Population Pharmacokinetics of Prednisolone in Relation to Clinical Outcome in Children With Nephrotic Syndrome.
The relapse frequency in children with nephrotic syndrome (NS) is highly variable despite standardized prednisolone treatment regimens. Existing evidence on the relationship between prednisolone pharmacokinetics (PK) and clinical response in children with NS is scarce and limited. The aim of this study was to develop a pediatric popPK model for prednisolone based on our previous model based on healthy adults using salivary measurements in children with NS and to correlate clinical outcome with between-subject variability in prednisolone exposure.



The pharmacokinetics of prednisolone in a well-defined, prospective cohort consisting of 104 children with NS while in remission was determined. Pharmacokinetic parameters were analyzed in relation to relapse patterns and side effects. Noninvasive salivary prednisolone measurements were performed using a sparse sampling strategy. A population pharmacokinetic approach was used to derive individual estimates of apparent clearance (CL/F) and apparent volume of distribution (V/F) from the salivary concentration-time curve, followed by calculation of the area under the curve (AUC) of free prednisolone. The individual free serum prednisolone exposure from prednisolone in saliva was derived from the salivary concentration-time curves. Genetic polymorphisms of CYP3A4, CYP3A5, ABCB1, NR1L2, and POR were explored in relation to between-subject variability of CL/F.



Moderate interindividual variability was found for CL/F (CV, 44.7%). Unexplained random between-subject variability (eta) of CL/F was lower in patients carrying 1 or 2 ABCB1 3435C>T alleles compared to wild type: median -0.04 (interquartile range, -0.17 to 0.21) and 0.00 (-0.11 to 0.16) versus 0.17 (-0.08 to 0.47), P = 0.046. Exposure to free prednisolone was not associated with frequent relapses or adverse effects.



This study provides evidence for the possibility of prednisolone drug monitoring through salivary measurements and this may be of particular usefulness in pediatric patients. However, the observed variability in prednisolone exposure, in the therapeutic dose range studied, is not considered to be a major determinant of clinical outcome in children with NS.
*Department of Pediatrics, Division of Nephrology, Erasmus University Medical Centre, Sophia Children's Hospital, Rotterdam; †Centre for Human Drug Research, Leiden; ‡Department of Public and Occupational Health, EMGO Institute for Health and Care Research, VU University Medical Centre; §Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Amsterdam; Departments of ¶Clinical Chemistry, ‖Internal Medicine, and **Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, the Netherlands.
Nynke
N
Teeninga
Zheng
Z
Guan
Jasper
J
Stevens
Joana E
JE
Kist-van Holthe
Mariëtte T
MT
Ackermans
Albert J
AJ
van der Heijden
Ron H N
RH
van Schaik
Teun
T
van Gelder
Jeroen
J
Nauta
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011239:Prednisolone / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011446:Prospective Studies; D055815:Young Adult
D007166:Immunosuppressive Agents; D011239:Prednisolone