João A Abrantes (1), Elisabet I Nielsen (1), Joan Korth-Bradley (2), Lutz Harnisch (3), Siv Jönsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Pfizer Inc, Collegeville, Pennsylvania, USA, (3) Global Clinical Pharmacology, Pfizer, Sandwich, UK
Objectives: Moroctocog alfa is a B-domain deleted recombinant factor VIII (FVIII) indicated for the treatment and prophylaxis of bleeding in adults and children with haemophilia A. The aim of this study is to develop a population pharmacokinetic model of FVIII activity following moroctocog alfa treatment in moderate to severe haemophilia A patients using all available clinical study data.
Methods: A population pharmacokinetic model (NONMEM 7.3) was developed with data from 13 trials involving IV administration of moroctocog alfa products (Refacto®, Refacto AF®, Xyntha® Wyeth Pharmaceuticals Inc. [Pfizer], Philadelphia, USA). The studies were conducted from 1993 to 2013 in 25 countries, and included rich sampling (≥10 samples post-dose, n=4), sparse sampling (2-3 samples per occasion, n=5) or both (n=4). The influence of age, measures of body size, race, ethnicity, inhibitor status and titre, assay, year of study, study and country, were investigated. Data below the lower limit of quantification were handled using the M5 method [1] and correlated residual errors for repeated analyses were accounted for by using the L2 data item [2]. Qualification of the models included pcVPCs and parameter uncertainty was obtained with SIR [3].
Results: A total of 259 children and adolescents and 497 adults with moderate to severe haemophilia A (FVIII ≤5 IU/dL) were included in the analysis. Age ranged from 1 day to 73 years and weight from 3 to 134 kg. A two-compartment model with allometrically scaled body weight on disposition parameters was found to adequately describe the combined data. Pre-dose activity observations were described by estimating two endogenous FVIII activity levels at 0.474 IU/dL and 1.59 IU/dL together with an additive component accounting for residual activity from previous unknown doses (2.84 IU/dL at time 0, declining over time in line with FVIII disposition). For a 70-kg, 20-year-old patient with moderate or severe haemophilia A, FVIII activity clearance was estimated at 2.76 dL/h, central volume of distribution at 24.5 dL, peripheral volume of distribution at 9.23 dL, and inter-compartmental clearance at 25.1 dL/h.
Conclusions: The model is capable of describing and predicting reasonably well the data and when used with patient observations in a therapeutic drug monitoring context may be an aid in dose individualization, with the ultimate goal of a safer and more effective treatment with moroctocog alfa.
References:
[1] Ahn JE, Karlsson MO, Dunne A, Ludden TM. 2008. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn 35(4):401-21
[2] Karlsson MO, Beal SL, Sheiner LB. 1995. Three new residual error models for population PK/PD analyses. J Pharmacokinet Biopharm 23:651–672
[3] Dosne AG, Bergstrand M, Karlsson, MO. Application of Sampling Importance Resampling to estimate parameter uncertainty distributions. PAGE 22 (2013) Abstr 2907 [www.page-meeting.org/?abstract=2907]
Reference: PAGE 25 () Abstr 5942 [www.page-meeting.org/?abstract=5942]
Poster: Drug/Disease modeling - Other topics