Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient's psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions. Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the threo pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance. Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain. Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum. There is marked individual variability in the dose-response relationship for methylphenidate, and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods for the analysis of the active component, d-threo-methylphenidate. It is difficult to predict which children will have a favourable response to methylphenidate. Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. The use of individual single-blind medication trials may be a practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g. misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens.

The population pharmacokinetic analysis confirmed that etanercept is slowly absorbed and eliminated after subcutaneous administration. The logistic model linking cumulative AUC with ACR20 adequately characterized the time course of clinical improvement in patients with rheumatoid arthritis receiving etanercept.

). Monte Carlo simulation was performed with the ADAPT II program to estimate the PTA at which the free drug concentrations exceed the MIC for 30 to 60% of the dosing interval (30 to 60% fT > MIC). For ceftobiprole at 500 mg i.v. q12h, the probabilities of achieving 30% and 50% fT > MIC exceeded 90% for MICs <2 mg/liter and <1 mg/liter, respectively, For ceftobiprole at 500 mg i.v. q8h, the probabilities of achieving 40 and 60% fT > MIC exceeded 90% for MICs <4 mg/liter and <2 mg/liter, respectively. For ceftobiprole at both 500 mg i.v. q12h and 500 mg i.v. q8h, the probability of achieving a nearly bactericidal effect (50% fT > MIC) exceeded 90% for methicillin-susceptible S. aureus and MRSA. For gram-negative pathogens, the PTA for achieving a nearly maximal bactericidal effect (60% fT > MIC) for ceftobiprole at 500 mg i.v. q8h exceeded 90% for non-AmpCproducing gram-negative organisms. Ceftobiprole at 500 mg i.v. q12h, for patients who had a creatinine clearance rate of <50 ml/min, was identified as the most appropriate treatment regimen for patients who require renal dose adjustment for mild to moderate renal impairment.Methicillin-resistant Staphylococcus aureus (MRSA) has recently emerged as a serious problem in the community (13,18,21,23,(25)(26)(27), and it already represents 40 to 50% of staphylococcal isolates in many health care institutions (2). Given the magnitude of the problem, new agents with activity against MRSA are a welcome addition to the physician's therapeutic armamentarium. While new agents such as linezolid, new glycopeptides, and daptomycin have become available (5, 31), clinicians have long experience and trust in ␤-lactam antibiotics as therapeutic agents for life-threatening infections, and these drugs also have a broad margin of safety.MRSA isolates are endowed with a mecA cassette that allows the strain to express a new penicillin-binding protein (PBP 2a or PBP 2Ј). This protein has a markedly diminished affinity for acylating most ␤-lactam drugs, which is the genesis of its clinical resistance to such agents (17). Ceftobiprole, an investigational cephalosporin currently in phase III trials for complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia (NP), represents a major advance among the ␤-lactam antibiotics, in that its structure allows it to bind to PBP 2a and thus kill MRSA (4). Indeed, a considerable amount of preclinical data demonstrate that ceftobiprole acts in a bactericidal fashion in preclinical infection models, both in vitro and in vivo (3,6,9,10,12,15,16,19,33,34). The drug possesses excellent activity against MRSA and other resistant gram-positive pathogens, such as penicillin-resistant Streptococcus pneumoniae (3,6,9,12,16,19). Ceftobiprole also possesses activity against the common gram-negative pathogens often seen in the health care setting, making it a unique broadspectrum agent with potential for early, empirical use (3,9,15,34). Data from the laboratory of Andes and Craig demonstrated that pharmacodynamics of ceftobiprole are simila...

A completed phase 3 trial result was simulated 100 times on the basis of a simulation model of quetiapine fumarate (Seroquel), an antischizophrenic agent. The simulation was executed by analysts who were completely blinded from results of the actual trial until after the simulations were submitted to the holder of the trial results. Data from two clinical investigations of quetiapine in patients with schizophrenia were analyzed by use of nonlinear mixed effects modeling to derive a population pharmacokinetic- and pharmacodynamic-based simulation model. The time course of quetiapine concentrations was described by use of a one-compartment open linear pharmacokinetic model with first-order absorption and elimination. The combination of an inhibitory maximum effect pharmacodynamic model for the active treatment effect and a linear function of time for the placebo effect characterized the observed time course of change in the Brief Psychiatric Rating Scale. Simulation results were compared with those in the actual trial to evaluate how well the simulations predicted the outcome. The actual trial results for all doses except the placebo group fell within the predicted Brief Psychiatric Rating Scale scores +/- 1 SE. Unlike the phase 2 trial, from which the pharmacokinetic/pharmacodynamic model was developed, the placebo group in the actual phase 3 trial showed deterioration of Brief Psychiatric Rating Scale scores with time. We conclude that variable placebo responses observed in short-term studies of schizophrenia provide an inadequate basis for the modeling and simulation of placebo subjects in clinical trials. Knowledge of the range of placebo response observed in other studies may have provided an improved basis for the placebo effect model. The model for active drug produced adequate predictions of the actual trial outcomes.

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-␤-cyclodextrin (HP-␤-CD) after intravenous administration to children at risk for fungal infection. Thirty-three children aged 7 months to 17 years received a single dose of itraconazole (2.5 mg/kg in 0.1-g/kg HP-␤-CD) administered over 1 h by intravenous infusion. Plasma samples for the determination of the analytes of interest were drawn over 120 h and analyzed by high-pressure liquid chromatography, and the pharmacokinetics were determined by traditional noncompartmental analysis. Consistent with the role of CYP3A4 in the biotransformation of itraconazole, a substantial degree of variability was observed in the pharmacokinetics of this drug after IV administration. The maximum plasma concentrations (C max ) for itraconazole, hydroxyitraconazole, and HP-␤-CD averaged 1,015 ؎ 692 ng/ml, 293 ؎ 133 ng/ml, and 329 ؎ 200 g/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-␤-CD averaged 4,922 ؎ 6,784 ng ⅐ h/ml, 3,811 ؎ 2,794 ng ⅐ h/ml, and 641.5 ؎ 265.0 g ⅐ h/ml, respectively, with no significant age dependence observed among the children evaluated. Similarly, there was no relationship between age and total body clearance (702.8 ؎ 499.4 ml/h/kg); however, weak associations between age and the itraconazole distribution volume (r 2 ‫؍‬ 0.18, P ‫؍‬ 0.02), C max (r 2 ‫؍‬ 0.14, P ‫؍‬ 0.045), and terminal elimination rate (r 2 ‫؍‬ 0.26, P < 0.01) were noted. Itraconazole infusion appeared to be well tolerated in this population with a single adverse event (stinging at the site of infusion) deemed to be related to study drug administration. Based on the findings of this investigation, it appears that intravenous itraconazole can be administered to infants beyond 6 months, children, and adolescents using a weight-normalized approach to dosing.With both traditional and emerging fungal pathogens contributing to an increasing rate of morbidity, invasive mycoses remain a serious and potentially fatal complication for immunocompromised children (1,16,23,26,27,31). In recent years, a growing number of new therapeutic agents have found their way to market (28). However, the management of systemic fungal infections is still restricted to a relatively small number of drug classes encompassing a limited number of pharmacologic actions (i.e., most are cell wall-acting agents). As such, the spectrum of activity and established efficacy, in combination with the pharmacokinetic and toxicity profiles of each agent, will shape their role in therapy.Itraconazole is a first-generation synthetic triazole antifungal that has been in clinical use for nearly two decades. Although fungistatic against pathogenic yeast, itraconazole retains activity against a portion of fluconazole-resistant isolates and demonstrates fungicidal activity against a number of filamentous organisms that cause severe invasive disease (25). Compa...

Pharmacokinetic/pharmacodynamic (PK/PD) models for hematological drug effects exist that assume that cells are produced by a zero- or first-order process, survive for a specific duration (cell lifespan), and then are lost. Due to the fact that delay differential equations (DDE) are needed for cell lifespan models, their software implementation is not straightforward. Our objective is to demonstrate methods to implement three different cell lifespan models for dealing with hematological drug effects and to evaluate the performance of NONMEM to estimate the model parameters. For the basic lifespan indirect response (LIDR) model, cells are produced by a zero-order process and removed due to senescence. The modified LIDR model adds a precursor pool. The LIDR model of cytotoxicity assumes a three-pool indirect model to account for the cell proliferation with capacity-limited cytotoxicity followed by maturation, and removal from the circulation. A numerical method (method of steps) implementing DDE in NONMEM was introduced. Simulation followed by estimation was used to evaluate NONMEM performance and the impact of the minimization algorithm (first-order method vs. first-order conditional estimation method) and the model for residual variability on the estimates of the population parameters. The FOCE method combined with log-transformation of data was found to be superior. This report provides methodology that will assist in application of population methods for assessing hematological responses to various types of drugs.

Iron derived from SFGC appears to be rapidly transferred to a bioavailable iron compartment as transferrin-bound iron after digestion in the RES. At the doses administered in this study, liberation of potentially toxic, free iron was not detectable.

These results suggest that no titration period is required in patients receiving stable doses of twice-daily IR galantamine who are switched to once-daily ER galantamine. The once-daily dosage regimen of ER galantamine without a titration period should prove convenient for AD patients and their caregivers and should increase treatment compliance.