There are 6 clinical trials
This 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 ---
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 hoursDabigatran (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 --- --- G2677T --- --- C1236T ---
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 1Oral administration has many advantages above intravenously administrated drugs for patients. Up to now, oral administration of docetaxel as single agent has not been feasible due to low and variable bioavailability. This low systematic exposure to docetaxel can effectively be increased after co-administration of ritonavir. The department of pharmacy of the Slotervaart Hospital and Netherlands Cancer Institute developed a solid oral dosage form for docetaxel, ModraDoc001 10 mg capsules. Two other novel dosage forms of docetaxel with improved pharmaceutical characteristics, have been developed: ModraDoc003 10 mg tablets and ModraDoc004 10/50 mg tablets. The systemic exposure after administration of those forms is now being investigated.
To establish the effect of functional genetic polymorphisms, C1236T (for MDR1) and CYP3A4*1B, on pharmacokinetics of orally administered docetaxel.. Inclusion Criteria: 1. Histological or cytological proof of cancer 2. Patients for whom no standard therapy of proven benefit exist 3. Patients who might benefit from treatment with docetaxel, e.g. --- C1236T ---
Another part of this study is the screening for 2 different polymorphism, C1236T (for MDR1)and CYP3A4*1B. --- C1236T ---
Description: The maximal tolerated dose (defined as the highest dose resulting in no more that 1/6 probability of causing a dose limiting toxicities defined in the protocol) of bi-daily ModraDoc001 10mg capsules with ritonavir will be assessed in Arm A. Weekly safety assessments for Arm A and Arm B: signs and symptoms/adverse events, physical examination, clinical laboratory tests (hematology, clinical chemistry and urinalysis), 12-lead ECG monitoring (Day 0, End of Th). The incidence of serious AEs (SAEs) and AE related to oral docetaxel and/or to ritonavir will be determined.
Measure: Number and percentage of Participants with Adverse Events Time: AE will be collected during the study treatment and 30 days after discontinuation of the study treatment due to disease progression or unacceptable treatment related toxicityDescription: The PK of bi-daily ModraDoc001 10mg, ModraDoc003 10mg tablets both in combination with ritonavir capsules and ModraDoc004 10/50mg tablets will be determed using non-compartmental methods and compartmental methods using NONMEM. Correlation between PK data and toxicity are subsequently analyzed for their significance.
Measure: Pharmacokinetics assessments Time: Day 1 of week: 1, 2 and 3Description: Weekly safety assessments for Arm B (administration of ModraDoc003 10mg capsules and ritonavir and ModraDoc004 10/50 mg tablets) are: signs and symptoms/adverse events, physical examination, clinical laboratory tests (hematology, clinical chemistry and urinalysis), 12-lead ECG monitoring (Day 0, End of Th). The incidence of serious AEs (SAEs) and AE related to oral docetaxel and/or to ritonavir will be determined.
Measure: Number and percentage of Participants with Adverse Events Time: during the study treatment and 30 days after the study discontinuationDescription: Tumor measurement according to RECIST
Measure: Radiological antitumor activity Time: at least every six weeksDescription: To establish the effect of functional genetic polymorphisms, C1236T (for MDR1) and CYP3A4*1B, on pharmacokinetics of orally administered docetaxel.
Measure: Pharmacogenetic sampling Time: Day 1 - predoseCiclosporin 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 --- --- G2677T --- --- C1236T ---
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.
Serum Digoxin Concentration by ABCB1 Single Nucleotide Polymorphism (SNP) C1236T. --- C1236T ---
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 ---
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