The use of solid drug nanoparticles (SDN) has become an established approach to improve drug delivery, supporting enhancement of oral absorption and long-acting administration strategies. A broad range of SDNs have been successfully utilised for multiple products and several development programmes are currently underway across different therapeutic areas. With some approaches, a large range of material space is available with diversity in physical characteristics, excipient choice and pharmacological behaviour. The selection of SDN lead candidates is a complex process including a broad range of in vitro and in vivo data, and a better understanding of how physical characteristics relate to performance is required. Physiologically-based pharmacokinetic (PBPK) modelling is based upon a comprehensive integration of experimental data into a mathematical description of drug distribution, allowing simulation of SDN pharmacokinetics that can be qualified in vivo prior to human prediction. This review aims to provide a description of how PBPK can find application into the development of SDN. Integration of predictive PBPK modelling into SDN development allows a better understanding of the SDN dose-response relationship, supporting a framework for rational optimisation while reducing the risk of failure in developing safe and effective nanomedicines.