摘要:

Bisphosphonates suppress osteoclast-mediated bone resorption and are widely used in the management of osteoporosis. Daily oral administration of alendronic acid and risedronic acid have been shown to reduce the risk of vertebral and non-vertebral fractures. Once-weekly regimens with these bisphosphonates are pharmacologically equivalent to daily regimens. Regimens with treatment-free intervals longer than 1 week present an attractive therapeutic option as they may offer additional patient convenience and long-term adherence to treatment. However, until recently, such regimens, usually referred to as intermittent or cyclical, have not shown any convincing antifracture efficacy in clinical trials, probably because of the empirical manner in which the design of these regimens has been approached. Investigation of pharmacokinetics/pharmacodynamics of bisphosphonates may help in the design of effective intermittent dosage regimens.Bisphosphonates are poorly absorbed from the gastrointestinal tract and about 50% of the absorbed drug is taken up selectively by the skeleton, while the rest is excreted unaltered in urine. Bisphosphonates exert their action at the bone surface, where they are taken up by the osteoclasts during bone resorption. Therefore, when describing the pharmacokinetics of bisphosphonates in relation to the pharmacodynamics, the amount of bisphosphonate at the skeleton should be accounted for. Few of the reported clinical pharmacokinetic studies addressed this issue. This is partly due to the absence of study design elements to account for skeletal binding of the drugs. Pharmacokinetic studies have also been hampered by technical difficulties in determining the concentration of bisphosphonates in serum and urine. Moreover, most clinical pharmacokinetic (but also pharmacokinetic/pharmacodynamic) studies have primarily used noncompartmental analysis, leaving out the distinct advantages of modelling and simulation techniques.Clinically, the primary action of bisphosphonates can be assessed by the measurement of biochemical markers of bone resorption. Recent studies indicate that the pattern of these markers during bisphosphonate treatment may be predictive of antifracture efficacy; however, only limited data are available for the development of pharmacokinetic/pharmacodynamic models that are able to predict the response of these markers to different treatment regimens with bisphosphonates. Recently, pharmacokinetic/pharmacodynamic models for response to bisphosphonates have been described and, at present, some of them are being used in the design of bisphosphonate regimens with long drug-free intervals.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Atomoxetine (Strattera®), a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation andN-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine.The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1–2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Population pharmacokinetics has been an important technique used to explore and define relevant sources of variation in drug exposure and response in patient populations. This has been especially true in the area of antiretroviral therapy where the assurance of adequate and sustained drug exposure of multiple agents is highly correlated with therapeutic success. Population pharmacokinetic analyses across the four drug classes and 20 US FDA-approved products used to treat HIV have been published to date. The published reports were predominantly based on actual clinical trials conducted in HIV-infected patients with one or more agents administered.Modelling and simulation approaches have been used in the evaluation of antiretroviral agent outcomes incorporating problematic design and analysis factors such as sparse plasma sampling, data imbalance and censored data. Additional benefits of population modelling approaches applied to the investigation of antiretroviral agents include the ability to assess dosing compliance, understanding and quantifying drug-drug interactions in order to select dosing regimens and the screening of new drug candidates. Pharmacokinetic/pharmacodynamic models have been used to characterise the relationship between drug exposure and virological and immunological response, and to predict clinical outcome. These models offer the best opportunity for individualising and optimising patient therapy, particularly when adjusted for adherence/compliance.The impact of population pharmacokinetics in the area of antiretroviral therapy can be directly assessed by its role in the validation of surrogate markers such as viral RNA load, therapeutic drug monitoring and the management of individual patient outcomes via exposure-toxicity relationships. Each of these population pharmacokinetic outcomes has contributed to the current regulatory environment, specifically in the area of accelerated approval of new antiretroviral agents.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveA prospective pharmacokinetic study was performed in Caucasian patients from an intensive care unit with respiratory support to evaluate the influence of this circumstance on the pharmacokinetic behaviour of levofloxacin.Patients and methodsA standard dosage regimen of 500 mg/day was administered to nine Caucasian patients included in the study, irrespective of their demographic characteristics. The experimental data on plasma concentrations were analysed by independent-modelling techniques to estimate the following pharmacokinetic parameters: area under the plasma concentration-time curve (AUC), volume of distribution at steady state (Vss), plasma clearance (CL), maximum plasma concentration at steady state (Cmax,ss) and elimination half-life (t½β). Multiple regression analysis was applied to establish the type of correlation between the pharmacokinetic parameters and patient characteristics; the Monte Carlo simulation technique was implemented for the pharmacokinetic/pharmacodynamic analysis based on the probability distribution of the values of AUC/minimum inhibitory concentration (MIC) and Cmax,ss/MIC observed in this group of patients.Results and conclusionThe results show that for AUC the simplest linear model with creatinine clearance as the only independent variable fits the data at a 99% confidence level, explaining more than 85% of the observed variability in this parameter. The volume of distribution, however, showed a statistical correlation with the severity of the illness (Simplified Acute Physiology Score II), although total bodyweight also explains a high percentage of variability of these parameters. Since the group of patients included in the study was small and also included obese individuals, it is difficult to estimate with precision the contribution of each circumstance (overweight or illness severity) to the pharmacokinetic behaviour of levofloxacin.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundThe neurokinin NK1-receptor antagonist aprepitant has demonstrated efficacy in preventing highly emetogenic chemotherapy-induced nausea and vomiting.ObjectiveThe objective of the present study was to investigate the effects of impaired renal function on the pharmacokinetics and safety of aprepitant.Subjects and methodsA total of 32 patients and healthy subjects were evaluated in this open-label, two-part study. Pharmacokinetic parameters after a single oral dose of aprepitant 240mg were measured in eight patients with end-stage renal disease (ESRD) requiring haemodialysis, eight patients with severe renal insufficiency (SRI [24-hour creatinine clearance <30 mL/min/1.73m2]) and 16 healthy and age-, sex- and weight-matched subjects (controls).ResultsIn ESRD patients, the area under the plasma concentration-time curve (AUC) from 0 to 48 hours (AUC48) for aprepitant was on average approximately 36% lower than that observed in control subjects (ratio [ESRD patients/healthy controls] of geometric means = 0.64), but the 90% confidence interval 0.52, 0.78 for the ratio of true mean AUC48fell within the predefined target interval of 0.5, 2.0. Also in ESRD patients, there was no statistically or clinically significant difference in unbound aprepitant AUC (which may be more clinically relevant than total aprepitant AUC) when compared with healthy control subjects. Aprepitant pharmacokinetic parameters in ESRD patients were clinically similar when haemodialysis was initiated at 4 hours or 48 hours after aprepitant administration. In SRI patients, the ratio (SRI patients/healthy controls) of aprepitant AUC from zero to infinity (AUC∞) geometric mean value was 0.79 with a 90% confidence interval of 0.56, 1.10. On average, in SRI patients the principal aprepitant pharmacokinetic parameters (AUC∞, initial maximum plasma concentration [Cmax], time to initial Cmax, and apparent elimination half-life) were not statistically different from those obtained in healthy control subjects. Aprepitant was generally well tolerated in both ESRD and SRI patients.ConclusionThe results of this study demonstrate that ESRD, haemodialysis and SRI have no clinically meaningful effect on aprepitant pharmacokinetics. Therefore, no dosage adjustment of aprepitant is warranted in SRI or ESRD patients.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative typically used for recreational purposes. The participation of cytochrome P450 (CYP) 2D6 in the oxidative metabolism of MDMA may suggest an increased risk of acute toxicity in CYP2D6 poor metabolisers. This study was aimed at assessing the contribution of CYP2D6 to MDMA dispositionin vivousing paroxetine as a metabolic probe inhibitor. Paroxetine, a CYP2D6 inhibitor, was repeatedly administered before MDMA administration.Study designThis was a randomised, double-blind, crossover, placebo-controlled trial conducted in seven healthy male volunteers who were CYP2D6 extensive metabolisers. Treatment conditions (paroxetine/MDMA and placebo/MDMA) were randomly assigned. Each volunteer participated in two 3-day sessions. On days 1, 2 and 3 subjects received a single oral dose of paroxetine or placebo 20mg. On the third day, a single oral dose of MDMA 100mg was administered in both paroxetine and placebo conditions.MethodsPlasma concentration-time profiles and urinary recoveries of MDMA and its metabolites were measured, as well as plasma concentrations of paroxetine, (3S,4R)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine, and (3S,4R)-4-(4-fluorophenyl)-3-(3-methoxy-4-hydroxyphenoxymethyl)-piperidine (HM-paroxetine).ResultsParoxetine given before MDMA resulted in significant increases of MDMA area under the plasma concentration-time curve from 0 to 27 hours (AUC27) [23%], AUC from zero to infinity (AUC∞) [27%] and maximum plasma concentration (Cmax) [17%], without significant differences in MDMA time to reach Cmax(tmax). MDMA elimination-related pharmacokinetic parameters showed a significant reduction of MDMA elimination rate constant (Ke) [−14%] and plasmatic clearance (CLP) [−29%]. In the case of 3,4-dihydroxymethamphetamine (HHMA), a 21% decrease in Cmaxwith no significant differences in AUC27, AUC∞, Keand elimination half-life) were found. 4-Hydroxy-3-methoxymethamphetamine (HMMA) showed a decrease in plasma concentrations with a reduction in AUC27(−28%), AUC∞(−20%) and Cmax(−46%). In the case of 3,4-methylenedioxyamphetamine (MDA) an increase in Cmax(17%) and AUC27(16%) was found. Following paroxetine pretreatment, the urinary recovery (0–45 hours) of MDMA increased by 11%; HHMA and HMMA urinary recoveries were 27% and 16% lower, respectively compared with placebo. The ratio of Cmaxvalues of paroxetine and its metabolite on days 1 and 3 showed a 3-fold reduction, with no differences in tmax.Discussion and conclusionThe contribution of CYP2D6 to MDMA metabolism in humans is not >30%, therefore other CYP isoenzymes may contribute toO-demethylenation of MDMA. Accordingly, the relevance of genetic polymorphism in CYP2D6 activity on MDMA effects and MDMA-induced acute toxicity should be examined as well as the interactions of other CYP2D6 substrates with MDMA, once the enzyme is inhibited. The pharmacokinetics of HM-paroxetine in humans after the administration of repeated doses is reported for the first time in this study.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS