Inosine monophosphate dehydrogenase activity and mycophenolate pharmacokinetics in children with nephrotic syndrome treated with mycophenolate mofetil

Abstract

Some studies have shown that the area under the concentration-time curve (AUC) of mycophenolic acid (MPA) should be higher for children with nephrotic syndrome (NS) than after renal transplantation. The pharmacodynamic aspect of MPA, the activity of inosine monophosphate dehydrogenase (IMPDH), has not been studied in children with NS. The study included 21 children (4-16 years old) with NS treated with mycophenolate mofetil. MPA and its glucuronide plasma concentrations were determined using validated high-performance liquid chromatography-ultraviolet (HPLC-UV). The separate HPLC-UV method was applied for IMPDH activity determination. The variability was expressed by the coefficient of variation (CV). IMPDH activity and MPA concentration (C_trough ) before the morning dose amounted to 29.95 μmol s^-1 mol^-1 adenosine monophosphate (AMP) (range, 6.71-98.60 μmol s^-1 mol^-1 AMP) and 1.72 μg/mL (range, 0.39-4.34 μg/mL), respectively, whereas the area under the effect-time curve from 0 to 4 h and MPA AUC_0-4 were 130.36 μmol s^-1 mol^-1 AMP × h (range, 23.58-306.57 μmol s^-1 mol^-1 AMP × h) and 24.63 μg h/mL (range, 12.21-67.48 μg h/mL), respectively. IMPDH activity decreased concomitantly with MPA concentration increase, however, the variability of the pharmacodynamic parameters was greater than of the pharmacokinetics. The median degree of maximum IMPDH inhibition was 61%. MPA C_trough and predicted AUC were lower than in our previous study. Only a few MPA pharmacokinetic parameters correlated with the pharmacodynamics. IMPDH activity did not correlate with the children's age and did not differ between boys and girls. MPA clearance was the highest in younger children (median, 10.54 L/m² /h) and cholesterol correlated negatively with the children's age (r = -0.659, P = 0.003). IMPDH minimum activity and the degree of maximum IMPDH inhibition were similar to those obtained in renal transplant recipients. IMPDH activity does not undergo developmental or gender-specific regulation in children with NS. MPA underexposure might be more frequent in younger children, especially with high cholesterol and triglycerides levels because of high MPA clearance.

Keywords: children; mycophenolic acid; nephrotic syndrome; pharmacodynamics; pharmacokinetics.