kinetic-pharmacodynamic models: applications, limitations and perspectives: A systematic review

Pharmacometrics is instrumental in drug development, guiding decisions on dose selection, study design, formulation optimization, biomarker identification and commercial viability. While traditional Pharmacokinetic-Pharmacodynamic (PK/PD) modeling is widely embraced, Kinetic-Pharmacodynamic (KPD) modeling remains relatively underutilized. This paper introduces KPD modeling as an alternative approach for understanding dose-effect relationships in scenarios where conventional PK data is limited. KPD models use dose as the primary input to predict key parameters, offering a valuable tool for clinical applications. To explore KPD modeling’s scope and potential benefits, we conducted a systematic review following PRISMA guidelines. The research question was “Where can KPD modeling be applied, and what are the main outcomes from KPD models?”. We searched databases, including PubMed, Web of Science, Cochrane and EMBASE, using specific terms. Eligible articles had to be in english and discuss KPD modeling applications or its role in model development. Our review covered 132 articles published from January 2004 to October 2023, identifying 51 meeting inclusion criteria. Data included publication year, country, institution, study type, studied compounds, software tools, KPD applications, and outcomes. This paper presents a comprehensive analysis of reviewed studies, highlighting diverse KPD modeling applications in clinical and preclinical settings. It outlines limitations and suggests avenues for rational KPD integration into research, clinical trials, and regulatory approvals. By harnessing KPD modeling’s power, pharmacometrics can enhance decision-making, addressing challenges posed by limited PK data, ultimately advancing drug development and patient care.