Glucocorticoid Treatment in Childhood Nephrotic Syndrome : weighting the cornerstone

Understanding which factors influence relapse patterns in childhood nephrotic syndrome is clinically very relevant and could aid in developing new treatment strategies. Clinicians are continuously challenged to reduce relapse rates and at the same time to avoid glucocorticoid toxicity. Both intrinsic and environmental factors may take part in the underlying pathophysiological process and its impact on clinical course. Though glucocorticoids are the cornerstone of treatment, little is known about how individual handling of these drugs may affect the clinical course in children with nephrotic syndrome. Possible explanations for this include the complicated methods required to evaluate these factors and the low incidence of the disease. The general aim of this thesis is to provide better understanding of the variability in the clinical course of childhood nephrotic syndrome. Within this context, special attention is given to the role of glucocorticoids in terms of treatment duration, metabolism and sensitivity

Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome

xtabstractProlonged prednisolone treatment for the initial episode of childhood nephrotic syndrome may reduce relapse rate, butwhether this results fromthe increased duration of treatment or a higher cumulative dose remains unclear.We conducted a randomized, double-blind, placebo-controlled trial in 69 hospitals in The Netherlands. We randomly assigned 150 children (9 months to 17 years) presenting with nephrotic syndrome to either 3 months of prednisolone followed by 3 months of placebo ( n=74) or 6 months of prednisolone (n=76), and median follow-up was 47 months. Both groups received equal cumulative doses of prednisolone (approximately 3360 mg/m2). Among the 126 children who started trial medication, relapses occurred in 48 (77%) of 62 patients who received 3 months of prednisolone and 51 (80%) of 64 patients who received 6 months of prednisolone. Frequent relapses, according to international criteria, occurred with similar frequency between groups as well (45% versus 50%). In addition, there were no statistically significant differences between groups with respect to the eventual initiation of prednisolone maintenance and/or other immunosuppressive therapy (50% versus 59%), steroid dependence, or adverse effects. In conclusion, in this trial, extending initial prednisolone treatment from 3 to 6 months without increasing cumulative dose did not bene fit clinical outcome in children with nephrotic syndrome. Previous findings indicating that prolonged treatment regimens reduce relapses most likely resulted from increased cumulative dose rather than the treatment duration. Copyrig

Monitoring Prednisolone and Prednisone in Saliva: a population pharmacokinetic approach in healthy volunteers

Background: Prednisolone (PLN) is a widely used corticosteroid in a variety of immune-mediated diseases. Treatment regimes generally consist of empirically derived treatment doses, whereas therapeutic response among patients is highly variable. Drug monitoring of serum PLN levels might support a more rational approach to dose selection, yet is invasive and laborious. In analogy to cortisol, salivary PLN may offer a good alternative for serum PLN, being a representative approximation of free serum PLN. The aims of this study were to evaluate the correlation between free serum and salivary PLN levels and to quantify this relationship within a population pharmacokinetic model.Methods: PLN and prednisone (PN) concentrations were measured in 396 samples from 19 healthy volunteers after oral ingestion of 80 mg PLN. Measurements in serum, ultrafiltrate, and saliva were performed with a recently validated liquid chromatography tandem mass spectrometry method. Population pharmacokinetic analysis was performed with nonlinear mixed effect modeling using NONMEM.Results: Salivary PLN levels correlated well with free serum PLN levels (r = 0.931, P <0.01). A weaker correlation was found for PN (r = 0.318, P <0.01), which may be explained by the finding that salivary PN levels mainly seemed to consist of PLN enzymatically converted to PN. Total and free serum PLN concentrations decreased over time after drug administration and showed a nonlinear mutual relationship, consistent with concentration-dependent protein binding. Modeled PLN pharmacokinetics corresponded with previous reports. Low to moderate interindividual variability was found for V/F and CL/F (coefficients of variation were 13.8% and 14.6%, respectively). Free and salivary PLN showed a nonlinear relationship with total PLN. An equation predicting free serum levels from salivary levels was successfully derived from the data.Conclusions: This study is the first to describe the relationship between salivary and (free) serum PLN using a population pharmacokinetic model. Salivary PLN was found to be a reliable predictor of free and total serum PLN in healthy volunteers. The results of this study encourage further exploration of the use of saliva as a noninvasive and feasible method for drug monitoring of PL