Pharmacokinetics of prednisone and its metabolite prednisolone in children with nephrotic syndrome during the active phase and in remission.

Gatti, G.; Perucca, Emilio; Frigo, G. M.; Notarangelo, LD; Barberis, L; Martini, A

doi:10.1111/j.1365-2125.1984.tb02367.x

Cited by 20 publications

(13 citation statements)

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“…Studies performed in children with nephrotic syndrome demonstrated that prednisolone PK parameters did not correlate with clinical effectiveness 8 and that PK is unlikely associated with steroid unresponsiveness in children with nephrotic syndrome. 26 Another study performed in children with steroid-dependent asthma showed that the PK of prednisolone (administered intravenously in this study) is unrelated to patients’ clinical response to therapy. 27 …”

Section: Discussionmentioning

confidence: 64%

Pharmacokinetics of Prednisolone at Steady State in Young Patients With Systemic Lupus Erythematosus on Prednisone Therapy: An Open-Label, Single-Dose Study

Sagcal‐Gironella¹,

Sherwin²,

Tirona³

et al. 2011

Clinical Therapeutics

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Background Current prednisone dosing in the treatment of young patients with childhood-onset systemic lupus erythematosus (cSLE) is largely based on achieving balance between therapeutic efficacy and toxicity, with weight-based dosing a common clinical practice. Despite the widespread use of prednisone, few attempts have been made to improve its clinical dosing regimen and response to prednisone therapy remains variable. Objectives To characterize the pharmacokinetics (PK) of prednisolone, the metabolite of the prodrug prednisone, in cSLE patients and explore the relationship between PK and cSLE disease activity. Methods Blood samples were taken 1 hour before the morning prednisone dose and at 20, 40, 60, 90 minutes, and 2, 3, 4, 6, and 9 hours from 8 patients (age 12–28 years) after an 8-hour fast. Average weight-adjusted daily prednisone dose, stable at least 30 days pre-study, was 0.29 mg/kg/day. PK analysis of prednisolone was performed using non-compartmental analysis with WinNonlin®. cSLE disease activity was measured using the British Isles Lupus Assessment Group (BILAG) index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results Mean total prednisolone area under the curve (AUC0-9), apparent oral clearance of prednisone at steady state, and half-life were 1094 (range: 467–2404) ng*hr/mL, 11 (range: 6.7–13.7) L/hr, and 2.6 (range: 1.3–3.9) hours. Mean total prednisolone AUC0-9 normalized to prednisone dose by weight was 4361 (range: 1136 – 9580) ng*hr/mL/mg/kg. Mean total prednisolone Cmax normalized to prednisone dose by weight was 1097 (range: 301 – 2211) ng/mL/mg/kg at 1.84 (range: 0.48 – 4) hours (Tmax). Patients on prednisone had inter-individual variability in prednisolone AUC0-9 (coefficient of variation, CV: 61%) and dose-adjusted AUC0-9 (CV: 58%). Conclusions Inter-individual variability in systemic exposure to prednisolone in cSLE patients was observed.

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Section: Discussionmentioning

confidence: 64%

Pharmacokinetics of Prednisolone at Steady State in Young Patients With Systemic Lupus Erythematosus on Prednisone Therapy: An Open-Label, Single-Dose Study

Sagcal‐Gironella¹,

Sherwin²,

Tirona³

et al. 2011

Clinical Therapeutics

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“…This reduced protein binding may also give rise to accelerated overall clearance of the drug. These two potential mechanisms often offset each other and render the influence of hypoalbuminemia on the pharmacokinetics negligible [36][37][38].…”

Section: Discussionmentioning

confidence: 96%

Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease

2009

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Obesity is associated with an increased concentration of inflammatory mediators, which in turn, in adults, reduces the response to calcium channel blockers (CCBs). We reviewed the medical charts of 263 pediatric nephrology patients with renal conditions, with the aim of studying the effect of obesity on the response to L-type CCBs, angiotensin interrupting agents (ANGIs), or a combination of the two. Forty-eight patients were ultimately enrolled in the study: 25 obese and 23 non-obese patients. The effect of the treatments on lowering the blood pressure was compared in obese versus non-obese patients. The systolic response to CCBs, measured as at least a 10% reduction from the baseline, was significantly lower in the obese (12.5%) patients than in the non-obese (52.9%) ones. The differences in diastolic response (58.8 and 25% for non-obese and obese patients, respectively) did not reach significance. The percentage response to CCBs, however, was significantly less in the obese patients than in the non-obese patients for both systolic and diastolic blood pressure. Corticosteroids also significantly influenced the response to CCBs in terms of diastolic pressure (62.9 and 25% for non-obese and obese patients, respectively). None of the tested covariates, including obesity, was found to significantly influence the response to ANGIs alone or in various combinations with CCBs. In conclusion, obesity and corticosteroid therapy should be considered when initiating antihypertensive drug treatment in children with kidney disease as both may contribute to a reduced efficacy of the antihypertensive therapy.

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“…Certain drugs which interfere at the cellular transporter level, such as diltiazem, are capable of inhibiting P-gp function and increasing systemic prednisolone exposure and its antilymphocytic effects [23]. Nevertheless, previous studies carried out in nephrotic children showed no apparent correlation between the concentration-time profile of prednisone or prednisolone administered orally in a commercially available form and treatment outcome in terms of relapse rate [24,25]. To our knowledge, there are no clinical studies addressing the role of P-gp in prednisone/prednisolone absorption or excretion.…”

Section: Discussionmentioning

confidence: 97%

MDR-1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children

et al. 2007

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The study was aimed at investigating the association between MDR-1 genetic polymorphisms [C1236T, G2677T(A), C3435T] and parameters describing the clinical course and treatment response of childhood steroid-responsive nephrotic syndrome (SRNS). Three MDR-1 genetic markers were analyzed in 108 children diagnosed with SRNS and in 135 healthy controls with neither allergic nor renal disease. All subjects were genotyped by PCR-restriction fragment length polymorphism (RFLP) analysis, and an EM algorithm-based analysis was utilized to estimate haplotype frequencies. As expected, there was no difference in genotypic and allelic distribution between and among SRNS patients and healthy children. However, all individual polymorphisms were strongly associated with time to response to initial prednisone therapy. The frequencies of the mutated alleles were higher in late responders (time to remission: >7 days) to oral prednisone (0.53, 0.52,0.66) than in early responders (time to remission: <7 days; 0.24, 0.19, 0.32), with all p values <0.001 for positions 1236, 2677 and 3435, respectively). Odds ratios (ORs) reflecting the strength of the associations were as follows: 6.79 (95% CI:1.96- 23.54) for 1236 T/T, 13.7 (95% CI:2.78-67) for 2677 T/T and 9.92 (95% CI: 3.01-32.71) for 3435 T/T as compared to the respective-wild type homozygotes. The TTT haplotype was similarly found to be significantly associated with late oral steroid response (0.49 vs. 0.19, p=0.0003). Variants 1236T, 2677TA and 3435T identify patients that respond slower to oral prednisone. Although the functional properties of the substitutions investigated here are still to be determined, our findings may be a small step toward the optimization of immunosuppressive therapy in SRNS children.

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Pharmacokinetics of prednisone and its metabolite prednisolone in children with nephrotic syndrome during the active phase and in remission.

Cited by 20 publications

References 10 publications

Pharmacokinetics of Prednisolone at Steady State in Young Patients With Systemic Lupus Erythematosus on Prednisone Therapy: An Open-Label, Single-Dose Study

Pharmacokinetics of Prednisolone at Steady State in Young Patients With Systemic Lupus Erythematosus on Prednisone Therapy: An Open-Label, Single-Dose Study

Effect of obesity on response to cardiovascular drugs in pediatric patients with renal disease

MDR-1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children

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