title: Clearance of drugs for multiple myeloma therapy during in vitro high-cutoff hemodialysis.
abstract: Current chemotherapy for multiple myeloma is based on bortezomib (BOR), dexamethasone (DEX), and thalidomide (THA). The purpose of the present study was to examine their clearance during high-cutoff (HCO) 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 HCO dialyzer (Theralite, 2.1 m(2) ) to a high-flux dialyzer (PFX; 2.1 m(2) ), ultrafiltered volume was replaced by saline containing 30 g/L urea. After recirculation for equilibration, BOR was injected, and arterial and venous samples were drawn after 10, 11, and 12 min to measure the plasma clearance (K) of both urea and BOR. The same procedure was performed with THA and DEX. By mathematical simulation, the influence of varying plasma albumin concentrations (CHSA ) on the protein-bound drug fraction (PBF) and K was assessed. Plasma K values of HCO and PFX for THA, BOR, and DEX were about 40% (80 ± 7 vs. 65 ± 6 mL/min; P < 0.05), 70% (40 ± 8 vs. 33 ± 4 mL/min; P < 0.05), and 65% (47 ± 11 vs. 38 ± 7 mL/min; P < 0.05), respectively-lower (P < 0.0001) compared with urea (125 ± 7 vs. 122 ± 5 mL/min). K was highest (P < 0.0001) for THA. K was negatively correlated with CHSA (THA, r(2)  = 0.58, P < 0.001; BOR, r(2)  = 0.24, P < 0.05; DEX, r(2)  = 0.22, P < 0.05). CHSA continually decreased (P < 0.05) over time only with HCO, resulting in lower calculated PBF. Compared with BOR and DEX (minimum 72 and 56%, respectively), the PBF of THA (37%) was significantly lower (P < 0.001). A mathematical simulation based on the K values of urea and the drugs reliably estimated PBF (r(2)  = 0.886, P < 0.001). Drugs for multiple myeloma therapy are significantly removed with both HCO and PFX, with important implications for the dosing and timing of administration, particularly in patients with cast nephropathy receiving extended dialysis. If the Kurea of a dialyzer and the PBF of any given drug are known, Kdrug can be reliably estimated by mathematical simulation.
authors.affiliation: Division of Nephrology, Department of Medicine, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Detlef H
authors.initials: DH
authors.lastname: Krieter
authors.forename: Eric
authors.initials: E
authors.lastname: Devine
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Markus
authors.initials: M
authors.lastname: Storr
authors.forename: Bernd
authors.initials: B
authors.lastname: Krause
authors.forename: Horst-Dieter
authors.initials: HD
authors.lastname: Lemke
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000628:therapy*; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001897:Boronic Acids / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069286:Bortezomib; D003907:Dexamethasone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy*; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006435:Renal Dialysis / Q000379:methods; D013792:Thalidomide / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone
keywords: Bortezomib; Dexamethasone; High-cutoff dialysis; Multiple myeloma; Protein binding; Thalidomide