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
Simcyp Simulator는 첫 인체 임상시험(First-in-Human) 투여 용량 결정, 임상시험 설계 최적화, 새로운 약물 제형 평가, 시험되지 않은 모집단의 용량 설정, 가상 생물학적 동등성 분석 수행, 약물 상호작용 예측을 위한 제약 산업에서 가장 정교한 생리학적 기반 약동학(physiologically based pharmacokinetics, PBPK) 플랫폼입니다. Simcyp PBPK 모델은 다양한 신체 조직의 생리학적 관점에서 각 조직에서의 약물작용을 설명합니다. 각 구획에서의 약물 농도는 시스템 데이터, 약물 데이터 및 임상시험 설계 정보를 결합하여 결정됩니다. We combine in vitro-in vivo extrapolation (IVIVE) and PBPK approaches in virtual individuals to predict drug concentration and effect.
