Dataset Information

Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex.

ABSTRACT: Sirolimus is already used in the treatment of tuberous sclerosis complex (TSC), however, with narrow therapeutic range and considerable inter- and intra-individual pharmacokinetic variability, making it hard to develop an appropriate sirolimus initial dosage regimen, especially in children with TSC. The aim of this study was to recommend the optimal sirolimus initial dosing regimen in pediatric patients with TSC. Underlying physiological and genetic factors were collected to explore the effects on clinical sirolimus concentrations by establishing a nonlinear mixed effect (NONMEM) model, and to further simulate the optimal sirolimus initial dosing regimen using Monte Carlo method in pediatric patients with TSC. The once-daily regimen and the twice-daily regimen were recommended, respectively. For once-daily regimen, the dosages of 0.10, 0.07, 0.05, 0.04, 0.03 mg/kg/day were recommended for children with weights of 5-10, 10-20, 20-30, 30-50, and 50-60 kg, respectively. For twice-daily regimen, the dosages of 0.04, 0.03, 0.02 mg/kg/day (the daily dose was divided evenly into two doses) were recommended for children with weights of 5-20, 20-40, 40-60 kg, respectively. The initial dosages of sirolimus in children with TSC were recommended for the first time.

SUBMITTER: Wang DD

PROVIDER: S-EPMC7300220 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex.

Wang Dong-Dong DD Chen Xiao X Xu Hong H Li Zhi-Ping ZP

Frontiers in pharmacology 20200611

Sirolimus is already used in the treatment of tuberous sclerosis complex (TSC), however, with narrow therapeutic range and considerable inter- and intra-individual pharmacokinetic variability, making it hard to develop an appropriate sirolimus initial dosage regimen, especially in children with TSC. The aim of this study was to recommend the optimal sirolimus initial dosing regimen in pediatric patients with TSC. Underlying physiological and genetic factors were collected to explore the effects ...[more]

PMID: 32595509

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Project description:Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Project description:Importance:Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment. Objective:To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions. Design, Setting, and Patients:Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC. Interventions:Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks. Main Outcomes and Measures:The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated." Results:Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment. Conclusions and Relevance:Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality. Trial Registration:ClinicalTrials.gov Identifier: NCT02635789.

Dataset Information

Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex.

Publications

Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex.

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