Using repeated-time-to-event modelling and simulation of spontaneous bleeding events in the F8 KO rat model for informed decision making of study design
Malte Selch Larsen {1,4}, Rasmus Vestergaard Juul {2}, Ulrika S. H. Simonsson {3}, Annemarie T. Kristensen {4}, Mads Kjelgaard-Hansen {5}, Mads Kreilgaard {1}
{1} Haemophilia PK & ADME, Haemophilia Research, Global Research, Novo Nordisk A/S, Maaloev, Denmark; {2} Quantitative Clinical Pharmacology, Novo Nordisk A/S, Soeborg, Denmark; {3} Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; {4} Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark, {5} Haemophilia Biology, Haemophilia Research, Global Research, Novo Nordisk A/S, Maaloev, Denmark
Objectives: The spontaneously bleeding coagulation factor VIII-gene knock-out (F8 KO) rat model presents a unique opportunity to investigate the exposure-response relationship in close agreement with the clinical setting. However, preclinical studies are often limited by small study populations and short study durations which may impede identification of a significant treatment effect. In the current study, it was investigated whether disease progression in terms of bleeding risk in the F8 KO rat model could be described using repeated-time-to-event (RTTE) modelling. Secondly, applying stochastic simulation and estimation (SSE), three different study designs were evaluated on the basis of the power to identify a significant treatment effect.
Methods: The occurrence of spontaneous bleeding events in 89 untreated F8 KO rats, examined daily for bleedings for a period of 52 weeks (1), was described by a RTTE model in NONMEM 7.3 (Laplacian estimation method). SSEs (1000 samples) with and without recombinant FVIII treatment were made using the developed RTTE model, a hypothetical one-compartmental intravenous pharmacokinetic model (Vd=30 mL/kg and CL=4.1 mL/h·kg) and a literature derived exposure-response relationship (2). For all simulations study duration was set to 16 weeks (week 4 to 20). Different conditions were investigated, including three dosing regimens (50 IU/kg every second day, 50 IU/kg daily and 100 IU/kg daily) and sample sizes ranging from 20 to 100 rats. The power to identify a significant treatment effect was evaluated at a significance level of 0.05 for each study condition, aiming for at least 80% power.
Results: The initial increase and subsequent decline in the hazard was best described by a surge function (3). The highest bleeding risk was observed at week 10 (5 bleeds per year) showing a 6-fold increase relative to baseline. A sample size of approximately 30 rats was required to detect a significant reduction in the bleeding risk with a power of at least 80% using a dose regimen of 100 IU/kg daily. The equivalent sample size at a dose regimen of 50 IU/kg daily and 50 IU/kg every second day was 45 and more than 100, respectively.
Conclusions: The occurrence of bleeding events in the F8 KO rat model was well described using RTTE modelling with a surge function. The current study, demonstrates the need for frequent dosing and/or high dose treatment to compensate for small group sizes in F8 KO rat efficacy studies.
References:
[1] Nielsen, L.N., J Thromb Haemost 2014:12(8):1274-1282
[2] PAGE 24 (2015) Abstr 3683 [www.page-meeting.org/?abstract=3683]
[3] Plan, E.L., J Pharmacol Exp Ther 2011:339(3): 878-885
