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- Eriksson, Ulf G, et al.
(författare)
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Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran : a population model analysis
- 2003
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Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 42:7, s. 687-701
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.
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- Kerbusch, Thomas, et al.
(författare)
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Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability
- 2003
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 56:6, s. 639-652
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored. METHODS: Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1-45 mg). RESULTS: Non-linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two-compartment disposition model with first order absorption. The values (mean +/- standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 +/- 2.0 l h-1 and 34.7 +/- 4.6 l h-1, respectively, in a typical male CYP2D6 homozygote-extensive metabolizer (Hom-EM). The absolute bioavailability (F) of darifenacin in a Hom-EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively. Factors influencing F were formulation (70-110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype [heterozygote-extensive metabolizers (Het-EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom-EM irrespective of dose administered] and saturable first-pass metabolism (dose nonlinearity 1.05-1.43-fold). Race affected F, which was 56% lower in Japanese males. The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5%. CL was 31% lower in females and 10% lower at night. Formulation affected the metabolite absorption/formation rate. Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively. The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin. CONCLUSIONS: The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.
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- Simonsen, Lena E., et al.
(författare)
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Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats
- 2000
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 20:3A, s. 1519-1525
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Tidskriftsartikel (refereegranskat)abstract
- AIM To study the effects of single and fractionated doses of 5-fluorouracil and epirubicin on the leukocyte counts in rats. METHODS Six different dosing patterns of each drug were injected within one day. The leukocytes were followed for 11-15 days. Pharmacokinetic models were developed using NONMEM. Quantitative and qualitative pharmacokinetic-pharmacodynamic relationships were investigated. RESULTS A one-compartment model with non-linear elimination described 5-fluorouracil pharmacokinetics and a three-compartment model described epirubicin concentration data. Sigmoidal or basic Emax-models quantified the relationships between individual AUCs and decreases in leukocytes, for both drugs. Similar relationships between AUC and toxicity were found, regardless of whether the drugs were given as single or fractionated doses. CONCLUSION Quantitative relationships between AUC and the effect on leukocytes were established for 5-fluorouracil and epirubicin. However, no schedule dependence was indicated for the schedules used in the study.
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- Wählby, Ulrika, 1972-
(författare)
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Methodological Studies on Covariate Model Building in Population Pharmacokinetic-Pharmacodynamic Analysis
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Population pharmacokinetic (PK) – pharmacodynamic (PD) modelling, using nonlinear mixed effects models, is increasingly being applied to obtain PK-PD information in drug development. Covariate modelling, the establishment of relationships between model parameters and patient characteristics, is undertaken to explain PK-PD variability and facilitate dose adjustment decisions, and is consequently an important objective of population PK-PD.The aims of this thesis were to increase the efficiency, predictability and robustness of covariate model building by examining in detail a number of aspects related to covariate modelling. The thesis demonstrates that the likelihood ratio (LR) test can be applied with confidence, in the assessment of statistical significance of parameter-covariate relationships (in NONMEM analyses), only if an estimation method appropriate for the data- and error-structure is utilised. Conversely, caution is needed in the interpretation of the LR test when variance or covariance parameters are modelled, since the type I error rate may be severely upward biased if the assumptions of normally distributed residuals and/or enough information in the data are violated. The two stepwise covariate model building procedures, using generalised additive models and NONMEM, were found to perform similarly in the examples examined. However, differences in performance may prevail in other situations, e.g. when sparse sampling precludes reliable individual parameter estimates. Stepwise selection was shown to result in over-estimated covariate effects (selection bias), but the imprecision in the estimates exceeded this bias. Important information about the PK-PD characteristics of a drug is obtainable on the application of covariate models for time-varying covariates that account for differences in variability between and within individuals, or estimate interindividual variability in the covariate effect. The knowledge gained in this thesis will contribute to the development of more predictable and robust covariate models, important both in individualisation of dosage and the development of new drugs.
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