摘要:

Since it is difficult to improve patient compliance to drug prescriptions, an alternative is to select a drug with less consequences for poor compliance, that is, a drug that has the capacity of ’forgiveness’. Forgiveness is the property of a drug which, when compared with another medicine with different pharmacokinetics and/or concentration-effect relationships, blunts the consequences of missing one or two doses in a row, or has a greater variability in the timing of intake. Simulations show that drugs with a concentration-effect relationship modelled with an effect compartment, for example a delayed response, have more forgiveness. A marker of forgiveness would be of some help for doctors deciding which drug to prescribe to patients who are poor compliers.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II type 1 (AT1) receptor antagonist. Absorbed candesartan cilexetil is completely metabolised to candesartan. Oral bioavailability is low (about 40%) because of incomplete absorption. Plasma protein binding in humans is more than 99%. The volume of distribution in healthy individuals is 0.13 L/kg. CV-15959 is the inactive metabolite of candesartan.Candesartan that reaches the systemic circulation is mainly cleared by the kidneys, and to a smaller extent by the biliary or intestinal route. The apparent oral clearance of candesartan is 0.25 L/h/kg after a single dose in healthy individuals. Oral clearance (3.4 to 28.4 L/h) is highly variable among patients. No relevant pharmacokinetic drug-food or drug-drug interactions are known. The terminal elimination half-life remains unclear, but appears to be longer than the currently used range of 4 to 9 hours.Non-compartmental models do not appear to be appropriate for the analysis of candesartan pharmacokinetic data. A 2-compartment analysis revealed a much longer half-life of 29 hours using data from patients with hypertension. However, a further indepth analysis has never been performed. The concentration-effect relationship is unaffected by age. No gender or race differences have been shown in the effect or pharmacokinetics of candesartan.Renal function affects the pharmacokinetic profile of candesartan. For patients with creatinine clearances of >60 ml/min • 1.73m2, 30 to 60 ml/min • 1.73m2and 15 to 30 ml/min • 1.73m2, the elimination half-life is 7.1, 10.0 and 15.7 hours, respectively, at a dose of 8 mg/day. However, at 12 mg/day an accumulation factor of 1.71 was found. Thus, a maximum daily dose of up to 8mg appears suitable in patients with severe renal dysfunction. No significant elimination of candesartan occurs with haemodialysis. In patients with mild to moderate hepatic impairment, no relevant pharmacokinetic alterations have been observed. Dosages of up to 12 mg/day do not require precautions in patients with mild to moderate liver disease.Clinically effective dosages range between 8 and 32 mg/day. The response rate of monotherapy with candesartan in patients with hypertension increases with dosage, but never exceeds 60% at a daily dosage of 16mg of candesartan. Dosages up to 32 mg/day do not increase this response rate.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Salmeterol is an inhaled long-acting selective β2-adrenoceptor agonist that is commercially available as the xinafoate (1-hydroxy-2-naphthoic acid) salt of the racemic mixture of the two optical isomers, (R)- and (S)-, of salmeterol. It acts locally in the lung through action on β2receptors.Limited data have been published on the pharmacokinetics of salmeterol. Moreover, there are no data on the extent to which inhaled salmeterol undergoes first-pass metabolism. This lack of information is most likely due to the very low plasma concentrations reached after inhalation of therapeutic doses of salmeterol and the problems in developing an analytical method that is sensitive enough to determine these concentrations.When salmeterol is inhaled, plasma concentrations of the drug often cannot be detected, even at 30 minutes after administration of therapeutic doses. Larger inhaled doses give approximately proportionally increased blood concentrations. Plasma salmeterol concentrations of 0.1 to 0.2 and 1 to 2 μg/L have been attained in healthy volunteers about 5 to 15 minutes after inhalation of a single dose of 50 and 400 μg, respectively. In patients who inhaled salmeterol 50μg twice daily for 10 months, a second peak concentration of 0.07 to 0.2 μg/L occurred 45 to 90 minutes after inhalation, probably because of the gastrointestinal absorption of the swallowed drug.Salmeterol xinafoate dissociates in solution to salmeterol and 1-hydroxy-2-naphthoic acid. These two compounds are then absorbed, distributed, metabolised and excreted independently. The xinafoate moiety has no apparent pharmacological activity, is highly protein bound (>99%), largely to albumin, and has a long elimination half-life of about 12 to 15 days in healthy individuals. For this reason, it accumulates in plasma during repeated administration, with steady-state concentrations reaching about 80 to 90 μg/L in patients treated with salmeterol 50μg twice daily for several months.The cytochrome P450 (CYP) isoform 3A4 is responsible for aliphatic oxidation of salmeterol base, which is extensively metabolised by hydroxylation with the major metabolite being α-hydroxysalmeterol, with subsequent elimination predominantly in the faeces. It has been demonstrated that 57.4% of administered radioactivity is recovered in the faeces and 23% in the urine; most is recovered between 24 and 72 hours after administration. Unchanged salmeterol accounts for <5% of the excreted dose in the urine.Since the therapeutic dose of salmeterol is very low, it is unlikely that any clinically relevant interactions will be observed as a consequence of the coadministration of salmeterol and other drugs, such as fluticasone propionate, that are metabolised by CYP3A.All the available data clearly show that at the recommended doses of salmeterol, systemic concentrations are low or even undetectable. This is an important point, because it has been demonstrated that the systemic effects of salmeterol are more likely to occur with higher doses, which lead to approximately proportionally increased blood concentrations.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems.Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of α1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance.Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or α2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

BackgroundThe microemulsion formulation of cyclosporin (CsA-ME) has a less variable absorption profile than the standard formulation (CsA-S), but only limited information is available about once-daily administration of CsA-ME.ObjectiveTo develop a population pharmacokinetic model for once-daily CsA-ME that enables the prediction of individual steady-state area under the concentration-time curve (AUC) on the basis of blood concentration measurements and patient covariates.Patients and methodsThe steady-state pharmacokinetics of once-daily cyclosporin were studied in 60 stable renal transplant recipients before and after conversion from CsA-S to CsA-ME. For each formulation, 7 blood samples were collected from 50 patients (group A) at sparse timepoints over 2 weeks, and 10 blood samples were collected from 10 patients (group B) at fixed timepoints over 24 hours. A 2-compartment population model assuming time-lagged first-order oral absorption was fitted to the data from group A, using nonlinear mixed effects modelling (NONMEM). The data from group B were used to evaluate the predictive performance of the model.ResultsMean [± SD; coefficient of variation (%CV)] CsA-S doses of 245mg (± 92) resulted in cyclosporin blood concentrations of 214 μg/L (± 70) after 12 hours and 108 μg/L (± 23) after 24 hours; the mean estimated AUC to 24 hours was 7658 μg • h/L (30%). With mean CsA-ME doses of 206mg (± 59), cyclosporin blood concentrations were 212 μg/L (± 33) and 132 μg/L (25%) after 12 and 24 hours, respectively, and the mean estimated AUC24was 9357 μg • h/L (23%). A strong correlation between 12-hour concentrations and AUC24was observed for CsA-ME (r = 0.95, p < 0.001), but not for CsA-S (r = 0.59, nonsignificant); the correlation between 24-hour trough concentrations and AUC24was weaker for both formulations (r = 0.64, p < 0.05 and r = 0.37, nonsignificant, respectively). On the basis of the population model derived from group A, the single best timepoint to predict AUC24from blood cyclosporin concentration was at 8 hours [AUC24(μg • h/L) = 19.6 • cyclosporin concentration at 8 hours (μg/L) + 3035], resulting in a prediction error of 8.3 ± 6.6% when applied to the measured AUC24of group B. Adverse events were observed after conversion in 18 patients; these events generally resolved spontaneously or after dosage reduction, but twice-daily administration was required in some patients.ConclusionsSwitching from once-daily CsA-S to CsA-ME results in more consistent and predictable cyclosporin pharmacokinetics. Adjustment of dosage or regimen may be required in some patients.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo develop a maximuma posterioriprobability (MAP) Bayesian estimator for the pharmacokinetics of oral cyclosporin, based on only three timepoints, and evaluate its performance with respect to a full-profile nonlinear regression approach.Patients20 adult patients with stable renal transplants given orally administered microemulsified cyclosporin and mycophenolate.MethodsCyclosporin was assayed by liquid chromatography-mass spectrometry. Nonlinear regression and MAP Bayesian estimation were performed using a home-made program and a previously designed pharmacokinetic model including an S-shaped absorption profile described by a gamma distribution.Outcome measures and resultsMAP Bayesian estimation using the best limited sampling strategy (before administration, and 1 and 3 hours after administration) was compared with nonlinear regression (taken as the reference method) for the prediction of the different pharmacokinetic parameters and exposure indices. Median relative prediction error was −0.49 and −3.42% for area under the concentration-time curve over the administration interval of 12 hours (AUC12) and estimated peak drug concentration (Cmax), respectively (nonsignificant). Relative precision was 2.00 and 4.32%, and correlation coefficient (r) was 0.985 and 0.955, for AUC12and Cmax, respectively.ConclusionThis paper reports preliminary results in a stable renal transplant patient population, showing that MAP Bayesian estimation can allow accurate prediction of AUC12and Cmaxwith only three samples (0, 1 and 3 hours). Although these results require confirmation by further studies in other clinical settings, using other drug combinations, other analytical methods and commercially available pharmacokinetic software, the method seems promising as a tool for the therapeutic drug monitoring of cyclosporin in clinical practice or for exposure-controlled studies.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS