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

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Aims The purpose was to determine the exposure-response 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. Methods One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2: 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA). Results Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus. Conclusions These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.

Original languageEnglish (US)
Pages (from-to)958-970
Number of pages13
JournalBritish Journal of Clinical Pharmacology
Volume81
Issue number5
DOIs
StatePublished - May 1 2016

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Lymphangioleiomyomatosis
Angiomyolipoma
Tuberous Sclerosis
Pharmacokinetics
Kidney
Biomarkers
Vascular Endothelial Growth Factor D
Collagen Type IV
Placebos
Everolimus
Vascular Endothelial Growth Factor A
Therapeutics
Enzyme-Linked Immunosorbent Assay
Confidence Intervals
Growth

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

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; Urva, Shweta; Brechenmacher, Thomas; Stein, Karen; Chen, David; Kingswood, John Christopher; Bissler, John.

In: British Journal of Clinical Pharmacology, Vol. 81, No. 5, 01.05.2016, p. 958-970.

Research output: Contribution to journalArticle

Budde, Klemens ; Zonnenberg, Bernard A. ; Frost, Michael ; Cheung, Wing ; Urva, Shweta ; Brechenmacher, Thomas ; Stein, Karen ; Chen, David ; Kingswood, John Christopher ; Bissler, John. / Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis. In: British Journal of Clinical Pharmacology. 2016 ; Vol. 81, No. 5. pp. 958-970.
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T1 - Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis

AU - Budde, Klemens

AU - Zonnenberg, Bernard A.

AU - Frost, Michael

AU - Cheung, Wing

AU - Urva, Shweta

AU - Brechenmacher, Thomas

AU - Stein, Karen

AU - Chen, David

AU - Kingswood, John Christopher

AU - Bissler, John

PY - 2016/5/1

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N2 - Aims The purpose was to determine the exposure-response 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. Methods One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2: 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA). Results Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus. Conclusions These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.

AB - Aims The purpose was to determine the exposure-response 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. Methods One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2: 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA). Results Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus. Conclusions These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.

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