PKPD modelling of MYCN-inhibition in vitro and in vivo in a mouse model of neuroblastoma
Sean Oosterholt (1), Anna Lisa Scardovi (2), Roberto Tonelli (3), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom, (2) BIOGENERA S.p.A., Ozzano dell'Emilia, Italy, (3) Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy
Objectives: This work evaluates the PK-PD relationships of a NCE aimed at the inhibition of oncogene amplification through in vitro models for cell viability and mRNA transcription, and in-vivo PK and tumor growth experiments in mice and rabbits. Model-derived parameters are then used to propose a starting dose in children and a suitable trial design for assessing the safety, tolerability and pharmacological profile of the NCE in patients with relapsed refractory neuroblastoma.
Methods: First, in vitro experiments exploring cell viability and mRNA inhibition levels were analyzed and characterized. Next, in vivo data containing 7 different dose groups ranging from 2.5 to 50 mg/kg was pooled together to describe the plasma concentration over time. Tumor concentration measurements were linked to the plasma PK model. The PK model in combination with the in vitro models were used in describing the drug effect on tumor growth in mice following 2 weeks of treatment. Finally, several scenarios were simulated to explore the effect of the drug on tumor growth in humans. PK data were extrapolated based on allometric scaling concepts.
Results: The PK of the drug after IV or SC administration was best described by a two-compartment model with first order absorption and elimination. Solubility issues resulted in non-linear exposure and was described by variability on bioavailability. In vitro cell viability and mRNA transcription inhibition experiments revealed the minimum inhibition level of 80% for the drug to have an effect. The combined PKPD model describing plasma PK and tumor weight was used in simulations of a range of drug exposure levels, this suggested a target range from 50 h*ng/ml to 1400 h*ng/ml. For a 70 kg human, equivalent exposures would be reached by a predicted dose range starting at 0.08 mg/kg up to 2.2 mg/kg.
Conclusion: The use of a model-based approach allows effective integration of in vitro and in vivo data. It does not only allow for the characterization of the parameters of interest, but also for the optimization of dose rationale in oncology trials, where the principle of target attainment is still replaced by the use of toxicity as marker for dose escalation in humans (i.e., MTD).