PK) parameters of voriconazole. METHODS: Pubmed, Embase, Cochrane Library, Clinicaltrials.gov and three Chinese databases (CNKI, CBM and WanFang) were searched through January 2016. Interventional and observational studies comparing the PK parameters of voriconazole used alone or with CYP450 inducers in healthy volunteers and patients were included. The outcomes included were the area under the plasma concentration-time curve (AUC), peak plasma concentrations (Cmax ) and trough plasma concentrations (Cmin ). The quality of the included studies was assessed using Cochrane's risk of bias tool, Newcastle-Ottawa Scale (NOS) and a modified risk of bias tool for pharmacokinetic before-and-after studies. RESULTS AND DISCUSSION: Sixteen studies were included in this review: three randomized controlled trials (RCTs), five single-arm before-after studies (SBAs), six cohort studies and two case reports. All studies except case reports had moderate to high quality. Of the 11 inducers reviewed, efavirenz, ritonavir (chronic use), phenytoin, rifampin and rifabutin significantly decreased mean AUC and Cmax of voriconazole; St John's wort significantly decreased only mean AUC; rifampin, rifabutin, phenobarbital and carbamazepine significantly decreased mean Cmin . Etravirine and Ginkgo biloba did not reveal any such influence. The influence of glucocorticoids may depend on its type and dose. WHAT IS NEW AND CONCLUSIONS: To conclude, the combination use of high-dose efavirenz, high-dose ritonavir, St John's wort, rifampin, phenobarbital, or carbamazepine with voriconazole is contraindicated as instructed in the drug label. Low-dose efavirenz, low-dose ritonavir, rifabutin and phenytoin may be used together with voriconazole provided TDM and dose adjustment of voriconazole. Moreover, this study shows there is low risk of drug-drug interactions when voriconazole is co-administered with etravirine or G. biloba; however, whether the use of glucocorticoids has a clinically significant effect on voriconazole still requires more evidence. This study also highlights the lack of clinical studies and future high-quality studies assessing the influence of CYP450 inducers on voriconazole. PK parameters and dosing optimization should be designed to provide a more definitive answer regarding the necessity of TDM and the recommendations for dose adjustment of voriconazole.

CYP2C9 Genetic Polymorphism is a Potential Predictive Marker for the Efficacy of Rosuvastatin Therapy.

BACKGROUND: There is well-known inter-individual variability in the cholesterol-lowering effect of statins. However, inter-individual variability in response to rosuvastatin treatment in subjects with hypercholesterolemia has not been clearly established. This study aimed to evaluate the associations of CYP2C9 genetic polymorphism with the efficacy and safety of rosuvastatin in Chinese patients with hyperlipidemia. METHODS: A total of 218 patients with hyperlipidemia were selected and treated with 10 mg rosuvastatin per day for 12 weeks. Blood samples were collected prior to the treatment and after 4, 8, and 12 weeks of treatment. Clinical biochemistry analyses for serum lipid profiles were performed. Genotyping for CYP2C9 polymorphisms was performed using allele-specific real-time PCR. RESULTS: 197 out of 218 patients featured a wild-type CYP2C9*1/*1 genotype, and 21 patients featured a CYP2C9*1/*3 or CYP2C9*3/*3 mutation genotype. No patients with CYP2C9*2 alleles were identified. Sixteen patients discontinued the medication due to adverse effects. No serious adverse events (i.e., hepatotoxicity or myolysis) were observed. After the 12 weeks of treatment, we observed significant reductions in total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) levels compared to baseline (p < 0.05). Patients with the mutant genotype showed a higher TC-lowering and LDL-lowing effect compared to those with wild-type genotypes (TC: 45.05% vs. 38.96%, p = 0.041; LDL: 44.97% vs. 39.28%, p = 0.029). The frequency of adverse drug reactions in the studied patients did not differ by CYP2C9 genotypes (p > 0.05). CONCLUSIONS: This study suggests that the CYP2C9 polymorphism may be involved in the lipid-lowering efficacy of rosuvastatin in patients with hyperlipidemia.

[Drug resistant epilepsy. Clinical and neurobiological concepts]. / Farmacorresistencia en epilepsia. Conceptos clínicos y neurobiológicos.

Drug-resistant epilepsy, is a condition defined by the International League Against Epilepsy as persistent seizures despite having used at least two appropriate and adequate antiepileptic drug treatments. Approximately 20-30% of patients with epilepsy are going to be resistant to antiepileptic drugs, with different patterns of clinical presentation, which are related to the biological basis of this disease (de novo resistance, relapsing-remitting and progressive). Drug resistant epilepsy, impacts negatively the quality of life and significantly increases the risk of premature death. From the neurobiological point of view, this medical condition is the result of the interaction of multiple variables related to the underlying disease, drug interactions and proper genetic aspects of each patient. Thanks to advances in pharmacogenetics and molecular biology research, currently some hypotheses may explain the cause of this condition and promote the study of new therapeutic options. Currently, overexpression of membrane transporters such as P-glycoprotein, appears to be one of the most important mechanisms in the development of drug resistant epilepsy. The objective of this review is to deepen the general aspects of this clinical condition, addressing the definition, epidemiology, differential diagnosis and the pathophysiological bases.

TITLE: Farmacorresistencia en epilepsia. Conceptos clinicos y neurobiologicos.La epilepsia farmacorresistente es una condicion definida por la Liga Internacional contra la Epilepsia como la persistencia de crisis epilepticas a pesar de haber utilizado al menos dos tratamientos con farmacos antiepilepticos apropiados y adecuados. Cerca de un 20-30% de los pacientes con epilepsia van a ser resistentes a los farmacos antiepilepticos, con diferentes patrones de presentacion clinica, los cuales estan en relacion con las bases biologicas de esta enfermedad (resistencia de novo, recaida-remision y progresiva). La farmacorresistencia en epilepsia impacta negativamente en la calidad de vida y aumenta significativamente el riesgo de muerte prematura. Desde el punto de vista neurobiologico, esta condicion clinica es el resultado de la interaccion de multiples variables relacionadas con la enfermedad de base, las interacciones medicamentosas y los aspectos geneticos propios de cada paciente. Gracias a los avances en la investigacion farmacogenetica y de biologia molecular, actualmente se plantean algunas hipotesis que podrian explicar la causa de esta condicion y que promueven el estudio de nuevas opciones terapeuticas. En la actualidad, la sobreexpresion de transportadores de membrana, como la glucoproteina P, parece ser uno de los mecanismos mas importantes en el desarrollo de la farmacorresistencia en epilepsia. El objetivo de esta revision es profundizar en los aspectos generales de esta condicion clinica, abordando la definicion, los aspectos epidemiologicos, los diagnosticos diferenciales y las bases fisiopatologicas.