Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Abstract

Purpose The aim of this study was to explore possible differences in the pharmacokinetics (PK) of recombinant factor VIII:C (ReFacto® -ReFacto ) in HIV+ vs. HIVpatients and also differences in the chromogenic substrate bioassay (CHS) and one-stage clotting (OSC) methods. Methods Twenty-eight haemophilia A adults (20 HIV-and eight HIV+) were assayed with both the CHS and OSC methods. An average of two and six samples were collected per patient for HIV-/+, respectively, after one, and occasionally two more, prophylactic doses (mean 2,003 IU; range 1,000-4,300 IU). The observations were analysed with the mixed-effects (population) compartmental PK modelling package NONMEM (nonlinear mixed-effects modelling) and the FOCE (first-order conditional estimation) method. Base modelling was performed independently for the CHS and OSC bioassays for comparison, and covariate models and simulation tests were done only for the commonly used OSC bioassay. The final covariate model was validated using the bootstrap method. Monte Carlo simulations were used to estimate the expected probability of exceeding 20%, 40% or 60% of normal factor VIII:C in plasma after a single dose, corresponding to required levels for preventing mild, moderate and lifethreatening haemorrhages. Results One-compartment base-model population PK parameters were [mean parameter (interpatient variability %)] for CHS: clearance (CL)=2.56 dl h −1 (33.2%); volume of distribution (V)=34.8 dl (12.8%); and for OSC: CL= 3.83 dl h −1 (47.8%), V=53.7 dl (22.4%). The volumes differed significantly between the CHS and OSC methods (p<0.0001), and variabilities were higher for OSC. Nevertheless, the empirical half-lives (t 1/2 =l n (2) × V/CL) were similar for CHS and OSC, [(mean ± standard deviation (SD)], 9.5 ± 3 h and 10.2 ± 4 h, respectively. In covariate modelling with the OSC-derived model, HIV status (VIR) was a significant categorical predictor (p<0.005) for V.The final covariate models with OSC were for CL=3.93 + 0.09 × (WT-75) and for V=48.6 × (1 + 0.36 × VIR) + 0.55 × (WT-75); therefore, V for the typical HIV+ patient was 36% higher than for the HIV-patient. Conclusions Both HIV-and HIV+ patients showed 100% success with the 20% threshold at doses >20 IU/kg. HIVpatients receiving >50 IU/kg had a 100% expected chance of success for all thresholds. HIV+ patients for moderate or life-threatening haemorrhage treatment need 10 IU/kg more than the HIV-patient equivalent to have the same probability of success.

Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8‐GP in haemophilia A dogs

“…The pharmacokinetic of N8 was in the present study best described by a two-compartmental model; this is in agreement with previous publications based on clinical data [23,24]. However, the best model will most likely vary with the sampling schedule used in the study, and previously one compartment models have also been used to characterize the pharmacokinetic of VIII [25]. The terminal half-life of turoctocog alfa was estimated to be 16 h (Table 2), this is longer than the 8.9 h previously reported in dogs [7], the observed differences are most likely caused by differences in the methods used (two-compartmental pharmacokinetic analysis vs. non-compartmental analysis).…”

Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight

“…27 Despite this, population PK modeling has been applied only recently to FVIII. 12,[16][17][18]28 None of these studies aimed to compare population PK modeling with conventional 21,22 methods for analysis of FVIII data. Our work, which, compared with previous studies, also includes the largest number of patients and the greatest spans in age and BW, clearly demonstrates the superiority of the population modeling.…”

Population pharmacokinetics of recombinant factor VIII Fc fusion protein

“…More recently, a number of population PK models and model implementations for several FVIII products have been published. [23][24][25][26] Clinical Pharmacology in Drug Development 2015, 4(3) 163-174…”