Pharmacokinetics in paediatric patients with cystic fibrosis

Stefanie Hennig, Carl Kirkpatrick and Bruce Charles (2007). Pharmacokinetics in paediatric patients with cystic fibrosis. In: PKUK Conference 2007, Edinburgh, Scotland, United Kingdom, (). 14-16 November 2007.

Author Stefanie Hennig
Carl Kirkpatrick
Bruce Charles
Title of paper Pharmacokinetics in paediatric patients with cystic fibrosis
Conference name PKUK Conference 2007
Conference location Edinburgh, Scotland, United Kingdom
Conference dates 14-16 November 2007
Publication Year 2007
Sub-type Fully published paper
Language eng
Abstract/Summary Cystic Fibrosis (CF) is the most common incurable lethal condition, due to an autosomal recessive disorder in Caucasians with an estimated incidence of 1 in 2,500 live births. CF is characterised by chronic airway obstruction, infection, and inflammation in the lungs, however other organs are also affected. The decrease of lung function remains the most significant cause of morbidity and mortality in patients with CF. The pharmacokinetics (PK) of some drugs in CF appear to be different from that in healthy volunteers, and non-CF patients,[1, 2] which makes it difficult to find the right dosage for appropriate therapy. One theory about the different drug disposition in patients with CF is that it is due to the clinical symptoms of the disease and effects in the major organs, such as the gastrointestinal tract, liver, and kidneys. Recently, it was reported that some of these differences might be due to differences in body composition (e.g. less adipose tissue as a result of malnutrition in CF patients).[3] There have been previously suggestions that initial doses in CF patients should be determined using lean body weight.[4] However, this might be only an explanation for the PK changes of hydrophilic drugs in CF patients. Furthermore, often pharmacodynamic (PD) endpoints have been adopted from other patients groups and were not evaluated in the CF population themselves. The use of a population PK approach has been shown to be more appropriate in clinical PK studies, especially in children, and they have been used in these patients for many years now.[5, 6] This is an increasingly popular and sensible way of performing PK and PD studies in paediatric patients, due to the ability to gain information from small numbers of samples (typically 2-5 per individual), and it is considered to be less invasive and, therefore, more ethical in children. Furthermore, this approach enables the quantification of PK and PD parameter values as well as the between-subject and between-occasion variability and random unexplained variability, but also for screening and quantification of factors (covariates) which modify PK and PD responses. Two examples will be shown here that have used a population PK approach to gain information about two commonly used drugs in CF, oral itraconazole and intravenous tobramycin, in which there has been either none or limited previous knowledge about the population PK in CF patients. The general aims of these studies were (1) to use modelling approaches to provide a better understanding of their PK, in particular; (2) to investigate the relative bioavailability of the two commercial formulations (capsule and oral solution) for itraconazole; and (3) to identify possible covariates in order to achieve better individualised therapy with target concentration intervention (TCI) where appropriate to maximise the benefits of these drugs.[7, 8] Such predictive models may assist clinicians to choose improved dosing strategies in this group of patients. For both drugs, a relationship between clearance and volume of distribution and allometric scaled body weight was established, which explained a significant amount of between-subject variability about these PK parameters. Therefore, a “one-dose-fits-all” approach is not appropriate. Several questions regarding the PK and PD of drugs administered to CF patients remain unanswered, particularly in terms of the factors which may affect the PK, and the high between-subject variability for lipophilic drugs, and putative TCI endpoints.
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Conference Paper
Collection: School of Pharmacy Publications
 
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Created: Wed, 23 Mar 2011, 11:01:12 EST by Dr Stefanie Hennig on behalf of School of Pharmacy