Biosimulation – the next step in PK modelling embraced by regulators
Biosimulation can give information about dose precision, drug-drug interaction on a molecular level, as well as physiologically-based pharmacokinetic (PBPK) modelling using sophisticated pharmacodynamics models of the heart, liver and other systems.
PBPK modelling – mathematical predictions of drug interactions with other drugs and the body – is already seeing popularity in drug discovery and early development, according to the US FDA’s Office of Clinical Pharmacology (OCP).
Now the agency is calling for use of this modelling to supplement clinical evidence in drug application reviews.
“Ethical and practical issues may limit the numbers of studies one can conduct to test all clinically relevant scenarios, a situation that has resulted in the need for innovation in drug development and evaluation to address these knowledge gaps,” said the Office of Clinical Pharmacology (OCP) in a 2014 paper.
PBPK may be useful in assessing the variability of the drug’s effect on different patient populations “for untested clinical scenarios” and “evaluating or confirming dosing recommendations in specific populations,” said OCP.
Modelling company Certara, which performs biosimulation for drugmakers and regulators, says its services are increasingly being used later in the development process.
“The more transformative tools are now being used more in preclinical and early clinical, in order to potentially avoid doing some studies, or at the very least informing them so they are accurate – selecting a population that’s more ethical in that regard and therefore safer,” Ellen Leinfuss, a spokeswoman for Certara, told us.
Gavin Nichols, Certara’s President of Technology, who joined the firm this month from Quintiles where he was VP of Strategy and R&D IT Innovation, told us a few years in the future, sponsor companies could expand the uses of PBPK:
“If a company is looking at an autoimmune molecule, and considering whether to run a whole series of expensive, timely and patient-burdensome studies – such as looking at non-inferiority to methotrexate – it could [use biosimulation] as a way to think about different patient profiles and indications.”
Modelling can help decide “which study to use as my pivotal study and which ones will I use as a strategy to do label extensions, or in patient populations which are maybe not ideally suited to traditional trial method, like paediatric.
“So we're enabling that disruptive transformation for discovery and pre-clinical but also the clinical space that can think about molecule optimisation in a very different way.”
Nichols told us PBPK modelling could allow pharma companies to pursue development of drugs that might otherwise be prohibitively expensive because they treat an orphan population.
“So the ability to use biosimulation in an ethical way to augment traditional methods of discovery and development gives large pharma organisations a way to optimise their portfolio.
“One of the beauties of biosimulation is you can increase the predictability of outcomes in whole populations and individual patients using PBPK methods to address outcomes and safety profiles, like age.”
The extra predictions about drug behaviour could give confidence to pharma companies and regulators about drug candidates, he said, bringing them to market faster.
“We’re a couple of years out” of using PBPK to its fullest potential, said Nichols. “As large pharma organisations see the regulators are accepting this, the impact on the downstream [will be great]. We see the traction in discovery and preclinical, I think that'll move into the clinical space.
“There's also impetus on the side of regulators in the US, EU and Japan. They’re increasingly using these tools, and also writing into guidance documents when and how you should use biosimulation. So it's one of these transformational and disruptive technologies whose day has really come.”