There are 14 clinical trials
LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Phase 1 studies demonstrated greater bioavailability than twice-daily tacrolimus capsules and no new safety concerns. - Stable kidney transplant patients can be safely converted from Adoport® twice-daily to LCP-Tacro®. - The greater bioavailability of LCP-Tacro after once-daily dosing results in similar (AUC) exposure, at a dose approximately 30% less, than the total daily dose of Adoport®. - LCP-Tacro provides a slow drug release and this results in flatter kinetics characterized by significantly lower peak-trough fluctuations. - CN is the major cellular target of the calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus. The ability of these drugs to inhibit CN activity is dependent on their binding to the respective immunophilins, cyclophilins A and B for CsA and FKBP12 for tacrolimus. - CN inhibition is a rate limiting phenomenon. Over concentrations of tacrolimus does not correlate with an increase in the CN activity.
Set TAC trough concentrations for optimal inhibition of CN.. drug exposure according to CYP3A (CYP3A4 and CYP3A5 * 22 * 3) and ABCB1 (C3435T) polymorphism.. Analysis of drug exposure according to CYP3A (CYP3A4 and CYP3A5 * 22 * 3) and ABCB1 (C3435T) polymorphism.. Inclusion Criteria: - Adult patients (≥ 18 years). --- C3435T ---
Set TAC trough concentrations for optimal inhibition of CN.. drug exposure according to CYP3A (CYP3A4 and CYP3A5 * 22 * 3) and ABCB1 (C3435T) polymorphism.. Analysis of drug exposure according to CYP3A (CYP3A4 and CYP3A5 * 22 * 3) and ABCB1 (C3435T) polymorphism.. Inclusion Criteria: - Adult patients (≥ 18 years). --- C3435T --- --- C3435T ---
Description: The main objective of this study is to compare the area under the curve (AUC) of CN activity after administration of a sustained release formulation (LCP- Tacro, Envarsus®) compared to an immediate release formulation (Prograf®) of TAC in renal transplant patients.
Measure: Area under the curve (AUC) of CN activity Time: Baseline and 35 days post conversionDescription: Pharmacokinetic study AUC 0-24 h of each TAC formulation 12h (Prograf®) and the new formulation of TAC every 24h (LCP- Tacro, Envarsus®).
Measure: Area Under the curve 0-24 h of each TAC formulation Time: Baseline and 35 days post conversionDescription: Study PK / PD: relationship PK TAC (drug exposure) and PD (activity CN) of both formulations. Set TAC trough concentrations for optimal inhibition of CN.
Measure: TAC trough concentrations for optimal inhibition of CN Time: Baseline and 35 days post conversionDescription: Analysis of drug exposure according to CYP3A (CYP3A4 and CYP3A5 * 22 * 3) and ABCB1 (C3435T) polymorphism.
Measure: drug exposure according to CYP3A (CYP3A4 and CYP3A5 * 22 * 3) and ABCB1 (C3435T) polymorphism. Time: Baseline and 35 days post conversionAn evaluation of the effects of genetically determined variant metabolizing and transporting proteins involved in the disposition of the immunosuppressive drug tacrolimus in renal transplant recipients. In a five year follow-up study tacrolimus dose-corrected exposure changes significantly and the effect(s) of single nucleotide polymorphisms of the CYP3A4/CYP3A5 and MDR1 genes on the latter is assessed in this study.
The effects of the CYP3A5*1, CYP3A4*1B, MDR1 G2677T/A and C3435T single nucleotide polymorphisms on the evolution of tacrolimus disposition are studied over 5 years in order to clarify the interrelationship between CYP3A5, CYP3A4 and MDR1 genotypes, time-dependent exposure and tacrolimus-related toxicity. --- G2677T --- --- C3435T ---
The main purpose of this study is to provide dose-guiding information by assessing the safety and tolerability of 4 different dosing regimens of an extended-release (ER) formulation of AZD0837 compared with well-controlled, dose-adjusted Vitamin-K antagonists (VKA) (aiming for an international normalized ratio (INR) 2.0 to 3.0) in patients with non-valvular atrial fibrillation (AF) with one or more additional risk factors for stroke.
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT. --- C3435T ---
Oral clearance of AR-H067637XX in subgroup of patients with genotype TT for gene polymorphism ABCB1 C3435T. --- C3435T ---
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC. --- C3435T ---
Oral clearance of AR-H067637XX in subgroup of patients with genotype TC for gene polymorphism ABCB1 C3435T. --- C3435T ---
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC. --- C3435T ---
Oral clearance of AR-H067637XX in subgroup of patients with genotype CC for gene polymorphism ABCB1 C3435T. --- C3435T ---
Description: Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once
Measure: Bleeding Events Time: 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit)Description: Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)
Measure: Creatinine Time: 12 weeks according to protocol.(baseline to week 12 visit)Description: Number of patients while on study drug with ALAT>=3 times upper limit of normal.l
Measure: Alanine Aminotransferase (ALAT) Time: 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit)Description: Number of patients while on study drug with Bilirubin>=2 times upper limit of normal
Measure: Bilirubin Time: 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit)Description: Change in D-Dimer values from enrolment to week 12 visit for VKA naïve patients while on study drug (week 12 visit-enrolment)
Measure: D-Dimer Time: 14 weeks according to protocol.(enrolment to week 12 visit)Description: Change in Activated partial thromboplastin time (APTT) from baseline to week 12 visit for VKA naïve patients while on study drug (week 12 visit-baseline)
Measure: Activated Partial Thromboplastin Time (APTT) Time: 12 weeks according to protocol.(baseline to week 12 visit)Description: Change in Ecarin clotting time (ECT) from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)
Measure: Ecarin Clotting Time (ECT) Time: 12 weeks according to protocol.(baseline to week 12 visit)Description: Assessment made on the week 12 visit
Measure: Plasma Concentration of AZD0837 (Prodrug) Time: 12 weeks after baseline according to protocolDescription: Assessment made on the week 12 visit
Measure: Plasma Concentration of AR-H067637XX (Active Metabolite) Time: 12 weeks after baseline according to protocolDescription: Oral clearance of AR-H067637XX in subgroup of patients with genotype TT for gene polymorphism ABCB1 C3435T
Measure: Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT Time: 36 weeks according to protocolDescription: Oral clearance of AR-H067637XX in subgroup of patients with genotype TC for gene polymorphism ABCB1 C3435T
Measure: Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC Time: 36 weeks according to protocolDescription: Oral clearance of AR-H067637XX in subgroup of patients with genotype CC for gene polymorphism ABCB1 C3435T
Measure: Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC Time: 36 weeks according to protocolThirty-two healthy volunteers will be submitted to experimental pain and on the 2 study days receive Oxycodone 20 mg po vs. placebo. Half of the volunteers will be poor metabolizers according to CYP2D6 genotype and half will be extensive metabolizers (EM) and have an enzyme with normal function. The study hypothesis is that PM will experience less pain relief than EM.
Among these are the A118G SNP in the μ-receptor gene OPRM1 and the C3435T and G2677T/A SNPs in the MDR-1 gene of P-glycoprotein. --- A118G --- --- C3435T ---
Patients undergoing surgery (thyroidectomy and hysterectomy) will postoperatively receive oxycodone intravenously (IV) as pain management with morphine as an escape medicine, if there is insufficient pain relief with oxycodone. Patients' pain and side effects will be registered and after 24 hours they will answer a questionnaire. All included patients will be genotyped accordingly to CYP2D6 and relevant single nucleotide polymorphisms (SNPs), and measures of plasma levels of oxycodone will be performed.
Among these are the A118G SNP in the μ-receptor gene OPRM1 and the C3435T and G2677T/A SNPs in the MDR-1 gene of P-glycoprotein. --- A118G --- --- C3435T ---
This study will examine whether a particular type of gene (MDR1) in the body can affect blood levels of two protease inhibitors, indinavir and saquinavir, which are used to treat people with HIV. If blood levels of these drugs are too low or too high, they may not work well or may cause side effects in patients. This study will determine how MDR1 genes might affect absorption of these medicines. Healthy normal volunteers between 18 and 50 years of age may be eligible for this study. Candidates will be screened with a medical history and blood and urine tests. The blood will be tested for: - Routine laboratory values for assessing general health - HIV - MDR1 gene type - Amount of P-glycoprotein (a protein made by the MDR1 gene) on T cells. Participants will have blood drawn three more times, as follows: - After one dose of the sedative midazolam (Versed(Registered Trademark)): Participants will take an 8-milligram dose of midazolam syrup by mouth. Four hours later, a single blood sample will be drawn through a needle in an arm vein. This part of the study will assess the efficiency of a certain enzyme involved in metabolizing (breaking down) indinavir and saquinavir. - After four doses of indinavir: About a week after taking the midazolam, participants will take 800 mg of indinavir (two capsules) 3 times a day (every 8 hours) for 1 day. The following morning they will come to the clinic, where a catheter (flexible plastic tube) will be placed in an arm vein for repeated blood draws. A blood sample will be drawn, and a fourth and final dose of indinavir will be given. Seven blood samples of about a teaspoon each will then be collected through the catheter over an 8-hour period to measure blood levels of the drug. - After 10 doses of saquinavir: About a week after the last dose of indinavir, participants will start taking 1,200 mg (6 capsules) of saquinavir soft-gelatin capsules 3 times a day for 3 days. On the fourth day, participants will come to the clinic. A catheter will be inserted into an arm vein and about 4 teaspoons of blood will be collected for routine laboratory tests and to measure saquinavir levels. A urine sample will also be collected for routine tests. Participants will then receive the tenth and final dose of saquinavir, and eight blood samples of about a teaspoon each will be collected through the catheter over an 8-hour period.
Healthy HIV Infections HIV Infections The expression of P-glycoprotein, a transporter protein present in enterocytes as well as other cells involved in the absorption and distribution of HIV protease inhibitors, has been linked to a single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T. --- C3435T ---
The purpose of the study is to examine cognitive and brain function in stage I-III breast cancer patients who have undergone adjuvant systemic therapy (chemotherapy or chemotherapy plus anti-hormonal therapy) in comparison to a group of healthy controls. Our hypothesis is that systemic adjuvant therapy in the form of chemotherapy or chemotherapy and anti-hormonal therapy given to primary breast cancer patients can cause cognitive impairment. We hypothesize that the use of simultaneous PET/MRI will allow us to determine key regions in the brain that show metabolic, structural, and functional deficits in a semi-quantitative manner and reveal subtle changes that are often missed during neuropsychological tests due to the low sensitivity of neuropsychological batteries.
For example, several genetic polymorphisms of multidrug resistance 1 (MDR1) have been identified that may influence P-glycoprotein (P-gp) function, one of the most studied polymorphisms being C3435T in exon26.P-gp which is present in the blood brain barrier affects the amount of drug uptake into the brain by actively transporting them out of the cells. --- C3435T ---
Description: We hope to gain a better understanding of the complex and currently poorly understood relationship between chemotherapy/anti-hormonal therapy and possible cognitive decline in patients undergoing such therapy. In current practice, a large number of patients with primary breast cancer are offered adjuvant chemotherapy after surgery, followed by hormonal therapy in patients whose tumours are hormone receptor-positive. The management of many adverse effects of chemotherapy, such as nausea, vomiting and febrile neutropenia has improved, and concern has shifted to more subtle and potentially chronic problems such as cognitive dysfunction, which may affect patients' quality of life.
Measure: Change the relationship between chemotherapy/anti-hormonal therapy and possible cognitive decline in patients undergoing such therapy Time: 1 yearThis study tested the hypothesis that response to digoxin is modulated by single Nucleotid Polymorphism (SNP): - Multi Drug Resistance (MDR1) gene haplotypes and Solute carrier organic anion transporter family member 1B3 (SLCO1B3) gene Polymorphism and their role in the response to treatement. - Aldosterone synthase (CYP11B2) gene and sodium channel, voltage-gated, type V alpha subunit gene (SCN5A) correlated with atrial fibrillation and their roles in response to digoxin.
The aim of the current study is to analyze the ABCB1: C1236T (Gly412Gly), G2677>T⁄A (Ala893Ser/ Thr) and C3435T (Il1145Ile) polymorphisms. --- C1236T --- --- Ala893Ser --- --- C3435T ---
Description: In the current study we aimed at outlining the different MDR-1, SLCO1B3, CYP11B12 and SCN5A genotypes in a sample of Tunisian patients, suffering from AF and taking digoxin, to assess the role of SNPs in affecting serum digoxin concentrations, and studying the consequences on patients' clinical outcome. Patients will be monitored for 24 hours in an intensive care unit;
Measure: Correlation between the response to digoxin and the genotypes of the patients Time: 24 hoursDescription: Rhythm control: rate and delay of return to sinusal rhythm. Rate control: reduction of heart rate : HR <100 bpm or 20% reduction from baseline
Measure: Rhythm and Rate control Time: 24 hoursInvestigator will assign 53 patients who had been histologically proven localized squamous cell carcinoma of esophagus to receive the induction chemotherapy regimen of ND-420 50 mg/m2 on day 1, cisplatin 70 mg/m2 on day1, plus fluorouracil 700 mg/m2 daily, day1 to day4, every 3 weeks for 2 cycles and then followed by surgical resection. The successful rate of complete treatment per protocol and complete resection will be the primary variant to evaluate in our study.
the correlation between clinical outcomes and the potential predictive genomic biomarkers(B-tubulin mutation, p53-Arg 72Pro, Bcl2-C938A, MDR1-C3435T polymorphism, TNFRSF1B-1466, GSTP1-l105V, CYP1B1, TS-5'UTR) for tumor response. --- C938A --- --- C3435T ---
The purpose of this study is to determine if non-invasive salivary genetic screening of breastfeeding mothers taking codeine will allow for the successful identification of mother-infant pairs susceptible to adverse events and to prevent these adverse events by personalizing their medication to their genetics.
Incidence of the C3435T polymorphism in the multi-drug resistance gene (MDR1) which has been associated with significantly greater pain relief from morphine treatment.. null. --- C3435T ---
Dabigatran (Pradaxa ®) is a new oral anticoagulant. It is used to prevent venous thromboembolism in orthopedic surgery and has recently demonstrated efficacy and safety at least as good as anticoagulants in the prevention of thromboembolism in atrial fibrillation and the treatment of venous thromboembolism. It is administered with fixed dose and does not require laboratory monitoring because of the low inter and intra individual pharmacokinetic (PK) and pharmacodynamics (PD) of dabigatran. However, the bioavailability of dabigatran is very low (6.5%) and is controlled by an efflux protein, P-GP. This molecule has a genetic polymorphism. The inhibition of this protein can cause a significant increase in intestinal absorption of dabigatran and expose patients to a risk of bleeding by overdose. Two major drug interactions have been identified : quinidine (cons-indication) and amiodarone (precautions). It is likely that other interactions exist and can be clinically significant in patients not selected such as testing. The development of tools to study the influence of P-GP on the PK and PD of dabigatran is therefore interesting. As the P-GP has a genetic polymorphism, the study of the latter is an important element in the detection of drug interactions. In this sense, clarithromycin, a potent inhibitor of P-GP is a good model to evaluate the primary mechanism of drug interaction of dabigatran and optimize the experimental design of studies to be conducted.
Genotyping of MDR-1 (gene for P-GP): C3435T SNP of exon 26, SNP G2677T / A of exon 21 and C1236T SNP of exon 12. Inclusion Criteria: - affiliated or beneficiary of a social security category - having signed the inform consent form - having signed the genetic consent form - weight between 60 and 85 kg - normal clinical exam - normal biological exam Exclusion Criteria: - contra-indication to dabigatran - contra-indication to clarithromycin - previous history of psychiatric disease, or antidepressant treatment, or convulsion, or hemorrhagic disease - smoker - peptic ulcer - severe liver disease - severe kidney failure - previous surgery within one month Inclusion Criteria: - affiliated or beneficiary of a social security category - having signed the inform consent form - having signed the genetic consent form - weight between 60 and 85 kg - normal clinical exam - normal biological exam Exclusion Criteria: - contra-indication to dabigatran - contra-indication to clarithromycin - previous history of psychiatric disease, or antidepressant treatment, or convulsion, or hemorrhagic disease - smoker - peptic ulcer - severe liver disease - severe kidney failure - previous surgery within one month Healthy null --- C3435T ---
Description: Calculating the area under the curve (AUC) from plasma concentrations of dabigatran versus time by the trapezoidal method. Determination of maximum concentration (Cmax)
Measure: Determination of dabigatran and its metabolites in plasma by LC/MS-MS method Time: At Day 4 and Day 11Description: Measures activated Partial Thromboplastin Time (aPTT)and measures ECarin Time (ECT),
Measure: Pharmacodynamic parameters Time: At Day 4 and Day 11Description: Genotyping of MDR-1 (gene for P-GP): C3435T SNP of exon 26, SNP G2677T / A of exon 21 and C1236T SNP of exon 12
Measure: Genotyping Time: At Day 1Ciclosporin inhibits P-glycoprotein should increase colchicine bioavailability whereas tacrolimus should not influence colchicine disposition. This is a prospective, controlled, open labeled study performed in renal graft recipients comparing colchicine single dose (1mg) pharmacokinetics in 14 patients treated with tacrolimus and 14 patients treated with cyclosporin.
ABCB1 Haplotypes composed of 3 SNPs: C3435T, G2677T / A and C1236T.. null. --- C3435T ---
Dosing methods for digoxin, a drug used to treat heart failure, have not been updated in decades despite evidence in recent years suggesting that blood levels of digoxin achieved with traditional dosing practices may increase the risk of adverse events. We developed a simple dosing tool that targets lower blood levels of digoxin that have been associated with improved outcomes compared to higher blood levels. The aim of this study is to determine if this simplified dosing tool is more effective than standard digoxin dosing practices at achieving lower blood levels and also to determine if digoxin dosing may be further optimized by incorporating patients' genetic information believed to influence the drug's properties.
We compared serum digoxin concentrations by ABCB1 genotype.. Serum Digoxin Concentration by ABCB1 SNP C3435T. --- C3435T ---
Serum digoxin concentration by genotypes for the ABCB1 SNP C3435T. --- C3435T ---
Description: 55 patients in the Digoxin Dosing per Nomogram group consented to the Pharmacogenetic substudy and provided blood samples to perform pharmacogenetic analyses. We compared serum digoxin concentrations by ABCB1 genotype.
Measure: Serum Digoxin Concentration by ABCB1 Single Nucleotide Polymorphism (SNP) C1236T Time: Steady-state (2 - 4 weeks after initiation)Description: Serum digoxin concentration by genotypes for the ABCB1 SNP C3435T
Measure: Serum Digoxin Concentration by ABCB1 SNP C3435T Time: Steady-state (2 - 4 weeks after initiation)Description: Serum digoxin concentration by ABCB1 SNP genotypes
Measure: Serum Digoxin Concentration by ABCB1 SNP G2677T/A Time: Steady-state (2 - 4 weeks after initiation)Solid organ transplant recipients would greatly benefit from pharmacogenetic evaluation since immunosuppressive drug regimens consist of multiple medications with narrow therapeutic ranges and toxic adverse event profiles. Tacrolimus is a potent immunosuppressive agent utilized for rejection prophylaxis. Intensive pharmacokinetic monitoring must be performed following organ transplantation to ensure therapeutic drug concentrations due to its highly variable pharmacokinetics profile and narrow therapeutic index. Tacrolimus is a substrate for CYP450 3A and for the membrane transporter p-glycoprotein (Pgp). Polymorphisms in the gene encoding for CYP3A5 have been extensively studied and have been found to influence the dosing of tacrolimus. The effect of ABCB1 gene polymorphisms (which encodes for Pgp) upon tacrolimus pharmacokinetics has been more difficult to establish. This study will determine if haplotypes derived from three frequent polymorphisms in the ABCB1 gene (C1236T, G2677T, C3435T) can predict the degree of drug interaction between tacrolimus (CYP3A5/Pgp substrate) and ketoconazole (CYP3A5/Pgp inhibitor) in patients who are CYP3A5 nonexpressors. This prospective pharmacokinetic and pharmacogenomic study will enroll 20 stable renal transplant recipients with the CYP3A5 *3/*3 genotype and grouped by ABCB1 haplotype (CGC vs TTT). Pharmacokinetics of tacrolimus will be assessed on 2 occasions with and without ketoconazole coadministration separated by 1 week. The order of study occasions will be randomized in a crossover design. The results of this study may identify a genomic marker for predicting drug-drug interactions. Knowing this information a priori will aid clinicians in modifying drug dosing and alleviate patients of the burden of significant drug toxicities.
This study will determine if haplotypes derived from three frequent polymorphisms in the ABCB1 gene (C1236T, G2677T, C3435T) can predict the degree of drug interaction between tacrolimus (CYP3A5/Pgp substrate) and ketoconazole (CYP3A5/Pgp inhibitor) in patients who are CYP3A5 nonexpressors. --- C1236T --- --- G2677T --- --- C3435T ---
Description: Tac bioavailability alone vs. Tac bioavailability with Keto. To determine F we took the ratio of area under the curve of the oral dose divided by the area under the curve of the IV dose. F was determined by fitting a model that considered the plasma concentration of tac with IV vs. oral dosing.
Measure: Tacrolimus Bioavailability (F) Time: baseline and 2 weeks