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- Alskär, Oskar, et al.
(författare)
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Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
- 2016
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 56:3, s. 340-348
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Tidskriftsartikel (refereegranskat)abstract
- The integrated glucose-insulin (IGI) model is a previously published semi-mechanistic model, which describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semi-physiological model developed performed better than previously published empirical models and allows for better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.
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- Jönsson, Siv, et al.
(författare)
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Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study
- 2015
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 55:11, s. 1268-1279
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Tidskriftsartikel (refereegranskat)abstract
- A model characterizing the population pharmacokinetics (PK) of edoxaban and its major metabolite, M4, following a single oral dose of 15mg administered to subjects with varying kidney function was developed. Thirty-two subjects contributed with edoxaban plasma, edoxaban urine, and M4 plasma concentrations. Edoxaban urine concentrations allowed estimation of renal clearance, and high contribution of renal to total clearance enabled estimation of absolute oral bioavailability. A 2-compartment model with delayed absorption and elimination parameterized as renal clearance linearly related to creatinine clearance (CLcr) and nonrenal clearance forming M4 described edoxaban PK. The PK of M4 was described with a 1-compartment model. For a typical subject (70kg; CLcr, 100mL/min) bioavailability, clearance, and central and peripheral volume of distribution for edoxaban was estimated to 72.3%, 21.0 L/h, 95.4 L, and 54.3 L, respectively. For both edoxaban and M4, the model predicted systemic exposure to increase 57.0%, 35.0%, and 11.6% in a subject having CLcr of 30, 50, and 80mL/min, respectively, compared with a subject having a CLcr of 100mL/min. Concentration ratios (M4 over edoxaban) were predicted to vary with time after dose, but with minor influence of kidney function and body weight. Results were in agreement with previous analyses.
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- Nielsen, Elisabet I., 1973-, et al.
(författare)
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Population Pharmacokinetic Analysis of Vaginally and Intravenously Administered Oxytocin in Postmenopausal Women
- 2017
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 57:12, s. 1573-1581
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Tidskriftsartikel (refereegranskat)abstract
- Oxytocin is a neuropeptide hormone used clinically for more than 50 years due to its ability to induce uterine contractions and milk ejection. Vagitocin is a vaginal oxytocin gel developed as a potential treatment of vaginal atrophy in postmenopausal women. The aim of this study was to characterize the oxytocin pharmacokinetics following vaginal and intravenous administration in postmenopausal women. Data from 33 participants enrolled in 2 clinical studies were used in the analysis, with a total of 651 observed oxytocin plasma concentrations, of which 78 were baseline observations, 178 observations following intravenous administration (10 IU), and 395 observations following vaginal administration (100 or 400 IU). The population pharmacokinetics of oxytocin was described using a 2-compartment disposition model with a flexible parallel absorption model accounting for double-peak profiles following vaginal administration. The clearance, volume of distribution at steady state, distribution half-life, and terminal half-life were estimated to be 27 L/h, 15 L, 5.5 minutes, and 1.2 hours, respectively. The bioavailability following vaginal administration was estimated to be 2.5% for the typical patient, but with considerable variability both between individuals (interindividual variability of 374%) and between occasions (interoccasion variability of 79%). The data and the developed model add new and important information as to the clinical pharmacokinetics of oxytocin.
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- Novakovic, Ana M., 1985-, et al.
(författare)
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Pharmacometric analysis of the relationship between absolute lymphocyte count, and expanded disability status scale and relapse rate, efficacy end points, in multiple sclerosis trials
- 2018
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 58:10, s. 1284-1294
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting-relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC-related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit-linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC-derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism-specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market.
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