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, PBPK simulations are performed with Simcyp Discovery using 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 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.
お客様の声
Exceeded Expectations on FIH dose estimation Project
“I’m thrilled to recommend Certara for FIH consulting projects. The PBPK consulting team delivered top-quality outputs, and their turnaround time was exceptional, and I especially appreciate the extra effort they put in to accommodating our tight deadlines. They went above and beyond to ensure our success.”
Vassilios Aslanis, Vice President – Head of Clinical Pharmacology at Sudo Biosciences
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?
Simcyp Simulator
Simcyp Simulatorは、ヒト初回投与量の決定、臨床試験デザインの最適化、新薬製剤の評価、未試験集団における投与量の設定、仮想生物学的同等性解析の実行、薬物間相互作用（DDI）の予測のための、製薬業界で最も洗練された生理学的薬物動態（PBPK）プラットフォームです。生体内の各臓器における薬物動態をメカニズムに基づいて記述した生理学的薬物速度論モデル各コンパートメントにおける薬剤の濃度は、システムデータ、薬剤データ、試験デザイン情報を組み合わせて決定されます。We combine in vitro-in vivo extrapolation (IVIVE) and PBPK approaches in virtual individuals to predict drug concentration and effect.
