Factor VIII concentrate dosing with lean body mass, ideal body weight and total body weight in overweight and obesity: A randomized, controlled, open‐label, 3 × 3 crossover trial

Abstract

Introduction Obesity alters the pharmacokinetic (PK) properties of drugs making it difficult to determine the appropriate dose when administering weight‐based medications. Alternative descriptors of body weight, such as lean body mass (LBM) and ideal body weight (IBW), are sometimes used in these situations. Methods We performed a single‐centre, randomized, controlled, open‐label, 3 × 3 crossover trial to determine whether recombinant factor VIII (rFVIII) dosing based on LBM and IBW achieves a targeted FVIII recovery with better precision than based on total body weight (TBW) in overweight and obese, adult males with haemophilia A. Participants were randomized to 1 of 6 possible FVIII concentrate dosing sequence scenarios (TBW, LBM and IBW). Recombinant FVIII was administered on 3 separate weeks following a washout period of at least 72 hours. Results A total of 19 participants were randomized and completed the study. FVIII recovery was lower at 30 minutes post‐rFVIII infusion in LBM vs TBW and IBW vs TBW‐based dosing, mean difference −0.38 (95% CI: −0.56, −0.20) and −0.28 (95% CI: −0.47, −0.10) IU/dL per IU/kg, respectively. In LBM vs TBW and IBW vs TBW‐based dosing, there was a non‐significant increase in the proportion of participants with a targeted FVIII recovery of 2.00 ± 0.20 IU/dl per IU/kg, OR = 1.93 (95% CI: 0.44, 8.55) and OR = 3.65 (0.80, 16.72), respectively. Discussion Based on our study's findings, overweight and obese patients with haemophilia A may benefit from an individualized PK analysis using LBM and IBW to determine the most accurate, and potentially cost‐effective, method of achieving targeted FVIII recovery.

Evidence-Based Minireview: For overweight or obese persons with hemophilia A, should factor VIII dosing be based on ideal or actual body weight?

“…The sec ond cross over trial, a 3 × 3 × 3 design of ABW vs IBW vs lean body mass (LBM), was conducted in 19 adults (mean BMI, 29.5) to deter mine which descrip tors of BW achieved the tar geted IVR of 2 with bet ter pre ci sion. 12 The mean IVR postrecom binant fac tor VIII (rFVIII) infu sion for ABW, LBM, and IBWbased dos ing was 2.46, 2.22, and 2.29, respec tively. The pro por tion of par tic i pants with an IVR of 2.00% ± 10% was 31.1%, 44.2%, and 49.0% for ABW, LBM, and IBWbased dos ing, respec tively.…”

“…All three stud ies used dif fer ent out come mea sures: peak FVIII lev els after a 50 IU/kg dose and clin i cal effec tive ness 10 ; per cent age of actual FVIII recov ery lev els over expected lev els after a 50 IU/kg dose 11 ; and FVIII IVR (Table 2). 12 Graham et al performed a ret ro spec tive study reporting peak FVIII lev els for 6 adults with BMIs ≥30 treated with recom bi nant FVIII 50 IU/kg dosed by IBW. 10 These patients had been previously receiving recom binant FVIII at 50 IU/kg dosed by ABW for prophylaxis or were undergoing surgery.…”

“…Our sys tem atic minireview iden ti fied 2 pro spec tive cross over stud ies that directly com pared IBW to ABW dos ing of FVIII con cen trates and 1 ret ro spec tive study that com pared IBW dos ing to his tor i cal ABW dos ing in over weight and obese per sons with hemo philia A. [10][11][12] A con cern with using IBW is the risk of under dosing, resulting in sub ther a peu tic FVIII lev els and increased risk of bleed ing. Overall, these 3 stud ies dem on strated favor able out comes using dif fer ent PK mea sures when dosed by IBW and sup port the use of IBW to per form indi vid u al ized PK anal y sis in over weight and obese per sons with hemo philia A.…”

“…Fulltext reviews by 2 inde pen dent review ers were conducted on the 27 remaining arti cles, and 3 stud ies were ulti mately included: 1 ret ro spec tive obser va tional study and 2 cross over tri als. [10][11][12]…”