Per regulatory guidance, estimation of a first-in-human (FIH) dose is an essential element in clinical development. Selection of that starting dose in humans is a complex process—it must be low enough to be safe but high enough to avoid excessive dose escalations. Pharmacokinetic (PK)-guided approaches provide a more mechanistic rationale, providing accurate predictions of human PK prior to phase 1 studies, resulting in significant cost and time savings of up to 6 months. Physiologically-based Pharmacokinetic Modeling (PBPK) can be applied for the purpose of PK and dose prediction across drug discovery and development from the early stages prior to lead development where limited data are available, enabling the understanding of the effect of physiological variables or disease status on PK.
The Simcyp Approach for FIH
Initially, the PBPK simulation is performed in animals with Simcyp Animal™, using animal in vitro data and compound-specific physicochemical data. The animal simulation is compared with the in vivo data; if this simulation in animals is reasonable, then the human simulation is performed with the Simcyp Simulator™, using human in vitro data and compound-specific physicochemical data. If there are mismatches in animals then hypotheses/new data may be generated to explain the observations.
PBPK models incorporate physiology and mechanisms specific to the species of interest, allowing for prediction of multi-phasic profiles, increased understanding of characteristics of molecule and PK properties (driving factors for PK). Simcyp facilitates interspecies extrapolation and prediction for the many mechanisms that do not scale well allometrically.
A FIH PK prediction package as shown above uses readily available physiochemical, in vitro and pre-clinical in vivo input data. Add ons can include early drug-drug interactions (DDI) prediction and formulation comparisons. The types of questions that can be answered at this stage with PBPK modelling are shown below.
Applications for Simcyp (PBPK) in FIH and Discovery and Pre-clinical Development
- What is the predicted FIH PK and dose?
- Can we use modelling to do some early formulation screening and development work?
- What is the predicted exposure in toxicology studies and how can it be enhanced using PBPK?
- Why do we have non-linear PK?
- What are the required laboratory objectives for a chemical series?
- Which compound should move to the clinic?
- What is the predicted DDI liability?
- Do we expect time-dependent PK?
- What is the expected inter-individual variability?
- Do we expect an impact of genetic polymorphisms?
The Simcyp Simulator
The Simcyp Simulator is the pharmaceutical industry’s most sophisticated physiologically based pharmacokinetics (PBPK) platform for determining first-in-human dosing, optimizing clinical study design, evaluating new drug formulations, setting the dose in untested populations, performing virtual bioequivalence analyses, and predicting drug-drug interactions (DDIs). Simcyp PBPK models describe the behavior of drugs in different body tissues, with each tissue considered a physiological compartment. The concentration of the drug in each compartment is determined by combining systems data, drug data, and trial design information. We combine in vitro-in vivo extrapolation (IVIVE) and PBPK approaches in virtual individuals to predict drug concentration and effect.