摘要:

This review seeks to apply a decision-making algorithm to establish whether clinical pharmacokinetic monitoring (CPM) of sirolimus (rapamycin) in solid organ transplantation is indicated in specific patient populations. The need for CPM of sirolimus, although a regulatory requirement in Europe, has not yet been firmly established in North America and other parts of the world.Sirolimus has demonstrated immunosuppressive efficacy in renal, pancreatic islet cell, liver and heart transplant recipients. The pharmacological response of immunosuppressive therapy with sirolimus cannot be readily evaluated; however, a relationship between trough blood sirolimus concentrations, area under the plasma concentration-time curve (AUC) and the incidence of rejection has been proposed. Furthermore, sirolimus can be measured in whole blood by several assays – high-performance liquid chromatography with detection by tandem mass spectrometry, or with ultraviolet detection, radioreceptor assay or microparticle enzyme immunoassay.Both experimental animal and clinical data suggest that adverse events and their associated severity are correlated with blood concentrations. To prevent rejection and minimise toxicity, a therapeutic range of 4–12 μg/L (measured via chromatographic assays) is recommended when sirolimus is used in conjunction with ciclosporin. If ciclosporin therapy is discontinued, a target trough range of 12–20 μg/L is recommended.Sirolimus pharmacokinetics display large inter- and intrapatient variability, which may change in specific patient populations due to disease states or concurrent immunosuppressants or other interacting drugs. Due to the long half-life of sirolimus, dosage adjustments would ideally be based on trough levels obtained more than 5–7 days after initiation of therapy or dosage change. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. After the first 2 months of dose titration, routine CPM of sirolimus is not necessary in all patients, but may be warranted to achieve target concentrations in certain populations of patients, but the frequency of further monitoring remains to be determined and should be individualised.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Remifentanil is a synthetic opioid that was developed in the early 1990s and introduced into clinical use in 1996. It is a methyl ester and is metabolised by nonspecific tissue and plasma esterases. Consequently, it is a drug that undergoes rapid elimination and has a reported terminal elimination half-life of between 10 and 35 minutes. Because there is no drug accumulation, the context-sensitive half-time remains constant; thus the pharmacokinetics of the drug do not change regardless of the duration of infusion. The organ-independent elimination of remifentanil, coupled with the fact that its clearance is greater in infants and neonates compared with older age groups, make its pharmacokinetic profile different from any other opioid. In addition, its unique metabolism confers predictability in its clinical use. Like other opioid μ receptor agonists, remifentanil provides dose-dependent analgesia, while the adverse effects of this drug, e.g. respiratory depression, are also thought to be dose related. The incidence of nausea and vomiting appear similar to other opioids. Its rapid and consistent metabolism regardless of duration of infusion has made remifentanil an attractive analgesic/anaesthetic option for paediatric care providers.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching maximum concentrations 1–2 hours post-administration. After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite. E 3174 is 10- to 40-fold more potent than its parent compound and its estimated terminal half-life ranges from 6 to 9 hours. The pharmacokinetics of losartan and E 3174 are linear, dose-proportional and do not substantially change with repetitive administration. The recommended dosage of losartan 50 mg/day can be administered without regard to food. There are no clinically significant effects of age, sex or race on the pharmacokinetics of losartan, and no dosage adjustment is necessary in patients with mild hepatic impairment or various degrees of renal insufficiency. Losartan, or its E 3174 metabolite, is not removed during haemodialysis.The major metabolic pathway for losartan is by the cytochrome P450 (CYP) 3A4, 2C9 and 2C10 isoenzymes. Overall, losartan has a favorable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between this drug and a range of inhibitors and stimulators of the CYP450 system. Losartan does not have a drug-drug interaction with hydrochlorothiazide, warfarin or digoxin. Losartan should be avoided in pregnancy, as is the case with all other angiotensin-receptor antagonists. When given in the second and third trimester of pregnancy, losartan is often associated with serious fetal toxicity. Losartan is a competitive antagonist that causes a parallel rightward shift of the concentration-contractile response curve to angiotensin-II, while E 3174 is a noncompetitive ‘insurmountable’ antagonist of angiotensin-II.The maximum recommended daily dose of losartan is 100mg, which can be given as a once-daily dose or by splitting the same total daily dose into two doses. Losartan reduces blood pressure comparably to other angiotensin-receptor antagonists. Losartan has been extensively studied relative to end-organ protection, with studies having been conducted in diabetic nephropathy, heart failure, post-myocardial infarction and hypertensive patients with left ventricular hypertrophy. The results of these studies have been sufficiently positive to support a more widespread use of angiotensin-receptor antagonists in the setting of various end-organ diseases. Losartan, like other angiotensin-receptor antagonists, is devoid of significant adverse effects.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Inhaled corticosteroids have a key role in the treatment of asthma and chronic obstructive pulmonary disease. In recent times, beclometasone dipropionate has been reformulated in pressurised metered dose inhalers (pMDIs), using hydrofluoroalkanes (HFAs) as a propellant. Extensive toxicological testing has shown that HFA-propellants are well tolerated.Among the reformulated beclometasone dipropionate-containing pMDIs, only the characteristics of the two Qvar™ formulations have been thoroughly explored. Compared to the reference beclometasone dipropionate formulation, the mass median aerodynamic diameter of the Qvar™ formulations are substantially smaller (1.1 vs 4.0µm), whereas that of Modulite®averages 2.6µm.Scintigraphic and pharmacokinetic studies indicate a higher lung deposition for both the Qvar™ and the Beclazone®formulations, compared with reference beclometasone dipropionate formulation. Since the 2- to 3-fold increase in pulmonary deposition results in a 2.6- to 3-fold difference in relative efficacy for Qvar™, half the dose of the reference beclometasone dipropionate formulation has been currently recommended in adult patients with asthma, a recommendation that is supported by a large number of clinical trials. Conversely, the design of the studies conducted to compare the efficacy of Qvar™ with fluticasone propionate and budesonide does not allow establishing their equivalence on a milligram per milligram basis. Good studies on the bioequivalence between the reference beclometasone dipropionate formulation and the Modulite®or Beclazone®formulations are not available.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundMycophenolic acid (MPA) shows complex plasma concentration-time profiles, particularly in the immediate (first month) post-transplantation phase for which no relevant pharmacokinetic model has been proposed thus far.ObjectiveThe aim of this study was to develop a model to accurately describe the time profile of plasma MPA concentrations after oral administration of mycophenolate mofetil in adult kidney transplant patients, in any post-transplantation period.MethodFull interdose pharmacokinetic profiles were collected in 45 adult renal transplant patients who were orally administered mycophenolate mofetil and ciclosporin; 25 patients werede novotransplant patients for whom individual pharmacokinetics were assessed at three post-transplantation periods (days 3, 7 and 30) and 20 patients were stable transplant patients (>3 months post-transplantation). MPA was determined in plasma by liquid chromatography-mass spectrometry. Models combining a single- or double-input (described as single or double gamma distributions) with one- or two-compartments were developed using in-house software and fitted to the individual profiles by nonlinear regression.ResultsVisual inspection of the pharmacokinetic profiles showed highly variable absorption profiles and secondary peaks of various intensity. The pharmacokinetic models including a double gamma distribution best fitted these various profiles in the immediate post-transplantation period (mean bias and precision of −0.92% and 20.19%; −1.5% and 18.02%, on day 7 and day 30, respectively), while in the stable post-grafting phase (beyond 3 months), the single- and double-absorption models performed similarly (mean bias and precision of −3.37% and 17.64%; −3.12% and 18.44%, on day 7 and day 30, respectively).ConclusionThe proposed pharmacokinetic models adequately describe the concentration-time profiles of MPA in renal transplant patients and could be helpful in the development of tools for MPA monitoring.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveThe aim of this study was to characterise the population pharmacokinetics of efavirenz in a representative patient population and to identify patient characteristics influencing the pharmacokinetics of efavirenz, with the ultimate goal of further developing techniques that can be applied to optimise therapeutic drug monitoring of antiretroviral agents.MethodsAmbulatory HIV-1-infected patients using an efavirenz-containing regimen were included. During regular visits, blood samples were collected for efavirenz plasma concentrations and clinical chemistry parameters. Concentrations of efavirenz were quantitatively assessed by a validated high-performance liquid chromatographic with ultraviolet detection method. Using nonlinear mixed-effect modelling (NONMEM), the pharmacokinetics of efavirenz were described. Disposition of efavirenz was described by a two-compartment model and absorption was modelled using a chain of three transition compartments. Apparent clearance (CL/F), volume of distribution after oral administration (Vd/F), intercompartmental clearance, the peripheral volume of distribution and the intercompartmental transition rate constant (ktr) were estimated. Furthermore, interindividual, interoccasion and residual variability were estimated. The influence of patient characteristics on the pharmacokinetic parameters of efavirenz was explored.ResultsFrom 172 patients, 40 full pharmacokinetic curves and 315 efavirenz plasma concentrations at a single timepoint were available, resulting in a database of 1009 efavirenz plasma concentrations. CL/F, Vd/F, and ktrwere 11.7 L/h (4.3% relative standard error [RSE]), 189L (14.6% RSE) and 3.07 h–1(11.2% RSE), respectively. Residual variability in the model was composed of 0.14 mg/L additive error and 8.85% proportional error. Asian race and baseline total bilirubin (TBR) increased the relative bioavailability of efavirenz by 56% and 57%, respectively. No significant covariates were found for CL/F or Vd/F.ConclusionThe pharmacokinetic parameters of efavirenz were adequately described with the developed population pharmacokinetic model. Asian race and baseline TBR were found to be significantly correlated with the bioavailability of efavirenz. The described model will be an essential tool in further optimisation of efavirenz-containing antiretroviral therapy, e.g. by the use of Bayesian estimation of individual pharmacokinetic parameters.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and objectivesNXY-059 (disufenton sodium, Cerovive®), a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population.MethodsNXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CLCR). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CLCRor bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfilment criteria and parsimony.PatientsPharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34–92 years with varying degrees of renal impairment (estimated CLCR20–143 mL/min).Main outcome measures and resultsThe final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CLCRand bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CLCRof 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CLCR(three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min.ConclusionThe results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS