| 1. |
- 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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| 2. |
- Olsson Gisleskog, Per
(författare)
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Clinical pharmacokinetic/pharmacodynamic modelling of 5a-reductase inhibitors for the treatment of benign prostatic hyperplasia
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dihydrotestosterone (DHT), a potent androgen necessary for the development of benign prostatic hyperplasia (BPH) is formed from testosterone by the enzyme 5α-reductase, of which there are two types. The irreversible 5α-reductase inhibitors dutasteride, which inhibits both isozymes, and finasteride, which inhibits only one, are intended for the treatment of BPH. Models, based on clinical data, were developed for dutasteride pharmacokinetics and for the effects of 5α-reductase inhibitors on enzyme activity and thereby on circulating DHT. Further was a relationship characterised between DHT suppression and changes in prostate specific antigen (PSA), a potential marker for disease progression. Model development progressed along three axes, from healthy volunteers to patients, from single dose to long-term treatment and from pharmacokinetics via biomarker to possible surrogate endpoint. Model predictiveness was validated and methods for propagation of information between studies were examined. Dutasteride pharmacokinetics was best described by a two-compartment model with parallel linear and nonlinear elimination, with a long terminal half-life (5 weeks) at clinical doses. A physiologically based model of DHT and 5α-reductase turnover and of irreversible 5α-reductase inhibition described the data well. This model could explain differences in rates of onset and offset of effect and offers a way to determine the potency of these irreversible inhibitors. The DHT model, derived from single dose data in healthy men, was found to be valid and predictive when compared to data from a 28-day repeat dose study in BPH patients. Using data from a six-month study, PSA was related to DHT by a model describing disease progression and an effect of DHT suppression on elimination of PSA producing cells. When propagating information, the simultaneous modelling of data proved a powerful approach to compare datasets, while the use of priors could stabilise the fitting of complex models to sparse data.
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| 3. |
- Olsson Gisleskog, Per, et al.
(författare)
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The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination
- 1999
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 47:1, s. 53-58
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Tidskriftsartikel (refereegranskat)abstract
- AIMS To characterize the pharmacokinetics of the dual 5alpha-reductase inhibitor GI198745 (dutasteride) to allow for more accurate predictions of GI198745 concentrations after different dosing schedules. METHODS In this randomized, single-blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONMEM where both linear and nonlinear pharmacokinetic models were examined. RESULTS The time course of GI198745 serum concentrations indicated concentration dependent elimination, with the apparent half-life increasing with dose. Data were best described by a two-compartment model with first order absorption and parallel linear and nonlinear elimination pathways. Drug absorption was rapid, and was followed by a short distribution phase. A high volume of distribution (511 l) and a low linear clearance (0.58 l h(-1)) combined to give a half-life of up to 5 (1-7) weeks at high concentrations. As concentrations declined towards Km (0.96 ng ml(-1)), the proportion eliminated by the relatively rapid saturable elimination pathway, with a maximum clearance of 6.2 l h(-1), increased and the half-life reduced to about 3 days. The estimated inter individual variability for the linear clearance was high (CV = 70%). CONCLUSIONS G1198745 pharmacokinetics are well described by a pharmacokinetic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concentrations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost entirely influenced by the linear pathway.
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| 4. |
- Wellhagen, Gustaf, 1988-
(författare)
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Pharmacometric Investigations of Prediction Precision and Advances of Models for Composite Scale Data
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Clinical trials are needed to evaluate new treatments. In late-stage clinical trials, failures are mostly due to lack of efficacy. Fit-for-purpose analysis methods will likely increase the success rates and advance drug development by providing higher precision to support decisions such as go/no-go, dose selection, or sample size. This thesis presents new methods for analysis of composite scale data, and comparisons of prediction precision of new and standard analysis methods. Composite scale data arise from questions/items rated with integers. A total score can be derived, which is discrete and bounded. Item response theory (IRT) models are the natural choice for such data, since they use the item-level information. However, when only the total score is available they cannot be used. The bounded integer (BI) model is a new method for discrete, bounded outcomes. With composite scale total score data, it had superior fit compared to standard methods, because it respects the nature of the data. Further, a new method, formally linking IRT models to models for total score, was developed. The expected mean and variance, given an IRT model, was implemented in BI and continuous variable models. This improved fit, allowed estimation of IRT parameters, and allowed comparison of different model types.The prediction precision of both outcome and parameters were investigated with different methods, ranging from t-test to mechanistic pharmacometric models, for composite scale and continuous data. The most suitable method depended on the purpose, for example mechanistic models are superior at establishing a drug’s site of action.In conclusion, the choice of method should be based on the primary question, and also the data collected. The method should not be more complex than necessary, and the nature of the data respected. This thesis will help modellers select the most appropriate analysis method for a problem at hand.
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