| 1. |
- Abrantes, João A., et al.
(författare)
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Elucidation of Factor VIII Activity Pharmacokinetics : A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
- 2017
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 102:6, s. 977-988
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.
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| 2. |
- Baverel, Paul G., et al.
(författare)
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Dose-Exposure-Response Relationship of the Investigational Anti-Interleukin-13 Monoclonal Antibody Tralokinumab in Patients With Severe, Uncontrolled Asthma
- 2018
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 103:5, s. 826-835
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G(4) monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which tralokinumab was administered subcutaneously. This investigation aimed to characterize tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV1)) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of tralokinumab's dose-exposure-FEV1 response relationship in patients with asthma. Near-maximal FEV1 increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma.
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| 3. |
- Bhatt, Deepak Kumar, et al.
(författare)
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Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver
- 2019
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 105:1, s. 131-141
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 The American Society for Clinical Pharmacology and Therapeutics. The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.
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| 4. |
- Brinkman, D. J., et al.
(författare)
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Essential Competencies in Prescribing: A First European Cross-Sectional Study Among 895 Final-Year Medical Students
- 2017
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY-BLACKWELL. - 0009-9236 .- 1532-6535. ; 101:2, s. 281-289
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Tidskriftsartikel (refereegranskat)abstract
- European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.
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| 5. |
- Cars, Thomas, et al.
(författare)
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Effectiveness of Drugs in Routine Care : A Model for Sequential Monitoring of New Medicines Using Dronedarone as Example
- 2018
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 103:3, s. 493-501
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Tidskriftsartikel (refereegranskat)abstract
- Although there is no doubt about the scientific value of randomized controlled clinical trials, they are usually conducted in selected populations different fromthose treated in clinical practice. Therefore, it is important to optimize real-time post-marketing evaluation of the effectiveness, safety, and cost of new drugs. Using electronic health records and administrative health databases froma well-defined region with universal access to healthcare, we have built a framework for real-time sequential monitoring of the effectiveness of newly marketed drugs in routine care. We chose the antiarrhythmic agent dronedarone as the study drug and flecainide as the comparator drug for illustration of the model. We demonstrate that this model produces consistent results with increasing precision over time as data accumulates in the clinical systems. We believe that use of this model at the introduction of new drugs can provide complementary evidence, especially in settings of adaptive licensing of new drugs.
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| 9. |
- de Lange, E. C. M., et al.
(författare)
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Translational Aspects of Blood-Brain Barrier Transport and Central Nervous System Effects of Drugs : From Discovery to Patients
- 2015
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 97:4, s. 380-394
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Tidskriftsartikel (refereegranskat)abstract
- The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment.
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| 10. |
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