Intraindividual Variability (intraindividual + variability)

Distribution by Scientific Domains

Selected Abstracts

Pharmacokinetic/pharmacodynamic studies in drug product development

Bernd Meibohm
Abstract In the quest of ways for rationalizing and accelerating drug product development, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts provide a highly promising tool. PK/PD modeling concepts can be applied in all stages of preclinical and clinical drug development, and their benefits are multifold. At the preclinical stage, potential applications might comprise the evaluation of in vivo potency and intrinsic activity, the identification of bio-/surrogate markers, as well as dosage form and regimen selection and optimization. At the clinical stage, analytical PK/PD applications include characterization of the dose,concentration,effect/toxicity relationship, evaluation of food, age and gender effects, drug/drug and drug/disease interactions, tolerance development, and inter- and intraindividual variability in response. Predictive PK/PD applications can also involve extrapolation from preclinical data, simulation of drug responses, as well as clinical trial forecasting. Rigorous implementation of the PK/PD concepts in drug product development provides a rationale, scientifically based framework for efficient decision making regarding the selection of potential drug candidates, for maximum information gain from the performed experiments and studies, and for conducting fewer, more focused clinical trials with improved efficiency and cost effectiveness. Thus, PK/PD concepts are believed to play a pivotal role in streamlining the drug development process of the future. 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:18,31, 2002 [source]

Effect of external cueing on gait in Huntington's disease

Arnaud Delval MD
Abstract In Huntington's disease (HD) patients, gait is characterized by a timing disorder with marked intraindividual variability in temporal gait parameters (caused by the presence of both hyperkinetic and hypokinetic features). We sought to determine the influence of use of a metronome on gait parameters in patients simultaneously performing motor or cognitive tasks that required attentional resources. The objective is to evaluate the influence of rhythmic cues on gait interference during self-regulated walking and a dual task paradigm in HD. Fifteen HD patients and 15 paired controls were asked to walk and simultaneously perform another motor task (carrying a tray with four full glasses) or a cognitive task (counting backwards). We evaluated the effect of a metronome (set at 100% and 120% of the subject's self-determined cadence) in three different task conditions (gait alone, gait + motor task, gait + cognitive task). The use of auditory cues during free gait and dual tasks did not improve kinematic parameters in HD patients, in contrast to the situation for control subjects (improvement in gait speed and cadence but not stride length when the metronome was set at 120% in all conditions). HD patients have difficulty in synchronizing their footsteps with a metronome, mainly due to attentional deficits. 2008 Movement Disorder Society [source]

Subthreshold Test Pulses Versus Low Energy Shock Delivery to Estimate High Energy Lead Impedance in Implanted Cardioverter Defibrillator Patients

VOLLMANN, D., et al.: Subthreshold Test Pulses Versus Low Energy Shock Delivery to Estimate High Energy Lead Impedance in Implanted Cardioverter Defibrillator Patients. The high energy lead impedance is valuable for detecting lead failure in ICDs, but until recently shock delivery was necessary for high energy impedance measurement. This study compared the use of subthreshold test pulses and low energy test shocks to estimate the high energy impedance. Immediately after implantation of Ventak Prizm ICDs in 29 patients, the lead impedance was measured with five subthreshold (0.4 ,J) test pulses, 5 low energy (1.1 J) shocks, and two to three high energy(16 4.5 J)shocks. The mean impedances measured using high energy shocks, low energy shocks, and subthreshold pulses were42.0 7.3 ,, 46.5 8.1 ,, and42.4 7.1 ,, respectively. The impedances measured using high and low energy shocks differed significantly(P <0.0001), while those obtained by high energy shocks and low energy pulses did not(P = 0.63). According to the Pearson correlation coefficient, the impedance measurements with subthreshold pulses and low energy shocks were both closely correlated(P < 0.0001)with impedance values determined with high energy shocks. However, while the impedance values tended to be higher when measured with low energy shocks, the concordance correlation coefficient (c) was higher for subthreshold test pulse versus high energy shock(c = 0.92)than for low versus high energy shock(c = 0.73). Furthermore, the intraindividual variability of impedance measurements was lower with subthreshold pulse measurements than with low energy shocks. Compared with low energy shocks, impedance measurement with subthreshold pulses has higher reproducibility and a higher correlation with the impedance obtained by high energy shock delivery. Safe and painless high energy impedance estimation with subthreshold pulses might, therefore, help to detect ICD lead failure during routine follow-up. (PACE 2003; 26:[Pt. II]:457,460) [source]

Variability of Eustachian Tube Function: Comparison of Ears With Retraction Disease and Normal Middle Ears ,

Marie Bunne MD
Abstract Objective To explore the short-term and long-term variability of tubal opening and closing in ears with advanced retractions and in healthy ears. Study Design/Methods Twenty ears with retraction type middle ear disease (R-MED) and 20 normal ears underwent direct recording of the middle ear pressure during repeated forced openings, equalization of +100 daPa and ,100 daPa by swallowing, Valsalva inflation, and forceful sniffing. Tests were performed twice (separated by 30 min) on each of 2 days separated by 3 to 4 months. Results There was considerable intraindividual variability of the forced opening pressure and the closing pressure in both groups, within as well as between sessions and test days. Although the variability was 1.5 to 2 times higher in ears with retraction than in the normal group, mean Po and Pc did not differ between the groups. Compared with normal ears, ears with retraction changed more frequently from a positive to negative test response, or vice versa, when re-tested after 30 minutes. Rates of positive response in the equalization and Valsalva tests were significantly lower in diseased ears compared with normal ears. Conclusions Eustachian tube opening and closing functions vary more in ears with retraction disease than in normal ears, which is consistent with the variable clinical course of R-MED and implies that single tubal function tests have little prognostic value on the individual level. [source]

Population pharmacokinetics of darbepoetin alfa in healthy subjects

Balaji Agoram
Aim To develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. Methods PK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75,8.0 g kg,1, or either 80 or 500 g). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. Results The population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate dose,exposure relationship at the 8.0 g kg,1 -dose relative to the 0.75 g kg,1 -dose may reflect changing relative bioavailability, which increased from ,,48% at 0.75 g kg,1 to 78% at 8.0 g kg,1. The covariate analysis showed that increasing body weight may be related to increasing clearance and central compartment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. Conclusion The developed population PK model describes the inter- and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens. [source]

Infrared-monitored cold response in the assessment of Raynaud's phenomenon

J. Foerster
Summary Background., Evaluation of treatments for Raynaud's phenomenon (RP) requires objective response parameters in addition to clinical activity scores. Thermographic monitoring of fingertip re-warming after cold challenge has been widely used but usually requires sophisticated equipment. We have previously shown that fingertip re-warming after cold challenge follows a first-order transient response curve that can be described by a single variable, designated ,. Objectives., Here, we describe a novel device termed a duosensor, which records the , value upon cold challenge in an automated manner. Methods., We determined , values in healthy probands, patients with primary or secondary RP associated with autoimmune disease and patients with scleroderma-associated RP following cold challenge, to determine assay variability, sensitivity and specificity. Results., Duosensor-based thermography exhibited low intraindividual variability in healthy probands. As expected, , values in RP patients were significantly increased compared with controls (8.08 3.65 min vs. 3.23 1.65 min). The duosensor-determined , value yielded a specificity of 94.6% and predictive value of 95.3% for the presence of RP in a retrospective analysis of 139 patients. Furthermore, in a cohort of scleroderma patients with RP, patient self-assessment of RP severity correlated with , values. Conclusions., Taken together, the present data suggest that , value determination provides a suitable outcome measure for clinical studies of novel RP treatments. As the duosensor is a simple stand-alone device requiring no supporting equipment and minimal personnel attention, it should allow RP activity monitoring even in clinical settings with minimal technical infrastructure. [source]