Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis

Budde, Klemens; Zonnenberg, Bernard A.; Frost, Michael; Cheung, Wing K.; Urva, Shweta; Brechenmacher, Thomas; Stein, Karen; Chen, David; Kingswood, J. C.; Bissler, John J.

doi:10.1111/bcp.12834

Cited by 24 publications

(20 citation statements)

References 36 publications

(60 reference statements)

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“…Linear mixed models supported a statistically and clinically signifi cant association between a two-times increase in TN C min and a 28•3% reduction in seizure frequency. In the studies of subependymal giant-cell astrocytoma and angiomyolipoma, a two-times C min increase was associated with a non-clinically signifi cant 10% (unpublished) and 13% statistically signifi cant reduction in volumes, 30 respectively. This diff erence in exposure-response relationship might relate to higher interindividual variability of exposure and a threshold eff ect in the tumour-volume-based trials, or greater sensitivity of synaptic plasticity and neuronal hyperexcitability in this seizure study.…”

Section: Discussionmentioning

confidence: 94%

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

French¹,

et al. 2016

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Section: Discussionmentioning

confidence: 94%

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

French¹,

et al. 2016

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“…Generell ist die Therapie bei TSC-assoziierten Symptomen eine lebenslange Therapie, da eine erneute Progression der Symptome nach Absetzen von Everolimus oder Sirolimus auftritt. In der Therapie der TSC-AML waren Talspiegel von Everolimus zwischen 3 und 8 ng/ml effektiv [66], möglicherweise sind auch niedrigere Talspiegel therapeutisch wirksam. Möglicherweise kann auch eine Dosisreduktion nach initialem Ansprechen sinnvoll sein [51,67].…”

Section: Sicherheit Einer Mtor-inhibitor-therapieunclassified

Sporadische Lymphangioleiomyomatose (sLAM) und Tuberöse-Sklerose-Komplex (TSC) – Pulmonale Manifestationen

et al. 2016

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Lymphangioleiomyomatosis (LAM) is a rare multi-system disorder affecting predominantly women of childbearing age. The disease entity is divided in sporadic LAM (sLAM) and LAM associated with tuberous sclerosis complex (TSC). In up to 50 % of female TSC-patients pulmonary involvement (TSC-LAM) can be found, with first clinical symptoms usually starting between 25 and 30 years of age. Progressive deterioration of lung function of 3 - 11 % of diffusion capacity per year has been described, that's why all female TSC patients should be screened for LAM (pulmonary function testing, 6-minute walk test, high-resolution chest CT scan). MTOR inhibitors such as Everolimus or Sirolimus are implemented in the treatment of TSC/LAM and found to control disease burden. Screening for all organ manifestations in TSC is recommended and allows to improve prognosis and to prevent complications in TSC.

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“…The eligibilities were carefully assessed in 11 full-text articles. Finally, only 9 studies met the inclusion criteria for the systematic review, including 2 RCTs [ 14 , 20 , 21 ], 6 single-arm trials [ 12 , 17 , 22 – 25 ], of which 7 studies were used for the meta-analysis. Notably, Budde et al [ 21 ] reported the accurate data on the serum VEGF-D levels, which were not elaborated in the initial study [ 20 ], so we cited the two separate studies as the same RCT.…”

Section: Resultsmentioning

confidence: 99%

The efficacy and adverse events of mTOR inhibitors in lymphangioleiomyomatosis: systematic review and meta-analysis

Gao¹,

Zhang²,

Ji³

et al. 2018

Orphanet J Rare Dis

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BackgroundLymphangioleiomyomatosis (LAM) is a rare lung disease and the mammalian target of the rapamycin (mTOR) inhibitors has been used as an effective therapy. Here we conducted a systematic review and meta-analysis with the aims to quantify the efficacy and safety of mTOR inhibitors in LAM patients.MethodsThe following databases were searched for clinical trials regarding LAM patients treated with mTOR inhibitors until December 2017: Pubmed, Embase, Cochrane Library and OVID medicine. Random effect models were used for the quantitative analysis.ResultsNine eligible studies were included in our systematic review, 7 of which were used for the meta-analysis. In LAM patients, mTOR inhibitors improved forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) significantly, with the weighted mean difference (WMD) 0.15 L (95%CI: 0.08 to 0.22, P < 0.01, I2 = 0%) and 0.22 L (95%: 0.11 to 0.32, P < 0.01, I2 = 0%) respectively. There was no significant change in neither the diffusing capacity for carbon monoxide (WMD: 0.51 ml/mm Hg/min, 95%CI: -0.48 to 1.49, P = 0.31, I2 = 0%) nor 6-min walking distance (WMD: 5.29 m, 95%CI: -18.01 to 28.59, P = 0.66, I2 = 1%). The weighted partial response rate was 0.68 (95%CI: 0.53 to 0.84, P < 0.01, I2 = 72%) for renal angiomylipoma. The cumulative incidence rates of common safety events were 50, 40, 23, 20 and 19% for oral mucositis, hyperlipidemia, headache, bone marrow suppression, and diarrhea, respectively. And most events were low grade and tolerant.ConclusionsIn LAM patients, there are improvements of FEV1 and FVC after the application of mTOR inhibitors and over a half achieved the shrinkage of renal angiomyolipoma.Trial registrationPROSPERO registration number: CRD42018085470. Registered 22 January 2018.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0874-7) contains supplementary material, which is available to authorized users.

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Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis

Abstract: AIMSThe purpose was to determine the exposureÀresponse relationship of everolimus in patients with angiomyolipoma from the EXIST-2 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients.

Cited by 24 publications

References 36 publications

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

Sporadische Lymphangioleiomyomatose (sLAM) und Tuberöse-Sklerose-Komplex (TSC) – Pulmonale Manifestationen

The efficacy and adverse events of mTOR inhibitors in lymphangioleiomyomatosis: systematic review and meta-analysis

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