WP10 - Clinical pharmacodynamics (PK/PD analysis)

 

Workpackage lead and partners:

WP leader:
Prof. Grard Pons, INSERM

WP partners:
 -

Workpackage objectives: 

  • To determine the pharmacokinetics (PK) and pharmacodynamics (PD) of dopamine
  • To investigate the possible influence of the polymorphisms of the genes coding for dopamine/epinephrine metabolizing enzymes, transport enzymes and  receptors on drug response
  • To develop and validate a single micro-assay for the simultaneous measurement of dopamine and norepinephrine in small volume plasma samples.
  • To develop an validate the pharmacogenetic assays for dopamine metabolizing enzymes and receptors
  • To determine dosing recommendations of dopamine in ELBW preterm neonates for the treatment of hypotension (Monte Carlo Simulations performed with the population PK/PD Model)
      

Workpackage description:

Dopamine is currently used for the treatment of hypotension in ELBW preterm neonates. However, the pharmacokinetics of this drug in this population has been poorly investigated and the relationship between drug exposure and efficacy is still unknown. As a consequence, the dose used may not be optimal for efficacy and/or safety of the drug.

The main aim of WP 10 will be to determine the pharmacokinetics and the pharmacokinetic/ pharmacodynamic of dopamine in ELBWs with hypotension and to establish the dosing recommendations that will provide the highest probability of efficacy and optimal therapeutic interval in this population. A secondary objective will be to investigate the possible relationship between the polymorphisms of the genes coding for the enzymes responsible for the transport (SLC6A, DAT), metabolism (Catechol-O-MethylTransferase, MonoAmineOxidase A and B, Dopa hydroxylase), and receptors (D2, beta-2) of catecholamines and the response to dopamine.

Task 1:

Determination of the optimal sampling design for the study: optimal number and sampling-times allowing the estimation of the pharmacokinetic parameters with the minimal uncertainty. 

Task 2:

Development and validation of the analytical methods using an assay allowing to quantify simultaneousl the 2 drugs of interest by liquid chromatography with electrochemical detection in a volume of plasma as low as possible (e.g. 100 l).  

Task 3:

Determination of storage and shipment conditions for the samples: temperature for storage and shipment and possible prior separation of plasma according to the stability of the compounds. 

Task 4:

Standard operating procedure (SOP) to be prepared including details on sampling frequency, sample volume, sampling technique, storage and shipping of blood samples and buccal swabs and to be available to all recruiting centres (WP04) and filed in the Trial Master File (tmf). 

Task 5:

Performance of the assays to determine dopamine plasma concentration (method cited above) in a subset of 200 babies (3  blood samples of 500 L per neonate) during the clinical study for the PK/PD study: one sample before drug administration for endogenous baseline level, and two samples after. Total volume drawn volume will not exceed 1 % of the total blood volume over the time of the study. Every effort will be made to take these samples together with routine blood samples in order to minimise pain and distress, and the risk of iatrogenic complications. Blood loss will be performed routinely and oral glucose will be used for pain relief as appropriate.

All the babies will be included in the pharmacogenetic study in order to provide the highest statistical power, taking into account the low incidence of some polymorphisms. This study will not require blood samples but mouth cells obtained by the use of a swab. Genotyping will be carried out using the Applied Biosystems TaqMan Technology for the selected single nucleotide and repetitive polymorphisms. 

Task 6:

Data modelling will be performed using a population approach (NONMEM software) that will allow to determine the covariates (gestational age, post-natal age, body weight, body surface area, genetic polymorphisms, blood pressure) explaining the interindividual variability of the pharmacokinetic parameters and of the pharmacokinetic/pharmacodynamic relationship of the drugs studied. Pharmacokinetic/Pharmacodynamic models will be developed and Monte Carlo Simulations will allow to determine the optimal dose for each drug in this population, taking into account the possible need for an individualization of the dose with respect to the relevant covariates.