Zheng Guan(1,2), Nynke Teeninga(3), Jeroen Nauta(3), Joana E. Kist-van Holthe(4), Mariëtte T. Ackermans(5), Ron H.N. van Schaik(6), Teun van Gelder(7), Jasper Stevens(1), Jan Freijer(1)
(1) Centre for Human Drug Research, Leiden, the Netherlands; (2) Leiden university medical centre, Leiden, the Netherlands; (3) Department of Pediatrics, division of Nephrology Erasmus University Medical Centre – Sophia Children’s Hospital, Rotterdam, the Netherlands; (4) Department of Public and Occupational Health, EMGO Institute for Health and Care Research, VU University Medical Centre, Amsterdam, the Netherlands; (5) Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Amsterdam, the Netherlands; (6) Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, the Netherlands; (7) Departments of Internal Medicine and Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, the Netherlands
Background: Prednisolone (PLN) represents the cornerstone for the treatment of childhood nephrotic syndrome (NS) since 1950’s. However, pediatric patients show considerable variability in therapeutic response and side-effects to standard, empirically based dosing regimens [1, 2, 3, 4, 5]. The question arises whether variability in PK can explain, as driving force for the PD, the differences in therapeutic response between individuals. Concentrations in saliva may represent free PLN levels in blood, as only free fraction of PLN can diffuse into target tissues and cells, and can therefore be considered clinically more relevant than total PLN concentrations [1, 2, 6, 7, 8]. Salivary sampling can also help to avoid burdensome in pediatric patients caused by blood sampling. In present study, we tested the influence of variability in PLN on clinical outcome in children with NS, based on only salivary sampling combined with translational modeling and simulation approaches from healthy adult model.
Methods: 385 salivary PLN measurements were obtained from 104 Dutch children with NS. The children received 40 mg/m2 oral PLN after induction dosing period of six weeks. Parents collected salivary samples at home with Salivette. We adapted the developed adult population PK model [9] to our current pediatric population using body weight-dependent exponent model [10]. Based on the individual parameters estimated and the actual PLN dose administered, individual post hoc curves of free serum PLN were simulated and then were used to derive area under the curve of free concentration of PLN in serum (AUCfree). Differences in the AUCfree between categories of clinical outcomes were assessed with either a Student’s T-test or ANOVA.
Results: Clearance and distribution volume were estimated to be 18.7 L/hr and 74.4 L with relatively small RSE values (23.0% and 10.4%). AUCfree was then calculated to be 859 (inter quartile range: 806-943) ng.hr/ml based on simulated individual free serum concentration-time profiles. AUCfree showed no significant correlation with therapeutic effect and adverse effects.
Conclusions: Using translational modeling and simulation, the model described in the present study supports the use of salivary PLN concentrations as a reliable predictor of free levels in serum. However, we conclude that it is unlikely that variability in PLN exposure in the therapeutic dose range studied is a major determinant of clinical outcome in children with NS.
References:
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Reference: PAGE 22 (2013) Abstr 2685 [www.page-meeting.org/?abstract=2685]
Poster: Paediatrics