The Experts below are selected from a list of 2844 Experts worldwide ranked by ideXlab platform
William J. Jusko - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic Pharmacodynamic Modeling of corticosterone suppression and lymphocytopenia by methylprednisolone in rats
Journal of Pharmaceutical Sciences, 2008Co-Authors: Debra C Dubois, Richard R Almon, William J. JuskoAbstract:Adrenal suppression and lymphocytopenia are commonly monitored pharmacological responses during systemic exposure to exogenously administered corticosteroids. The Pharmacodynamics of plasma corticosterone (CS) and blood lymphocytes were investigated in 60 normal rats which received either 50 mg/kg methylprednisolone (MPL) or vehicle intramuscularly. Blood samples were collected between 0.5 and 96 h following treatment. Plasma CS displayed a transient suppression with re-establishment of a normal circadian rhythm 24 h following drug treatment. An indirect response model with suppression of production well captured plasma CS profiles. An early stress-induced rise in CS was also factored into the model. Blood lymphocyte numbers exhibited a sharp decline and then returned to a new circadian rhythm which was half of the original baseline level. An integrated Pharmacodynamic (PD) model with inhibition of lymphocyte trafficking from tissue to blood by both MPL and CS and induction of cell apoptosis by MPL reasonably captured this lymphocytopenia. Rats and humans differ in lymphocyte responses with humans showing full recovery of baselines. Modeling provides a valuable tool in quantitative assessment of dual, complex drug responses.
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Pharmacokinetic and Pharmacodynamic Modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2005Co-Authors: Wojciech Krzyzanski, William J. Jusko, Mary C Wacholtz, Neil Minton, Wing K CheungAbstract:A pharmacokinetic and Pharmacodynamic (PK/PD) model for recombinant human erythropoietin (Epoetin alfa) in healthy subjects was developed to describe the time profiles of changes in serum Epoetin alfa and the pharmacological responses of percent reticulocytes, total red blood cell counts, and hemoglobin after single and multiple subcutaneous administration of Epoetin alfa. Data used in the development of the model were obtained from a clinical study carried out in healthy volunteers in which Epoetin alfa was administered either as 150 IU/kg three-times-a-week (t.i.w.) or fixed 40,000 IU weekly (q.w.) doses for 4 weeks. A dual-absorption rate model (fast zero-order and slow first-order inputs) with linear disposition kinetics was used to characterize the pharmacokinetics of erythropoietin after subcutaneous administration. A new catenary cell production and lifespan loss model was used to fit the Pharmacodynamic data yielding estimates of SC50, Smax, and other Pharmacodynamic parameters. Flip-flop kinetics was apparent in the pharmacokinetics as the absorption rate was slower (k(a) = 0.7 day(-1)) than the elimination rate (CL/V(d) = 1.2-9.2 day(-1)). In the Pharmacodynamics, an SC50 of 58 mIU/mL was estimated indicating that low serum erythropoietin concentrations were sufficient to produce pharmacological effects. The established PK/PD model predicts similar pharmacological responses of hemoglobin and total red blood cell counts for the 150 IU/kg t.i.w. and 40,000 IU q.w. regimens in healthy subjects.
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pharmacokinetic and Pharmacodynamic Modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers
The Journal of Clinical Pharmacology, 2004Co-Authors: Rohini Ramakrishnan, Neil Minton, Mary C Wacholtz, Wing K Cheung, William J. JuskoAbstract:This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the Pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were obtained from 4 clinical studies carried out in healthy volunteers. Epoetin alfa (rHuEpo) was administered as 5 single IV doses ranging from 10 to 500 IU/kg, as 8 single SC doses ranging from 300 to 2400 IU/kg, and as 2 multiple SC dosage regimens (150 IU/kg/3 times a week [tiw] and 600 IU/kg/wk). A dual-absorption rate model (fast zero-order and slow first-order inputs) with nonlinear disposition characterized the PK of SC rHuEpo. A high K(m) value was obtained indicating that clearance was mildly nonlinear. Absorption was slow (t(max) approximately 24 hours), and the bioavailability of SC rHuEpo increased with dose (ranging from 46%-100%). A catenary cell production and loss model with a feedback down regulation component was used to fit the reticulocyte data yielding estimates of the stimulatory capacity (S(max)), sensitivity (SC(50)), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. An SC(50) of 27 to 61 IU/L was estimated indicating that low physiological plasma rHuEpo concentrations were sufficient to produce pharmacological effects. No marked sex-dependent differences in clinical responses to rHuEpo therapy were found despite baseline differences. Realistic pharmacokinetic and physiological models accounted for clinical responses from a wide array of dosing conditions with rHuEpo. The rationale for greater efficacy of SC administration of rHuEpo compared to IV was ascertained.
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the genomic response of skeletal muscle to methylprednisolone using microarrays tailoring data mining to the structure of the pharmacogenomic time series
Pharmacogenomics, 2004Co-Authors: Richard R Almon, Debra C Dubois, William H Piel, William J. JuskoAbstract:High-throughput data collection using gene microarrays has great potential as a method for addressing the pharmacogenomics of complex biological systems. Similarly, mechanism-based pharmacokinetic/Pharmacodynamic Modeling provides a tool for formulating quantitative testable hypotheses concerning the responses of complex biological systems. As the response of such systems to drugs generally entails cascades of molecular events in time, a time series design provides the best approach to capturing the full scope of drug effects. A major problem in using microarrays for high-throughput data collection is sorting through the massive amount of data in order to identify probe sets and genes of interest. Due to its inherent redundancy, a rich time series containing many time points and multiple samples per time point allows for the use of less stringent criteria of expression, expression change and data quality for initial filtering of unwanted probe sets. The remaining probe sets can then become the focus of more intense scrutiny by other methods, including temporal clustering, functional clustering and pharmacokinetic/Pharmacodynamic Modeling, which provide additional ways of identifying the probes and genes of pharmacological interest.
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Modeling of dose response time data four examples of estimating the turnover parameters and generating kinetic functions from response profiles
Biopharmaceutics & Drug Disposition, 2000Co-Authors: Johan Gabrielsson, William J. Jusko, Liisi AlariAbstract:The most common approach to in vivo pharmacokinetic and Pharmacodynamic Modeling involves sequential analysis of the plasma concentration versus time and then response versus time data, such that the plasma kinetic model provides an independent function, driving the dynamics. However, response versus time data, even in the absence of measured drug concentrations, inherently contain useful information about the turnover characteristics of response (turnover rate, half-life of response), the drug's biophase kinetics (F, half-life) as well as the Pharmacodynamic characteristics (potency, intrinsic activity). Previous analyses have assumed linear kinetics, linear dynamics, no time lag between kinetics and dynamics (single-valued response), and time constant parameters. However, this report demonstrates that the drug effect can be indirect (antinociception, cortisol/adrenocorticotropin (ACTH), body temperature), display nonlinear kinetics, display feedback mechanisms (nonstationarity, cortisol/ACTH) and exhibit hysteresis with the drug levels in the biophase (antinociception, body temperature). It is also demonstrated that crucial determinants of the success of Modeling dose–response–time data are the dose selection, multiple dosing, and to some extent different input rates and routes. This report exemplifies the possibility of assigning kinetic forcing functions in Pharmacodynamic Modeling in both preclinical and clinical studies for the purpose of characterizing (discrimination between turnover and drug-specific parameters) response data and optimizing subsequent clinical protocols, and for identification of inter-individual differences. Copyright © 2000 John Wiley & Sons, Ltd.
Meindert Danhof - One of the best experts on this subject based on the ideXlab platform.
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dopamine d2 receptor occupancy as a predictor of catalepsy in rats a pharmacokinetic Pharmacodynamic Modeling approach
Pharmaceutical Research, 2014Co-Authors: Martin Johnson, An Vermeulen, Meindert Danhof, Magdalena Kozielska, Venkatesh Pilla Reddy, Hugh A Barton, Sarah Grimwood, Rik De Greef, Geny M M Groothuis, Johannes H ProostAbstract:Objectives Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy. Excessive D2RO (>80%) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human. The objective of this study was to use pharmacokinetic and Pharmacodynamic Modeling tools to relate CAT with D2RO in rats and to compare that with the relationship between D2RO and EPS in humans.
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pharmacokinetic Pharmacodynamic Modeling of the respiratory depressant effect of norbuprenorphine in rats
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Ashraf Yassen, Jingmin Kan, Erik Olofsen, Ernst Suidgeest, Albert Dahan, Meindert DanhofAbstract:The objective of this investigation was to characterize the pharmacokinetic-Pharmacodynamic (PK-PD) correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32-1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. A saturable biophase distribution model with a power PD model described the PK-PD relationship best. No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acts as a full agonist with regard to respiratory depression. Moreover, analysis of the hysteresis based on the combined receptor association-dissociation biophase distribution model yielded high values of the rate constants for receptor association and dissociation, indicating that these processes are not rate-limiting. In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.
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mechanism based pharmacokinetic Pharmacodynamic Modeling a new classification of biomarkers
Pharmaceutical Research, 2005Co-Authors: Meindert Danhof, Gunnar Alvan, Svein G Dahl, Jochen Kuhlmann, Gilles PaintaudAbstract:In recent years, pharmacokinetic/Pharmacodynamic (PK/PD) Modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD Modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.
Andrew J Mclachlan - One of the best experts on this subject based on the ideXlab platform.
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investigation of the effects of herbal medicines on warfarin response in healthy subjects a population pharmacokinetic Pharmacodynamic Modeling approach
The Journal of Clinical Pharmacology, 2006Co-Authors: Xuemin Jiang, Andrew J Mclachlan, Elaine Y L BlairAbstract:Systematic evidence regarding herb-drug interactions is lacking. This study investigated herb-drug interactions with warfarin. S-warfarin concentration and response (prothrombin complex activity) data from healthy subjects (n = 24) who received a single warfarin dose (25 mg) and either St John's wort, Asian ginseng, Ginkgo biloba, or ginger were analyzed using a population pharmacokinetic-Pharmacodynamic Modeling approach. The ratio of S-warfarin apparent clearance (CL/F) compared to control was 1.39 +/- 0.06 and 1.14 +/- 0.04 after St John's wort and Asian ginseng pretreatment, respectively. Other pharmacokinetic and Pharmacodynamic parameters were unaffected. Coadministration of St John's wort significantly increased S-warfarin CL/F, whereas treatment with Asian ginseng produced only a moderate increase in CL/F. Ginkgo and ginger did not affect the pharmacokinetics of warfarin in healthy subjects. None of the herbs studied had a direct effect on warfarin Pharmacodynamics. Studies in anticoagulated patients are warranted to assess the clinical significance of these herb-drug interactions.
Binghu Fang - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic Pharmacodynamic Modeling of tulathromycin against pasteurella multocida in a porcine tissue cage model
Frontiers in Pharmacology, 2017Co-Authors: Qiaoyi Zhou, Guijun Zhang, Qin Wang, Wenguang Liu, Yan Huang, Huanzhong Ding, Binghu FangAbstract:Tulathromycin, a macrolide antibiotic, is used for the treatment of respiratory disease in cattle and swine. The aim of our study was to investigate the in vitro and ex vivo activities of tulathromycin in serum, (noninflamed) transudate, and (inflamed) exudate against Pasteurella multocida in piglets. The pharmacokinetics properties of tulathromycin were studied for serum, transudate, and exudate using a tissue cage model. In vitro antibiotic susceptibility of P. multocida and dynamic time-kill curve experiments over eight tulathromycin concentrations were determined. The ratio of 24-h area under the concentration–time curve to minimum inhibitory concentration (AUC(0-24h)/MIC) was recognized as an important pharmacokinetic/Pharmacodynamic (PK/PD) parameter of tulathromycin for antibacterial efficiency (R2= 0.9969). In serum ex vivo, for bacteriostatic, bactericidal activity, and virtual bacterial eradication AUC(0-24h)/MIC values for tulathromycin were 44.55, 73.19, and 92.44 h by using sigmoid Emax model WinNonlin software, respectively, and lower values were obtained for exudate and transudate. In conjunction with the data on MIC90, the dose of tulathromycin for a bacteriostatic effect and virtual elimination of P. multocida as computed using the value of the PK/PD breakpoint obtained in serum were 6.39 and 13.25mg/kg. However, it would be preferable to calculate a dose combined with population pharmacokinetics data to optimize the dosage regimen for bacteriological and clinical cure.
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Pharmacokinetic/Pharmacodynamic Modeling of Tulathromycin against Pasteurella multocida in a Porcine Tissue Cage Model
Frontiers Media S.A., 2017Co-Authors: Qiaoyi Zhou, Guijun Zhang, Qin Wang, Wenguang Liu, Yan Huang, Huanzhong Ding, Binghu FangAbstract:Tulathromycin, a macrolide antibiotic, is used for the treatment of respiratory disease in cattle and swine. The aim of our study was to investigate the in vitro and ex vivo activities of tulathromycin in serum, (non-inflamed) transudate, and (inflamed) exudate against Pasteurella multocida in piglets. The pharmacokinetics properties of tulathromycin were studied for serum, transudate, and exudate using a tissue cage model. In vitro antibiotic susceptibility of P. multocida and dynamic time-kill curve experiments over eight tulathromycin concentrations were determined. The ratio of 24-h area under the concentration–time curve to minimum inhibitory concentration [AUC(0-24 h)/MIC] was recognized as an important pharmacokinetic/Pharmacodynamic (PK/PD) parameter of tulathromycin for antibacterial efficiency (R2 = 0.9969). In serum ex vivo, for bacteriostatic, bactericidal activity, and virtual bacterial eradication AUC(0-24 h)/MIC values for tulathromycin were 44.55, 73.19, and 92.44 h by using sigmoid Emax model WinNonlin software, respectively, and lower values were obtained for exudate and transudate. In conjunction with the data on MIC90, the dose of tulathromycin for a bacteriostatic effect and virtual elimination of P. multocida as computed using the value of the PK/PD breakpoint obtained in serum were 6.39 and 13.25 mg/kg. However, it would be preferable to calculate a dose combined with population pharmacokinetics data to optimize the dosage regimen for bacteriological and clinical cure
Gilles Paintaud - One of the best experts on this subject based on the ideXlab platform.
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mechanism based pharmacokinetic Pharmacodynamic Modeling a new classification of biomarkers
Pharmaceutical Research, 2005Co-Authors: Meindert Danhof, Gunnar Alvan, Svein G Dahl, Jochen Kuhlmann, Gilles PaintaudAbstract:In recent years, pharmacokinetic/Pharmacodynamic (PK/PD) Modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD Modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.