摘要:

Mirtazapine is the first noradrenergic and specific serotonergic antidepressant (‘NaSSA’). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way.The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance.There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(−)-enantiomer (18.0 ± 2.5h) compared with that of the (S)-(+)-enantiomer (9.9 ± 3.1h). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(−)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found.Approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations (17 and 32%, respectively) without leading to clinically relevant consequences. Enzyme induction by carbamazepine causes a considerable decrease (60%) in mirtazapine plasma concentrations. Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of coadministered drugs are hardly affected by mirtazapine.Although no concentration-effect relationship could be established, it was found that with therapeutic dosages of mirtazapine (15 to 45 mg/day), plasma concentrations range on average from 5 to 100 µg/L.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

This article reviews the clinical pharmacokinetics of a deoxycytidine analogue of cytarabine, 2′-deoxy-2′-methylidenecytidine (DMDC). DMDC belongs to the antimetabolite class of anticancer drugs and is phosphorylated into its active, triphosphate, form within the tumour cell. Cancer cell death appears to be a result of the impairment of DNA synthesis by the triphosphate form. DMDC undergoes deamination to the inactive 2′-deoxy-2′-methylideneuridine (DMDU), its main plasma metabolite.Following intravenous administration at 30 to 450 mg/m2, DMDC has low systemic clearance (10 to 15 L/h/m2), moderate volume of distribution (nominally similar to total body water) and a short elimination half-life of between 2 and 6 hours. Renal clearance of DMDC accounts for approximately 30 to 50% of total clearance.Following oral administration of DMDC at 12 to 50 mg/m2, mean maximum DMDC plasma concentrations are within the 100 to 400 µg/L range and are generally reached within 2 hours. Oral bioavailability of DMDC is in the order of 40%, largely as a result of first-pass metabolism in the gut and liver. This first-pass effect results in considerable interpatient variability in systemic exposure to DMDC after oral administration. The systemic availability of DMDC is proportional to the administered dose and, although there was evidence that systemic exposure to DMDC decreased on repeated administration, there are no excessive time-dependent changes in systemic exposure to DMDC.Following oral administration, DMDC is metabolised in the gut wall and liver by deamination to DMDU. The kidneys eliminate DMDC and DMDU, with up to 50% of the administered dose recovered in urine, on average, as parent drug and metabolite.Dose escalation to the maximum tolerated dose was facilitated by a pharmacokinetically guided dose escalation strategy. DMDC has shown activity in non−small-cell lung cancer and colorectal cancers following oral administration. Several tumour responses are observed at the highest doses of DMDC, indicating a possible dose-response relationship with this drug. The main clinical adverse event of DMDC therapy is myelotoxicity.The haematological toxicity of DMDC was schedule dependent; twice daily administration was associated with greater toxic effects than a once daily regimen. A pharmacokinetic-pharmacodynamic model characterised the relationship between plasma DMDC concentrations and the time-dissociated toxicity. This model-dependent approach may be used to predict the consequences of as-yet-untested therapy as well as relating acceptable risks of haematological toxicity to target drug exposure.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

Currently, 5 different main mechanisms of induction are distinguished for drug-metabolising enzymes. The ethanol type of induction is mediated by ligand stabilisation of the enzyme, but the others appear to be mediated by intracellular ‘receptors’. These are the aryl hydrocarbon (Ah) receptor, the peroxisome proliferator activated receptor (PPAR), the constitutive androstane receptor (CAR, phenobarbital induction) and the pregnane X receptor [PXR, rifampicin (rifampin) induction].Enzyme induction has the net effect of increasing protein levels. However, many inducers are also inhibitors of the enzymes they induce, and the inductive effects of a single drug may be mediated by more than one mechanism. Therefore, it appears that every inducer has its own pattern of induction; knowledge of the main mechanism is often not sufficient to predict the extent and time course of induction, but may serve to make the clinician aware of potential dangers.The possible pharmacokinetic consequences of enzyme induction depend on the localisation of the enzyme. They include decreased or absent bioavailability for orally administered drugs, increased hepatic clearance or accelerated formation of reactive metabolites, which is usually related to local toxicity. Although some severe drug-drug interactions are caused by enzyme induction, most of the effects of inducers are not detected in the background of nonspecific variation. For any potent inducer, however, its addition to, or withdrawal from, an existing drug regimen may cause pronounced concentration changes and should be done gradually and with appropriate monitoring of therapeutic efficacy and adverse events.The toxicological consequences of enzyme induction in humans are rare, and appear to be mainly limited to hepatoxicity in ethanol-type induction.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

ObjectiveTo analyse the population pharmacokinetic-pharmacodynamic relationships of racemic ibuprofen administered in suspension or as effervescent granules with the aim of exploring the effect of formulation on the relevant pharmacodynamic parameters.DesignThe pharmacokinetic model was developed from a randomised, crossover bioequivalence study of the 2 formulations in healthy adults. The pharmacodynamic model was developed from a randomised, multicentre, single dose efficacy and safety study of the 2 formulations in febrile children.Patients and participantsPharmacokinetics were studied in 18 healthy volunteers aged 18 to 45 years, and pharmacodynamics were studied in 103 febrile children aged between 4 and 16 years with bodyweight ≥25kg.MethodsThe pharmacokinetic study consisted of two 1-day study occasions, each separated by a 1-week washout period. On each occasion ibuprofen 400mg was administered orally as suspension or granules. The time course of the antipyretic effect was evaluated in febrile children receiving a single oral dose of 7 mg/kg in suspension or 200 or 400mg as effervescent granules. During the pharmacodynamic analysis, the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used.ResultsThe disposition of ibuprofen was described by a 2-compartment model. No statistical differences (p > 0.05) were found between the 2 formulations in the distribution and elimination parameters. Absorption of ibuprofen from suspension was adequately described by a first-order process; however, a model with 2 parallel first-order input sites was used for the drug given as effervescent granules, leading to time to reach maximum drug concentration (tmax) values of 0.9 and 1.9 hours for suspension and granules, respectively. The time course of the antipyretic effect was best described using an indirect response model. The estimates (with percentage coefficients of variation in parentheses) of Emax(maximum inhibition of the zero-order synthesis rate of the factor causing fever), EC50(plasma concentration eliciting half of Emax), n (slope parameter) and kout(first order rate constant of degradation) were 0.055 (10), 6.16 (14) mg/L, 2.71 (18) and 1.17 (23) h−1, respectively, where T0is the estimate of the basal temperature, 38.8 (1) °C. No significant (p > 0.05) covariate effects (including pharmaceutical formulation) were detected in any of the pharmacodynamic parameters.ConclusionsBecause of the indirect nature of the effect exerted by ibuprofen, the implications of differences found in the plasma drug concentration profiles between suspension and effervescent granules are less apparent in the therapeutic response.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS

摘要:

BackgroundLosartan is a selective angiotensin AT1receptor antagonist currently employed in the management of essential hypertension. This compound is in common use in populations with renal failure and end-stage renal disease (ESRD).ObjectiveTo investigate the pharmacokinetics and pharmacodynamics of losartan in patients with ESRD in order to establish administration guidelines.MethodsPatients were administered losartan 100 mg/day for 7 days, and after the seventh and final dose pharmacokinetic parameters were determined for both losartan and its active metabolite E-3174. During the study, the haemodialytic clearances of losartan and E-3174 were measured during a standard 4-hour dialysis session. Neurohumoral and biochemical changes were assessed during losartan administration.ResultsThe pharmacokinetics of losartan and E-3174 in haemodialysis patients did not alter to a clinically significant level. Losartan administration was accompanied by a decline in plasma aldosterone level as well as by an increase in plasma renin activity. Losartan administration resulted in a decline in plasma uric acid level, despite the fact that the study participants had no residual renal function. Losartan and E-3174 were not dialysable.ConclusionsThe pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure. In addition, postdialysis supplementation is not required for losartan because of the negligible dialysability of losartan and E-3174.

ISSN:0312-5963    

出版商:ADIS    

年代:2000

数据来源: ADIS