Clearance of Drugs for Multiple Myeloma Therapy During In Vitro High‐Cutoff Hemodialysis

Media type: E-Article
Title: Clearance of Drugs for Multiple Myeloma Therapy During In Vitro High‐Cutoff Hemodialysis
Contributor: Krieter, Detlef H.; Devine, Eric; Wanner, Christoph; Storr, Markus; Krause, Bernd; Lemke, Horst‐Dieter
imprint: Wiley, 2014
Published in: Artificial Organs
Language: English
DOI: 10.1111/aor.12248
ISSN: 0160-564X; 1525-1594
Keywords: Biomedical Engineering ; General Medicine ; Biomaterials ; Medicine (miscellaneous) ; Bioengineering
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:p>Current chemotherapy for multiple myeloma is based on bortezomib (<jats:styled-content style="fixed-case">BOR</jats:styled-content>), dexamethasone (<jats:styled-content style="fixed-case">DEX</jats:styled-content>), and thalidomide (<jats:styled-content style="fixed-case">THA</jats:styled-content>). The purpose of the present study was to examine their clearance during high‐cutoff (<jats:styled-content style="fixed-case">HCO</jats:styled-content>) hemodialysis and to accordingly apply the results to the dialytic removal of protein‐bound substances in general. During in vitro hemodialysis with human blood (blood, dialysate, and ultrafiltration flow rates 250, 500 and 5 mL/min, respectively) comparing a highly permeable <jats:styled-content style="fixed-case">HCO</jats:styled-content> dialyzer (<jats:styled-content style="fixed-case">T</jats:styled-content>heralite, 2.1 m<jats:sup>2</jats:sup>) to a high‐flux dialyzer (<jats:styled-content style="fixed-case">PFX</jats:styled-content>; 2.1 m<jats:sup>2</jats:sup>), ultrafiltered volume was replaced by saline containing 30 g/L urea. After recirculation for equilibration, <jats:styled-content style="fixed-case">BOR</jats:styled-content> was injected, and arterial and venous samples were drawn after 10, 11, and 12 min to measure the plasma clearance (<jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content>) of both urea and <jats:styled-content style="fixed-case">BOR</jats:styled-content>. The same procedure was performed with <jats:styled-content style="fixed-case">THA</jats:styled-content> and <jats:styled-content style="fixed-case">DEX</jats:styled-content>. By mathematical simulation, the influence of varying plasma albumin concentrations (<jats:styled-content style="fixed-case"><jats:italic>C</jats:italic></jats:styled-content><jats:sub>HSA</jats:sub>) on the protein‐bound drug fraction (<jats:styled-content style="fixed-case">PBF</jats:styled-content>) and <jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content> was assessed. Plasma <jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content> values of <jats:styled-content style="fixed-case">HCO</jats:styled-content> and <jats:styled-content style="fixed-case">PFX</jats:styled-content> for <jats:styled-content style="fixed-case">THA</jats:styled-content>, <jats:styled-content style="fixed-case">BOR</jats:styled-content>, and <jats:styled-content style="fixed-case">DEX</jats:styled-content> were about 40% (80 ± 7 vs. 65 ± 6 mL/min; <jats:italic>P</jats:italic> < 0.05), 70% (40 ± 8 vs. 33 ± 4 mL/min; <jats:italic>P</jats:italic> < 0.05), and 65% (47 ± 11 vs. 38 ± 7 mL/min; <jats:italic>P</jats:italic> < 0.05), respectively—lower (<jats:italic>P</jats:italic> < 0.0001) compared with urea (125 ± 7 vs. 122 ± 5 mL/min). <jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content> was highest (<jats:italic>P</jats:italic> < 0.0001) for <jats:styled-content style="fixed-case">THA</jats:styled-content>. <jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content> was negatively correlated with <jats:styled-content style="fixed-case"><jats:italic>C</jats:italic></jats:styled-content><jats:sub>HSA</jats:sub> (<jats:styled-content style="fixed-case">THA</jats:styled-content>, <jats:italic>r</jats:italic><jats:sup>2</jats:sup> = 0.58, <jats:italic>P</jats:italic> < 0.001; <jats:styled-content style="fixed-case">BOR</jats:styled-content>, <jats:italic>r</jats:italic><jats:sup>2</jats:sup> = 0.24, <jats:italic>P</jats:italic> < 0.05; <jats:styled-content style="fixed-case">DEX</jats:styled-content>, <jats:italic>r</jats:italic><jats:sup>2</jats:sup> = 0.22, <jats:italic>P</jats:italic> < 0.05). <jats:styled-content style="fixed-case"><jats:italic>C</jats:italic></jats:styled-content><jats:sub>HSA</jats:sub> continually decreased (<jats:italic>P</jats:italic> < 0.05) over time only with <jats:styled-content style="fixed-case">HCO</jats:styled-content>, resulting in lower calculated <jats:styled-content style="fixed-case">PBF</jats:styled-content>. Compared with <jats:styled-content style="fixed-case">BOR</jats:styled-content> and <jats:styled-content style="fixed-case">DEX</jats:styled-content> (minimum 72 and 56%, respectively), the <jats:styled-content style="fixed-case">PBF</jats:styled-content> of <jats:styled-content style="fixed-case">THA</jats:styled-content> (37%) was significantly lower (<jats:italic>P</jats:italic> < 0.001). A mathematical simulation based on the <jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content> values of urea and the drugs reliably estimated <jats:styled-content style="fixed-case">PBF</jats:styled-content> (<jats:italic>r</jats:italic><jats:sup>2</jats:sup> = 0.886, <jats:italic>P</jats:italic> < 0.001). Drugs for multiple myeloma therapy are significantly removed with both <jats:styled-content style="fixed-case">HCO</jats:styled-content> and <jats:styled-content style="fixed-case">PFX</jats:styled-content>, with important implications for the dosing and timing of administration, particularly in patients with cast nephropathy receiving extended dialysis. If the <jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content><jats:sub>urea</jats:sub> of a dialyzer and the <jats:styled-content style="fixed-case">PBF</jats:styled-content> of any given drug are known, <jats:styled-content style="fixed-case"><jats:italic>K</jats:italic></jats:styled-content><jats:sub>drug</jats:sub> can be reliably estimated by mathematical simulation.</jats:p>

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