European Journal of Clinical Pharmacology

, Volume 68, Issue 6, pp 913–922

Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid

  • A. Rother
  • P. Glander
  • E. Vitt
  • D. Czock
  • N. von Ahsen
  • V. W. Armstrong
  • M. Oellerich
  • K. Budde
  • R. Feneberg
  • B. Tönshoff
  • L. T. Weber
Pharmacodynamics

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

IMPDH activity Developmental regulation Pharmacodynamics Paediatric renal transplantation Mycophenolic acid 

Abbreviations

A

IMPDH activity

AEC

Area under the enzyme activity–time curve

AIC

Akaike information criterion

Alow

Maximal possible IMPDH inhibition

Amin

Minimum IMPDH activity

AMP

Adenosine monophosphate

ANOVA

Analysis of variance

AUC

Area under the concentration–time curve

BSA

Body surface area

BMI SDS

Body mass index standard deviation score

C

MPA concentration

CL/F

Apparent drug clearance

Cmax

Maximum MPA concentration

D

Administered MPA content

ESRD

End-stage renal disease

Freq

Frequency

H

Sigmoidicity parameter

HPLC

High-performance liquid chromatography

IMPDH

Inosine 5’-monophosphate dehydrogenase

MPA

Mycophenolic acid

MMF

Mycophenolate mofetil

PBMCs

Peripheral blood mononuclear cells

PD

Pharmacodynamic

PK

Pharmacokinetic

RTx

Renal transplantation

SD

Standard deviation

SNP

Single nucleotide polymorphism

tAmin

Time to minimum IMPDH activity

tCmax

Time of maximum MPA concentration in a dosing interval

XMP

Xanthosine 5’-monophosphate

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • A. Rother
    • 1
  • P. Glander
    • 2
  • E. Vitt
    • 3
  • D. Czock
    • 4
  • N. von Ahsen
    • 5
  • V. W. Armstrong
    • 5
  • M. Oellerich
    • 5
  • K. Budde
    • 2
  • R. Feneberg
    • 1
  • B. Tönshoff
    • 1
  • L. T. Weber
    • 3
    • 6
  1. 1.Department of Paediatrics IUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.Department of NephrologyCharité Universitätsmedizin BerlinBerlinGermany
  3. 3.Department of Paediatric NephrologyChildren’s Hospital of the Ludwig-Maximilians University of MunichMunichGermany
  4. 4.Department of Clinical Pharmacology and PharmacoepidemiologyUniversity Hospital HeidelbergHeidelbergGermany
  5. 5.Department of Clinical ChemistryUniversity of GöttingenGöttingenGermany
  6. 6.Paediatric NephrologyUniversity Children’s Hospital, Dr. von Haunersche KinderklinikMunichGermany

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