1.
Bååthe, Sofie, et al.
(författare)
Population pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in atrial fibrillation patients receiving long-term anticoagulation therapy
2006
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 45:8, s. 803-819
Tidskriftsartikel (refereegranskat) abstract
Background: Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran. Objective: To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events. Methods: A population pharmacokinetic model was developed based on data from three phase 11 studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model. Results: Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure. Conclusion: The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.
2.
Kloft, Charlotte, et al.
(författare)
Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification : comparison across anticancer drugs
2006
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 12:18, s. 5481-5490
Tidskriftsartikel (refereegranskat) abstract
Purpose: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs. Experimental Design: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made. Results: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha(1)-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction. Conclusions: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.
3.
Viberg, Anders, et al.
(författare)
A population pharmacokinetic model for cefuroxime using cystatin C as a marker of renal function
2006
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 62:3, s. 297-303
Tidskriftsartikel (refereegranskat) abstract
Aims: Since cefuroxime mainly is excreted by renal filtration, dosing is currently based on serum creatinine (Scr) or creatinine clearance (CLcr). However, it has been suggested that cystatin C (CysC) is superior to Scr as a marker of renal function. The aim of this prospective study was to develop a population model that describes the pharmacokinetics of cefuroxime and to investigate the usefulness of CysC as a covariate of the model parameters. Methods: Ninety-seven patients were studied (CLcr range 6.5-115 ml min(-1)). Blood samples (n = 407) for the determination of cefuroxime were withdrawn according to a sparse data sampling schedule and analysed by liquid chromatography mass spectrometry. The population analysis was performed in NONMEM. Results: A two-compartment model described the data well. The biomarkers Scr, CLcr and CysC were evaluated as covariates on clearance (CL). The model that included CysC generated the best fit. In the final population model CL was a function of CysC and body weight, whereas V-1 was only a function of body weight. Final parameter estimates (relative standard errors) were 6.00 (3.2%) l h(-1), 11.4 (5.3%) l and 5.11 (11%) l for CL, V-1 and V-2, respectively. Conclusion: Based on the results of the present study, and because CysC is practical to use in the clinic, it is suggested that individual dosing of cefuroxime may be based on CysC rather than on Scr or CLcr. Furthermore, our final population model may be useful as a tool when designing new dosing schedules for cefuroxime.
4.
Äbelö, Angela, et al.
(författare)
Application of a combined effect compartment and binding model for gastric acid inhibition of AR-HO47108 : a potassium competitive acid blocker, and its active metabolite AR-HO47116 in the dog
2006
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 29:2, s. 91-101
Tidskriftsartikel (refereegranskat) abstract
The effect of AR-HO47108, a potassium competitive acid blocker, and its active metabolite AR-HO47116 was studied in Heidenhain pouch dogs following administration of single oral and intravenous doses of the two compounds. The histamine-stimulated acid secretion was measured in different periods after dose up to 24 h. All data obtained in the different studies was pooled and analyzed by non-linear mixed effects modelling. It was found that there is a delay between the plasma concentration-time peak and the maximum inhibitory effect and that the effect persisted longer than anticipated from the plasma concentration half-lives of the compounds. in addition, it was found that the peak effect was reached earlier at higher doses. The effect data was well described by a combined effect compartment and binding model and both distribution to the biophase i.e. the canaliculus of the parietal cell and a rate limiting binding interaction between drug and enzyme appear to contribute to the observed delay. in addition, a secretion rate dependent washout from the biophase may contribute. Furthermore, because the parent compound and metabolite bind to the same enzyme, the effect is determined by competition between the two for the same enzyme. The metabolite was found to be less potent than the parent compound, with K-d values of the combined model of 125 and 11.2 nM for the metabolite and parent compound, respectively. However, the metabolite is generated in high concentrations that rapidly exceed the concentration of parent compound after oral administration of parent compound, and this together with its longer plasma half-life will make its contribution to -the overall effect increase with time and slightly prolong the duration of the effect.
