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Identifying Paediatric Needs in Cardiology and the Prediction of Sildenafil Exposure in Children with Pulmonary Arterial Hypertension

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Identifying Paediatric Needs in Cardiology and the Prediction of Sildenafil Exposure in Children with Pulmonary Arterial Hypertension Identifying paediatric needs in cardiology and the prediction of sildenafil exposure in children with pulmonary arterial hypertension Inauguraldissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Linda Hsien aus Latakia Juli 2010 Aus dem Institut für Klinische Pharmazie und Pharmakotherapie der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. med. S. Läer Koreferent: Prof. Dr. J. Breitkreutz Tag der mündlichen Prüfung: 12.07.2010 Table of contents 1 Introduction ...............................................................................................................1 1.1 Clinical studies in the paediatric population.........................................................1 1.2 Off-label drug use in paediatrics..........................................................................2 1.3 Off-label use of cardiovascular drugs in children .................................................3 1.4 Pulmonary arterial hypertension in children.........................................................4 1.5 Sildenafil for the treatment of paediatric pulmonary arterial hypertension............5 1.6 Pharmacokinetics of sildenafil .............................................................................6 1.7 Pharmacokinetic studies in paediatric patients ....................................................7 1.8 Whole body physiologically-based pharmacokinetic (PBPK) modelling in paediatric patients ...............................................................................................8 1.9 Aim of the project ..............................................................................................10 2 Methods ...................................................................................................................11 2.1 A prospective observational trial to analyse the off-label drug use in hospitalised children .............................................................................................................11 2.1.1 Trial design.............................................................................................11 2.1.2 Age classification....................................................................................11 2.1.3 Classification of diagnosis ......................................................................12 2.1.4 Classification of drug groups ..................................................................13 2.1.5 Reference sources for drug information..................................................14 2.1.6 Classification of off-label prescriptions....................................................15 2.1.7 Result comparison with the EMEA list of paediatric needs and the priority list...............................................................................................16 2.1.8 Data analysis..........................................................................................17 2.2 Development of a PBPK model for sildenafil in adults and children...................18 2.2.1 Pharmacokinetic simulation with PK-Sim® ..............................................18 2.2.2 Work flow for the development of a PBPK model for sildenafil in children ..................................................................................................21 2.2.3 Literature search ....................................................................................23 2.2.4 Development of a PBPK model for intravenous sildenafil in adults .........25 2.2.5 Simulation of the pharmacokinetics of intravenous sildenafil in a virtual adult population......................................................................................26 2.2.6 Development of a PBPK model for oral sildenafil in adults .....................26 2.2.7 Simulation of the pharmacokinetics of oral sildenafil in a virtual adult population ..............................................................................................27 2.2.8 Development of a PBPK model for oral sildenafil in children ..................27 2.2.9 Simulation of the pharmacokinetics of oral sildenafil in virtual paediatric populations.............................................................................................28 2.2.10 Calculation of the pharmacokinetic parameters ......................................28 2.2.11 Evaluation of the PBPK model of sildenafil.............................................29 3 Results .....................................................................................................................31 3.1 A prospective observational trial to analyse the off-label use of drugs in hospitalised children..........................................................................................31 3.1.1 Patients’ characteristics..........................................................................31 3.1.2 Most frequently prescribed drugs ...........................................................32 3.1.3 Drug prescriptions in the different drug groups .......................................33 3.1.4 Most frequently prescribed off-label drugs..............................................34 3.1.5 Off-label drug use among the different drug groups................................34 3.1.6 Off-label prescribed cardiovascular drugs in comparison with EMEA lists.........................................................................................................37 3.1.7 Average prescribed dose for the off-label prescribed cardiovascular drugs......................................................................................................39 3.2 Development of a PBPK model for sildenafil in adults and children...................40 3.2.1 Results of literature search.....................................................................40 3.2.2 Development and evaluation of a PBPK model for intravenous sildenafil in adults...................................................................................51 3.2.3 Simulation of the pharmacokinetics of intravenous sildenafil in a virtual adult population......................................................................................54 3.2.4 Development and evaluation of a PBPK model for oral sildenafil in adults .....................................................................................................57 3.2.5 Simulation of the pharmacokinetics of oral sildenafil in a virtual adult population ..............................................................................................61 3.2.6 Development and evaluation of a PBPK model for oral sildenafil in children ..................................................................................................65 3.2.7 Simulation of the pharmacokinetics of oral sildenafil in a virtual paediatric population ..............................................................................70 3.2.8 Age-related exposure of oral sildenafil....................................................71 3.2.9 Estimation of age-related doses of sildenafil and efficient sampling points for pharmacokinetic studies in children ........................................73 4 Discussion...............................................................................................................76 4.1 Most important results to be discussed .............................................................76 4.2 A prospective observational trial to analyse the off-label drug use in hospitalised children .............................................................................................................77 4.2.1 Most frequently prescribed off-label drugs..............................................78 4.2.2 Off-label drug use among cardiovascular drugs .....................................82 4.2.3 Off-label use of sildenafil in children with pulmonary arterial hypertension...........................................................................................85 4.3 Development of a PBPK model for sildenafil in adults and children...................86 4.3.1 Pharmacokinetic studies of sildenafil in the literature..............................86 4.3.2 PBPK model for intravenous sildenafil in adults......................................88 4.3.3 PBPK model for oral sildenafil in adults..................................................91 4.3.4 PBPK model for oral sildenafil in children ...............................................93 4.3.5 Age-related changes in sildenafil exposure and dosing in children .........95 5 Conclusion...............................................................................................................97 6 Summary..................................................................................................................98 6.1 Zusammenfassung............................................................................................98 6.2 Summary...........................................................................................................99 7 References.............................................................................................................100 8 Appendix................................................................................................................115 8.1 List of abbreviations ........................................................................................115 8.2 List of figures...................................................................................................117
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