## 3 Prediction of Human Pharmacokinetics
Moreover, PBPK modeling provides a powerful tool to study potential PK DDIs through incorporating the drug's physicochemical properties, PK properties, human physiological variables, and inter-individual variability estimates. Predictions of PK parameters use information from preclinical studies in animals to transition to clinical trials, i.e., FIH studies, when no clinical information is available to guide the decision of the starting dose. Thus, the estimation of the starting dose in human subjects relies on the PK knowledge of the drug from different species. It is essential to have preclinical PK data based on blood, plasma, and/or tissue sampled longitudinally to optimally capture the complete drug profile during a dosing interval. A model-based approach to the starting dose often uses allometric scaling to predict human drug clearance and distribution volumes. Allometric scaling is based on the assumption that physiological similarities exist between different species arising from anatomical similarities, specifically similarities in body weights and body surface areas [76]. Historically, a maximum dose for FIH studies was based on the no observed adverse effect level (NOAEL) in preclinical experiments, an arbitrary safety factor, and allometric scaling. This approach is empirical by nature and therefore limited. When more mechanistic data and models are available, a minimal anticipated biological effect level (MABEL) can be estimated [42]. For example, preclinical PK-PD and interspecies differences in the target can be utilized to estimate the MABEL for a FIH trial [77]. This has the benefit of being driven by pharmacology, where FIH trials will answer pharmacological questions on PK and PD, rather than being driven by toxicology or tolerability. Taking into account MABEL and safety factors, a first study with single ascending doses (SAD study) will quantify the PK and ensure safety and tolerability. A second study with multiple administered doses (MAD) can subsequently be designed accordingly [78]. In addition to allometric scaling, the use of IVIVC has markedly increased [79; 80; 81; 82]. It is suggested that animal PBPK models should be used as part of a stepwise approach, in which the first step uses animal data to understand the processes and verify the predictive power of _in vitro_ systems, and the second step is about forecasting human PK from _in vitro_ data and _in silico_ methods (learn-and-confirm) [82]. The first step in predicting drug CL using IVIVC is to obtain intrinsic CL (CLint) from _in vitro_ data [83; 84]. _In vitro_ CLint values determined from various systems including hepatocytes, cell transport models, liver or intestinal microsomes, or recombinant CYPs, either by substrate depletion or metabolite formation, are normalized for cell, microsomal protein or enzyme concentration. The next step consists of scaling the activity determined _in vitro_ to the whole liver by the use of a scaling factor, to account for incomplete microsomal recovery from the tissue to obtain _in vivo_ CLint. Finally, the third step involves the use of a liver model which incorporates the effects of hepatic blood flow, plasma protein-binding and blood cell partitioning to convert the estimated _in vivo_ CLint into a hepatic CL (CLH). The well-stirred liver model is most commonly used, but the dispersion model or the parallel tube model is also available [84]. Using high doses of oral anti-TB drugs may result in high plasma concentrations, leading to an increased risk of adverse effects [85] while not ensuring adequate concentrations at the site of action [85; 86]. This has prompted investigation into the use of the pulmonary route to deliver anti-TB drugs directly to the site of action in the lungs. Administering anti-TB drugs as inhaled formulations ensures the delivery of the drug directly to the target organ, avoiding any unwanted systemic side effects, thereby improving patient compliance [87].