S. Rossenu, J. Baumeister, J-B. Holz, M-L. Sargentini-Maier.
Ablynx NV, Zwijnaarde, Belgium
Objectives: Nanobodies® are therapeutic proteins based on the smallest functional fragments of heavy chain antibodies, naturally occurring in Camelidae. ALX-0081 is a bivalent Nanobody® drug product, targeting von Willebrand Factor (vWF). The developed pharmacokinetic (PK) /pharmacodynamic (PD) model was used to simulate the drug and biomarker profiles for a virtual paediatric population at steady-state and to compare the derived exposure parameters to those simulated in adults.
Methods: The paediatric simulations were performed using NONMEMVII in virtual adolescent populations created for different age groups (12- 18 years) receiving body-weight adjusted repeated SC administrations of ALX-0081. The simulations of PK (ALX-0081 levels) and PD (vWF levels) were done according to the developed PK/PD model1 with PK adapted to children through allometric scaling. The exposure parameters from the simulated steady-state plasma profiles were calculated and compared to adults.
Results: The predicted steady-state exposure parameters for the different age groups were similar to those in adults, except a slightly lower predicted trough concentration in the 12-year-old group. The biomarker profiles (vWF) were expected to be similar for the 16-18 year age group and in adults. For the 12-14 year age group, higher fluctuations of the free vWF during a dosing interval can lead to a decrease in duration of the inhibition of the clinically relevant biomarker. To reduce the fluctuations of the free vWF levels, a bis in die (bid) dosing of the same total daily dose would be preferred.
Conclusions: Simulations showed that a purely body-weight adjusted dosing regimen would be suitable in adolescents aged 16 to <18 years, where similar exposure compared to adults is expected. In order to achieve free vWF levels comparable to adults, it may be preferred to split the body-weight adjusted dose in two administrations per day in younger adolescents (12 to < 16 years).
References:
[1] Rossenu S. et al., Population Pharmacokinetic/Pharmacodynamic Modeling Of a New Antithrombotic Drug, The Nanobody® ALX-0081, PAGE 2011, Athens, Greece Abstr 1994 [www.page-meeting.org/?abstract=1994].
Reference: PAGE 21 () Abstr 2642 [www.page-meeting.org/?abstract=2642]
Poster: Paediatrics