摘要:

Adequate immunosuppression minimising the risk of organ rejection with acceptable tolerability of the used drugs is a crucial step in organ transplantation. The primary goal is to maintain a consistent time-dependent target concentration by tailoring individual dosage leading to the best efficacy and tolerability combination. The use of therapeutic drug monitoring (TDM) to optimise immunosuppressive therapy is routinely employed for maintenance drugs such as cyclosporin and tacrolimus. The question whether therapeutic monitoring of mycophenolic acid (MPA) in organ transplant recipients treated with mycophenolate mofetil is necessary is not definitely answered. The correlation of mycophenolic acid pharmacokinetic parameters with efficacy and toxicity makes the therapeutic monitoring of this drug promising. However, further studies are mandatory to draw the best guidelines in order to achieve higher levels of evidence that MPA-TDM may improve patient outcome.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Gender-related differences in pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. The mechanistic processes underlying gender-specific pharmacokinetics can be divided into molecular and physiological factors.Major molecular factors involved in drug disposition include drug transporters and drug-metabolising enzymes. Men seem to have a higher activity relative to women for the cytochrome P450 (CYP) isoenzymes CYP1A2 and potentially CYP2E1, for the drug efflux transporter P-glycoprotein, and for some isoforms of glucuronosyltransferases and sulfotransferases. Women were suggested to have a higher CYP2D6 activity. No major gender-specific differences seem to exist for CYP2C19 and CYP3A. The often-described higher hepatic clearance in women compared with men for substrates of CYP3A and P-glycoprotein, such as erythromycin and verapamil, may be explained by increased intrahepatocellular substrate availability due to lower hepatic P-glycoprotein activity in women relative to men.Physiological factors resulting in gender-related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate and different gastric motility in women compared with men.Although gender disparity in pharmacokinetics has been identified for numerous drugs, differences are generally only subtle. For a few drugs, e.g. verapamil, β-blockers and selective serotonin reuptake inhibitors, gender-related differences in pharmacokinetics have been shown to result in different pharmacological responses, but their clinical relevance remains unproven. In contrast, gender differences of clinical importance have clearly been identified for pharmacodynamic processes such as QTc prolongation, and intensive future research efforts are needed to assess the full scope and impact of pharmacodynamic gender disparity on applied pharmacotherapy.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions.Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold.Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring.Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

In order to compare the capacity for forgiveness of different drugs, i.e. the sensitivity of their effects to sporadic noncompliance, we propose the use of ‘sensitivity functions’ for drugs acting through direct pharmacokinetic-pharmacodynamic relationships. This approach is based on the concept of the partial derivative dE/dC (with E corresponding to the pharmacodynamic effect and C to the concentration of drug at the effect site), and the study of the variation of this function in terms of its maximum and inflexion points.Values of sensitivity functions are given for the three common direct response models, i.e. the linear, maximum effect (hyperbolic) and Hill (sigmoid) models. The capacity for forgiveness of drugs differing only by one parameter in their pharmacokinetic-pharmacodynamic relationship is assessed using this approach and illustrated with theoretical simulated examples.Examples of clinical application are then proposed, dealing with the effect of nifedipine on heart rate and diastolic blood pressure, and loop diuretics on natriuretic response, in patients with and without liver cirrhosis.Although the study of sensitivity functions is proposed as a theoretical approach, the relationships between noncompliance and its consequences for pharmacodynamic effect remain highly complex and, in most cases, numerical simulation is still needed.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo study the dose-response relationship of the pharmacokinetic interaction between diltiazem and tacrolimus in kidney and liver transplant recipients.DesignNonrandomised seven-period stepwise pharmacokinetic study.PatientsStable kidney (n = 2) and liver (n = 2) transplant recipients maintained on oral tacrolimus twice daily but not taking diltiazem.MethodsPatients were treated with seven incremental dosages of diltiazem (0 to 180 mg/day) at ≥ 2-weekly intervals. At the end of each interval, 13 blood samples were taken over a 24-hour period to allow determination of morning (AUC12), evening (AUC12-24) and 24-hour (AUC24) areas under the concentration-time curve for tacrolimus, as well as AUC24for diltiazem and three of its metabolites.ResultsThere was considerable interpatient variability in tacrolimus-sparing effect. In the two kidney transplant recipients, an increase in tacrolimus AUC24occurred following the 20 mg/day dosage of diltiazem (26 and 67%). The maximum increase in tacrolimus AUC24occurred at the maximum diltiazem dosage used (180 mg/day), when the increase was 48 and 177%. In the two liver transplant recipients, an increase in tacrolimus AUC24did not occur until a higher diltiazem dosage (60 to 120 mg/day) was given. The increase at the maximum diltiazem dosages used (120 mg/day in one and 180 mg/day in the other) was also lower (18 and 22%) than that exhibited by the kidney transplant recipients. The increase in tacrolimus AUC12was similar to the increase in AUC12-24when diltiazem was given in the morning only (dosages ≤60 mg/day). Hence, diltiazem affects blood tacrolimus concentrations for longer than would be predicted from the half-life of diltiazem in plasma.ConclusionsThe mean tacrolimus-sparing effect of diltiazem was similar in magnitude to the cyclosporin-sparing effect previously reported. Whether the lesser tacrolimus-sparing effect with diltiazem seen in the liver transplant recipients was due to functional differences in the transplanted liver is not known, but it was not due to lower plasma diltiazem concentrations. Diltiazem makes a logical tacrolimus-sparing agent because of the potential financial savings and therapeutic benefits. Because of interpatient variability, the sparing effect should be demonstrated in each patient and not merely assumed.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS