Massimo Cella(1), Emma Hawkins(1), Grace O’Leary(1), Rie Suzuki(2), Pinky Dua(1)
(1) Pharmatherapeutics Research Clinical Pharmacology, Pfizer Neusentis, Cambridge, UK. (2) Pfizer Neusentis, Cambridge, UK.
Objectives: Drug X is a humanized IgG1 monoclonal antibody (mAb) that is able to neutralize the Brain-derived neurotrophic factor (BDNF) by inhibiting interaction with its receptors. In sensory neurons, application of BDNF causes acute sensitization of peripheral nociceptors, leading to enhanced neuronal excitability and pain sensitivity, whilst promoting chronic pain processing via mechanisms involving gene transcription and alterations in the innervation pattern of sensory neurons.
The aim was to 1) build a mechanistic target-mediated drug disposition (TMDD) model and 2) use the model to influence the design of pre-clinical experiments and predict the relationship between mAb dose and BDNF suppression across species.
Methods: Plasma levels of mAb and total BDNF were measured after intravenous and subcutaneous administration of various drug amounts in rats (0.1 and 1 mg/kg) and cynomolgus monkeys (0.03 and 0.3 mg/kg). Using Matlab R2012b software a TMDD model was developed using rat data. This model was subsequently used to predict mAb PK and design the PK study in cynomolgus monkeys. Data from cynomolgus monkeys were then used to refine the model and extrapolate mAb PK and BDNF suppression over time at different doses in humans. All simulations were performed using Berkeley Madonna 8.3.18 software.
Results: In rats, the minimum dose that resulted in measurable efficacy 5 days post-dose was 0.03 mg/kg, which according to model simulation was predicted to cause an average free BDNF suppression of 37%. In cynomolgus monkeys, doses predicted to produce a range of free BDNF suppressions were identified (e.g. average 30, 70 and 90% over the considered interval). These doses were 0.03, 0.15 and 0.6 mg/kg for an 8 weeks dosing regimen. Finally, the same levels of suppression extrapolated to humans were obtained with 0.008, 0.03 and 0.125 mg/kg, respectively.
Conclusions: A TMDD model adequately described drug X pharmacokinetics and pharmacodynamics (defined as free BDNF concentration in central compartment). This analysis provides an example in which TMDD models were used to predict PKPD properties of a mAb across species, helping the design of preclinical studies and the mechanistic extrapolation of results to humans.
Reference: PAGE 24 (2015) Abstr 3550 [www.page-meeting.org/?abstract=3550]
Poster: Drug/Disease modeling - Other topics