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Biomedical subjects

Suneel Gupta

Publications and source records attributed to Suneel Gupta.

7 recordsLinked to original sources
PubMed2003

Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies.

BACKGROUND: The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. METHODS: Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. RESULTS: The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy. CONCLUSIONS: These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.

Administration, Oral↗
PubMed2002

Pharmacokinetics of controlled-release verapamil in healthy volunteers and patients with hypertension or angina.

AIMS: To study the dose-ranging population pharmacokinetics of controlled release verapamil in healthy subjects and patients with angina or hypertension. To characterize the pharmacodynamics of controlled-release verapamil in patients with hypertension. METHODS: Dose-ranging studies were conducted in healthy volunteers and patients with hypertension and angina. Subjects received doses of 120, 180, 360, or 540 mg racemic verapamil as an osmotic controlled-release formulation. A population pharmacokinetic model involving zero-order release of verapamil into the gastrointestinal tract with first-order absorption and elimination was used to describe the steady-state plasma concentration profile for R- and S-verapamil. A population sigmoid E(max) pharmacodynamic model was used to describe the effect of R- and S-verapamil on mean arterial blood pressure. RESULTS: S-verapamil had an approximate 4-fold greater apparent clearance than R-verapamil in both healthy volunteers and patients. The apparent plasma clearance of R- and S-verapamil in healthy volunteers decreased over the dose range of 120-540 mg. A similar dose-dependent decrease in apparent plasma clearance was also noted in patients. None of the patient demographic variables examined (age, total body weight, lean body weight, body mass index, and height) explained the variability in verapamil pharmacokinetics. The pharmacodynamic model describing the relationship between verapamil plasma concentration and mean arterial blood pressure indicated that the S-verapamil had a 3.6-fold lower estimated EC(50) compared to R-verapamil. CONCLUSIONS: The results from this dose-ranging pharmacokinetic investigation in healthy volunteers and patients are consistent with previous reports in healthy subjects. S-verapamil is cleared more rapidly than R-verapamil and the estimated EC(50) for S-verapamil was 3.6-fold lower than for R-verapamil. Estimated EC(50) values for R- and S-verapamil decreased with increasing age and decreasing weight.

Adult↗
PubMed2002

New perspectives on the overactive bladder: pharmacokinetics and bioavailability.

In the United States alone, approximately 17 million men and women have symptoms of overactive bladder (OAB). For many years, oxybutynin was the drug of choice for treating OAB. Although it provided effective treatment, multiple daily doses were required, and adverse events, such as dry mouth and constipation, were decided drawbacks. Controlled drug delivery systems seen in commercially available OAB formulations alter the pharmacokinetics of antimuscarinic medications in ways that maintain efficacy and allow once-daily dosing and reduction of adverse events. In the future, OAB medications will not only incorporate new chemical entities, such as the S-enantiomer of oxybutynin, but will also use novel drug delivery technologies, including transdermal patches and bladder implants.

Administration, Cutaneous↗
PubMed2002

Determination of an optimal dosage regimen using a Bayesian decision analysis of efficacy and adverse effect data.

One of the aims of Phase II clinical trials is to determine the dosage regimen(s) that will be investigated during a confirmatory Phase III clinical trial. During Phase II, pharmacodynamic data are collected that enables the efficacy and safety of the drug to be assessed. It is proposed in this paper to use Bayesian decision analysis to determine the optimal dosage regimen based on efficacy and toxicity of the drug oxybutynin used in the treatment of urinary urge incontinence. Such an approach results in a general framework allowing modeling, inference and decision making to be carried out. For oxybutynin, the repeated measurement efficacy and toxicity data were modeled using nonlinear hierarchical models and inferences were based on posterior probabilities. The optimal decision in this problem was to determine the dosage regimen that maximized the posterior expected utility given the prior information on the model parameters and the patient response data. The utility function was defined using clinical opinion on the satisfactory levels of efficacy and toxicity and then combined by weighting the relative importance of each pharmacodynamic response. Markov chain Monte Carlo (MCMC) methodology implemented in Win-BUGS 1.3 was used to obtain posterior estimates of the model parameters, probabilities and utilities.

Aged↗
PubMed2002

Efficacy of a new pattern of delivery of methylphenidate for the treatment of ADHD: effects on activity level in the classroom and on the playground.

OBJECTIVES: To evaluate the pharmacodynamic effects of an experimental (EXP) delivery of methylphenidate (MPH) in children with attention-deficit/hyperactivity disorder and to investigate the situational nature of effects in laboratory classroom and playground settings. METHOD: A "sipping" study methodology was used to deliver a bolus followed by small but increasing MPH doses as the EXP regimen. A randomized, double-blind crossover design was used to compare the EXP regimen to a thrice-daily (TID) regimen and a placebo (PLA) regimen. Measures of efficacy were obtained from a Motionlogger actigraph to quantify activity and from the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale to quantify two domains of behavior (attention and deportment). RESULTS: Compared with PLA, both EXP and TID delivery of MPH produced large, significant reductions in activity and inappropriate behavior in the classroom, but the two MPH regimens did not differ in onset or duration of effects across the day. The MPH effects were situationally dependent and were smaller for the playground than for the classroom settings. CONCLUSIONS: The findings of this "proof of concept" study support the efficacy of a continuous, ascending delivery of MPH. The situational effects of MPH provide support for the theory of selective effects of stimulants, dependent on the demands of the environment.

Attention Deficit Disorder with Hyperactivity↗
PubMed2002

Estimation and inference for a spline-enhanced population pharmacokinetic model.

This article is motivated by an application where subjects were dosed three times with the same drug and the drug concentration profiles appeared to be the lowest after the third dose. One possible explanation is that the pharmacokinetic (PK) parameters vary over time. Therefore, we consider population PK models with time-varying PK parameters. These time-varying PK parameters are modeled by natural cubic spline functions in the ordinary differential equations. Mean parameters, variance components, and smoothing parameters are jointly estimated by maximizing the double penalized log likelihood. Mean functions and their derivatives are obtained by the numerical solution of ordinary differential equations. The interpretation of PK parameters in the model and its flexibility are discussed. The proposed methods are illustrated by application to the data that motivated this article. The model's performance is evaluated through simulation.

Biometry↗