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PD Parameters (pd + parameter)
Selected AbstractsHow pharmacokinetic and pharmacodynamic principles pave the way for optimal basal insulin therapy in type 2 diabetesINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 10 2010S. Arnolds Summary This pedagogical review illustrates the differences between pharmacokinetic (PK) and pharmacodynamic (PD) measures, using insulin therapy as the primary example. The main conclusion is that PD parameters are of greater clinical significance for insulin therapy than PK parameters. The glucose-clamp technique, the optimal method for determining insulin PD, is explained so that the reader can understand the important studies in the literature. Key glucose-clamp studies that compare two basal insulin analogues , insulin glargine and insulin detemir , to Neutral Protamine Hagedorn insulin and to each other are then presented. The review further explains how PD parameters have been translated into useful clinical concepts and simple titration algorithms for everyday clinical practice. Finally, the necessity of overcoming patient and/or physician barriers to insulin therapy and providing continuing education and training is emphasised. [source] Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measureJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2010Mohamed A. Kamal Abstract Categorical measures of lorazepam sleepiness and dizziness were modeled to identify differences in pharmacodynamic (PD) parameters between these adverse events (AEs). Differences in data-derived PD parameters were compared with relative incidence rates in the drug label (15.7% and 6.9%, respectively). Healthy volunteers (n,=,20) received single oral doses of 2,mg lorazepam or placebo in a randomized, double-blind, cross-over fashion. A seven-point categorical scale measuring the intensity of AEs was serially administered over 24,h. The maximum score (MaxS), and area under the effect curve (AUEC) were determined by noncompartmental methods and compared using a paired t -test. Individual scores were modeled using a logistic function implemented in NONMEM. AUEC and MaxS for sleepiness were significantly higher than dizziness (20.35 vs. 9.76, p,<,0.01) and (2.35 vs. 1.45, p,<,0.01). Model slope estimates were similar for sleepiness and dizziness (0.21,logits,×,mL/ng vs. 0.19,logits,×,mL/ng), but baseline logits were significantly higher for sleepiness (,2.81 vs. ,4.34,logits). Data-derived PD parameters were in concordance with label incidence rates. The higher intensity of sleepiness may be directly related to baseline (no drug present) while the increase in intensity as a result of drug was relatively similar for both AEs. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3628,3641, 2010 [source] ORIGINAL RESEARCH,PEYRONIE'S DISEASE: Predicting Delay in Presentation in Men with Peyronie's DiseaseTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2010John P. Mulhall MD ABSTRACT Introduction., Many men with Peyronie's disease (PD) delay presentation to a urologist. The reasons for this are unclear. Aim., To define the differences in men who present early compared to those presenting in a delayed fashion and to determine predictors of delayed presentation. Methods., A retrospective analysis of all patients presenting for the first medical evaluation of PD. All patients underwent a standard history and physical examination and had a standardized deformity assessment. Demographic and PD parameters were recorded. Main Outcome Measures., Statistical comparison was used to define factors that were different between early and delayed presenters and multivariable analysis was used to define predictors of presentation >12 months. Results., 482 patients were analyzed, 61% presenting ,12 months, 39% >12 months. Mean patient age was 52 ± 13 years and mean duration of PD was 17 ± 30 months. Mean measured curvature was 42° ± 19°. Multivariable analysis revealed that delayed presentation patients were significantly more likely to be older (odds ratio [OR] = 4.0), to be in long-term relationships (OR = 3.6), to have dorsal curvature (OR = 2.5), to have curvature <45° (OR = 3.3), to be heterosexual (OR = 2.0), and to have simple deformity (OR = 1.5). Conclusions., One-third of men with PD presented in a delayed fashion and they tended to be older, to be in long-term relationships, to have dorsal curvature, or to have simple deformity. Mulhall JP, Alex B, and Choi JM. Predicting delay in presentation in men with Peyronie's disease. J Sex Med 2010;7:2226,2230. [source] The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic,pharmacodynamic modelingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2010Tomoya Ohno Abstract The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO-4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO-4641, a sphingosine 1-phosphate receptor modulator. Using a two-compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO-4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO-4641 was described by an indirect-response model. The indirect-response model had an Imax value of 0.828 and an IC50 value of 1.29,ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO-4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies. Copyright © 2010 John Wiley & Sons, Ltd. [source] The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Joachim Stangier Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10,400 mg (n = 40) or at multiple doses of 50,400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8,10 h and 14,17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430,2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min,1 (range 1480,2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration,time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted. [source] Pharmacokinetic-pharmacodynamic modelling in the early development phase of anti-psychotics: a comparison of the effects of clozapine, S 16924 and S 18327 in the EEG model in ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2001T J Parker The use of pharmacokinetic/pharmacodynamic (PK/PD) analysis in early compound development was investigated in the rat for two developmental anti-psychotic compounds with clozapine as a positive control. Three plasma samples were collected from each of eight animals according to a pre-defined sampling matrix allowing a total of 12 time points for PK analysis. Quantitative electroencephalography (QEEG), particularly the theta and beta frequencies, was used as a measurement of pharmacological effect. PK/KD modelling of the sparse PK data available relative to a rich set of PD data was achieved using a population approach in NONMEM (IV). Individual PK parameter estimates were incorporated into a PK/PD model. Qualitative EEG changes in rat and human were similar for clozapine, but different for the two developmental compounds, suggesting that changes in these PD parameters may not be specifically related to the anti-psychotic activity. Although no definitive data are available concerning the signal specificity of EEG frequency bands with respect to dopaminergic or serotonergic receptor activity, qualitative and quantitative differences seen in EEG parameters are likely to result from the multiple receptor occupancy for these compounds. The results confirm the value of population PK/PD modelling in conjunction with sparse sampling to enable determination of concentration effect relationships in the pre-clinical development programme of CNS-active drugs. British Journal of Pharmacology (2001) 132, 151,158; doi:10.1038/sj.bjp.0703791 [source] A preclinical pharmacokinetic/pharmacodynamic approach to determine a dose of GnRH, for treatment of ovarian follicular cyst in cattleJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2004S. MONNOYER The objective of this study was to explore the value of a preclinical PK/PD approach to determine a gonadotropin-releasing hormone (GnRH) dose in cows using the pituitary LH response as a surrogate endpoint. Using an indirect effect model with stimulation of the LH entry rate, the in vivo basic pharmacodynamic parameters of GnRH were determined. The EC50 of GnRH was 51 ± 16 pg/mL, the EC50 being the GnRH plasma concentration able to produce 50% of the maximum possible stimulation (Smax) of the hypophysis (Smax = 48 ± 13). From individual PK/PD parameters, the ED50 of GnRH, i.e. the estimated dose of GnRH required to determine half the maximum possible stimulating effect on LH release, was calculated to 62 ,g/h per cow. Using the PK/PD model, the GnRH dose required to achieve a selected breakpoint value of 5 ng/mL for maximum LH concentration (surrogate value for LH concentration predicting clinical efficacy for cystic conditions), was 52 ± 18 ,g and for a standard GnRH dose of 100 ,g, the mean maximum plasma LH concentration predicted by the model was 7.22 ± 0.98 ng/mL. [source] | ||||||||||