title: Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation.
abstract: Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n = 18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n = 11). In the PK analysis, we found significant interpatient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70 kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P = .003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: sonata.jodele@cchmc.org.
authors.forename: Sonata
authors.initials: S
authors.lastname: Jodele
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kana
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.affiliation: Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Laskin
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jens
authors.initials: J
authors.lastname: Goebel
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Dixon
authors.affiliation: Division of Critical Care, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Chima
authors.affiliation: Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Russel
authors.initials: R
authors.lastname: Hirsch
authors.affiliation: Department of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ashley
authors.initials: A
authors.lastname: Teusink
authors.affiliation: Department of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Danielle
authors.initials: D
authors.lastname: Lazear
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Adam
authors.initials: A
authors.lastname: Lane
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kasiani C
authors.initials: KC
authors.lastname: Myers
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Dandoy
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D057049:Thrombotic Microangiopathies / Q000188:drug therapy* / Q000209:etiology; D019172:Transplantation Conditioning / Q000009:adverse effects*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab
keywords: CH50; Complement; Eculizumab; Membrane attack complex; Thrombotic microangiopathy; sC5b-9