| 1. |
- Hénin, Emilie, et al.
(författare)
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A mechanism-Based Approach for Absorption Modeling : The Gastro-Intestinal Transit Time (GITT) Model
- 2012
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 14:2, s. 155-163
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Tidskriftsartikel (refereegranskat)abstract
- Absorption models used in the estimation of pharmacokinetic drug characteristics from plasma concentration data are generally empirical and simple, utilizing no prior information on gastro-intestinal (GI) transit patterns. Our aim was to develop and evaluate an estimation strategy based on a mechanism-based model for drug absorption, which takes into account the tablet movement through the GI transit. This work is an extension of a previous model utilizing tablet movement characteristics derived from magnetic marker monitoring (MMM) and pharmacokinetic data. The new approach, which replaces MMM data with a GI transit model, was evaluated in data sets where MMM data were available (felodipine) or not available (diclofenac). Pharmacokinetic profiles in both datasets were well described by the model according to goodness-of-fit plots. Visual predictive checks showed the model to give superior simulation properties compared with a standard empirical approach (first-order absorption rate + lag-time). This model represents a step towards an integrated mechanism-based NLME model, where the use of physiological knowledge and in vitro-in vivo correlation helps fully characterize PK and generate hypotheses for new formulations or specific populations.
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| 2. |
- Hennig, Stefanie, et al.
(författare)
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Population Pharmacokinetics of Tobramycin in Patients With and Without Cystic Fibrosis
- 2013
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 52:4, s. 289-301
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives While several studies have examined the pharmacokinetics of tobramycin in patients with cystic fibrosis (CF), there is no consensus on whether they differ in patients with and without CF. The objectives of this study were to identify covariates which explain pharmacokinetic variability and to examine whether having the disease CF in itself alters these relationships and drug dose requirements. Methods To investigate this issue, a population pharmacokinetic meta-analysis of data from eight centres was undertaken. NONMEM (R) 7.2 was used to analyse the data, which comprised 4,514 concentration-time measurements from 465 adults and children with CF and 1,095 concentration-time measurements from 267 adults and children without CF. Results Tobramycin disposition was well described by a two-compartment model with first-order elimination. Patient age, fat-free mass, serum creatinine concentration and sex were identified as significant covariates in the final model. Fat-free mass was superior to total bodyweight as a descriptor of clearance, volume of distribution of the central and peripheral compartments and inter-compartmental clearance. CF as an independent disease-specific factor had no significant influence on the pharmacokinetics of tobramycin at any stage during covariate model building. An optimal dose of 11 mg/kg every 24 h was defined for CF patients using a utility function approach. Conclusion The pharmacokinetics of tobramycin do not differ significantly in CF patients compared with patients without CF when subject age, fat-free mass, sex and renal function are taken into consideration. Variations in tobramycin dosing between CF and non-CF patients should therefore reflect target concentrations or exposures based on differences in expected pathogen sensitivity and not the presence of CF.
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| 3. |
- Johansson, Åsa M., et al.
(författare)
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A Population Pharmacokinetic/Pharmacodynamic Model of Methotrexate and Mucositis Scores in Osteosarcoma
- 2011
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 33:6, s. 711-718
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Tidskriftsartikel (refereegranskat)abstract
- Methotrexate, when used in high doses (12 g/m(2)) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4-51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age-and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and betweenoccasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V(1) = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V(2) = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score >= 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses.
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| 4. |
- Standing, Joseph F., et al.
(författare)
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Diclofenac pharmacokinetic meta-analysis and dose recommendations for surgical pain in children aged 1-12 years
- 2011
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Ingår i: Pediatric Anaesthesia. - : Wiley. - 1155-5645 .- 1460-9592. ; 21:3, s. 316-324
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diclofenac is an effective, opiate-sparing analgesic for acute pain in children, which is commonly used in pediatric surgical units. Recently, a Cochrane review concluded the major knowledge gap in diclofenac use is dosing information. A pharmacokinetic meta-analysis has been undertaken with the aim of recommending a dose for children aged 1-12 years. Methods: Studies containing diclofenac pharmacokinetic data were identified during a Cochrane systematic review, and authors were asked to provide raw data. A pooled population analysis was undertaken in NONMEM to define the pharmacokinetics of intravenous, oral, and rectal diclofenac in children. Simulations were performed to recommend a dose yielding an equivalent area under diclofenac concentration-time curve (AUC) to a 50-mg dispersible tablet in adults. Results: Data from 111 children aged 1-14 years consisting of 375 samples following intravenous, oral suspension, and suppositories were used. Adult dispersible tablet and suspension data were added to provide a reference AUC and support the absorption modeling, respectively. A three-compartment model described disposition, a dual-absorption compartment model was used for suspension and dispersible tablet data, and single-absorption compartment model for suppositories. The estimate of clearance was 16.51.h(-1).70 kg(-1) and bioavailabilities were 0.36, 0.63, and 0.35 for suspension, suppository, and dispersible tablets, respectively. Conclusions: Single doses of 0.3 mg.kg(-1) for intravenous, 0.5 mg.kg(-1) for suppositories, and 1 mg.kg(-1) for oral diclofenac in children aged 1 12 years are recommended as they yield a similar AUC to 50 mg in adults.
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