How can modelling and simulation optimize the clinical development of adalimumab biosimilar candidates?
Generally, PK trials for adalimumab biosimilar candidates are typically oversized (60 to 108 subjects per arm) as high variability is expected.. At the same time, an inadequate sample size can jeopardize the trial outcome. In this context, a population pharmacokinetic (PK) literature model of adalimumab in rheumatoid arthritis (RA) patients was used to obtain PK parameter estimates for a adalimumab biosimilar candidate in development. Subsequently, PK parameters for adalimumab EU- and US-approved formulations were implemented in the simulation software Simulo (www.exprimo.com/simulo).Simulations of adalimumab PK profiles were carried out at the recommended adalimumab dose for RA patients of 40 mg subcutaneous injection. In addition, the effect of subject´s body weight was implemented in the simulation software. The influence of neutralizing anti-adalimumab antibodies (AAA+) was also explored. The clinical trial simulations were carried out at various sample sizes and with different assumed differences between the biosimilar and the reference. The likelihood of demonstrating PK similarity was evaluated for each simulated study design scenario.
The population PK model was qualified using different approaches, including comparison of the predicted versus observed adalimumab serum concentrations and PK parameters validation. The model demonstrated good accuracy in describing the adalimumab PK and was thus considered well suited for this simulation task.
The power analysis showed that the probability to obtain bioequivalence did not improve significantly at larger (+150 subjects) compared with smaller trials. A 15% difference in AAA+ could decrease the chance to obtain successful results for all pairwise comparisons.
The model-based simulation approach, incorporating available information of adalimumab, reduced the sample size by 40-60%), compared to traditional methods.
Overall, this type of work can justify the design for adalimumab biosimilar candidate studies addressing PK similarity. The methods can easily be applied also for PD markers and clinical outcome endpoints.
The poster can be accessed with the following hyperlink.
- FDA. Adalimumab indications and usage. 2011
- EMA. Guideline on Similar Biological Medicinal Products, London, 30 Oct 2005. CHMP/437/04
- FDA draft guidance on Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. 2014. Accessed at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf (last accessed 12 May 2016). 2014.
- FDA. Adalimumab Product Approval Information – Licensing Action 12/31/02.
- EMA. Guideline on Similar Biological Medicinal Products, London, 30 Oct 2005. CHMP/437/