Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid
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- Rother, A., Glander, P., Vitt, E. et al. Eur J Clin Pharmacol (2012) 68: 913. doi:10.1007/s00228-011-1203-4
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Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5’-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation.
We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0–17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC.
Inosine 5’-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42–184] μmol/s/mol AMP), school-age children (61 [30–153]), adolescents (83 [43–154]) and healthy adults (83 [26–215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration.
In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.
KeywordsIMPDH activity Developmental regulation Pharmacodynamics Paediatric renal transplantation Mycophenolic acid
Area under the enzyme activity–time curve
Akaike information criterion
Maximal possible IMPDH inhibition
Minimum IMPDH activity
Analysis of variance
Area under the concentration–time curve
Body surface area
- BMI SDS
Body mass index standard deviation score
Apparent drug clearance
Maximum MPA concentration
Administered MPA content
End-stage renal disease
High-performance liquid chromatography
Inosine 5’-monophosphate dehydrogenase
Peripheral blood mononuclear cells
Single nucleotide polymorphism
Time to minimum IMPDH activity
Time of maximum MPA concentration in a dosing interval