Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery

Abstract

Meer FJM, Meijer K, Fijnvandraat K, Leebeek FWG, Collins PW, Cnossen MH, Mathôt RAA, for the OPTI-CLOT study group. Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery. J Thromb Haemost 2018; 16: 2196-207. Essentials• Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. • We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. • Population PK parameter values for clearance and V1 were 284 mL h À1 70 kg À1 and 5450 mL70 kg À1 . • Perioperative PK parameters differ from those during non-surgical prophylactic treatment.Summary. Background: Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under-and overdosing occurs frequently during surgery. Aim: The objective was to quantify and explain the interpatient variability of perioperatively administered plasmaderived (pd) and recombinant (r) FIX concentrates. Methods: Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NON-MEM. Results: Measured perioperative FIX level vs. time profiles were adequately described using a threecompartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h À1 70 kg À1 (18%); V1, 5450 mL70 kg À1 (19%); Q2, 110 mL h À1 70 kg À1 ; V2, 4800 mL70 kg À1 ; Q3, 1610 mL h À1 70 kg À1 ; V3, 2040 mL70 kg À1 . From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions: The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery.

Pediatric Dose Selection for Therapeutic Proteins

“…Most of the PK models used a 2‐compartment structure (n = 8), though 1‐compartment (n = 2) and 3‐compartment (n = 1) models were also used. Four of the models used at least 1 fixed allometric exponent (0.75 or 1) to describe the relationship between body weight and PK parameters according to conventional allometry 37–40 . Consistent with the allometry hypothesis, the median exponent for the effect of body weight on clearance was 0.80 (range, 0.76‐0.80) among the models in which body weight effects were estimated from the available data 41–44 .…”

Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS‐Hemo project

“…As a result, their accuracy when used for individual PK estimation is unknown. Second, many of these models include covariates that may be unavailable for WAPPS‐Hemo PK studies, in that they are not collected (ie race 17 ) or they are not usable in our context (ie trial identifier, 17,18 surgery 19 ). However, these models may be used for benchmarking purposes in specific cases.…”

Population Pharmacokinetic Modeling of von Willebrand Factor Activity in von Willebrand Disease Patients after Desmopressin Administration

“…The remaining missing values were imputed as described in the ►Supplementary Material (available in the online version). 26 F VD successfully corrected for the difference in baseline level just before administration of desmopressin and historical level of the VWF activity, without influencing any other parameter estimations. The interpatient variability of Cl, V, and F were…”