The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood–brain barrier (BBB) permeability evaluation tools are needed to explore drugs’ ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution. We aimed to qualify a PBPK platform model to be used as a tool to predict CNS concentrations when significant transporter activity is absent and human data are sparse or unavailable. Data from the literature on the plasma and CNS of rats and humans regarding acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam were collected. Human BBB permeability values were extrapolated from rats using inter-species differences in BBB surface area. The percentage of predicted AUC and Cmax within the 1.25-fold criterion was 85% and 100% for rats and humans, respectively, with an overall GMFE of <1.25 in all cases. This work demonstrated the successful application of the PBPK platform for predicting human CNS concentrations of drugs passively crossing the BBB. Future applications include the selection of promising CNS drug candidates and the evaluation of new posologies for existing drugs.

Neuropathic pain, often associated with diabetic neuropathy or nerve compression injuries, arises from damage or dysfunction in the somatosensory nervous system. Tramadol, frequently prescribed for this pain, has its fraction unbound and that of its active metabolite (M1) significantly altered by diabetes. Yet, dosing adjustments for diabetic neuropathic pain remain underexplored. This study developed a comprehensive population pharmacokinetics/pharmacodynamics (PK/PD) model for tramadol and its major metabolites, focusing on diabetes's impact on PK and PK‐PD relationship to identify optimal dosing regimens. Data from patients with chronic neuropathic pain on oral tramadol were used to develop enantiomer‐specific population models, considering both total and unbound concentrations. Tramadol's PK was best described by a two‐compartment model with Weibull absorption and linear elimination and a one‐compartment model with enterohepatic circulation and first‐pass metabolism for the active M1. Simulations showed higher unbound fractions of the active M1 in patients with type 1 and type 2 diabetes. Despite a 67% and 14% reduction in the AUC of total (1R,2R)‐M1 in patients with type 1 and type 2 diabetes, respectively, the AUC of unbound (1R,2R)‐M1 remained consistent. The unbound concentration of the active M1 required to achieve 50% of the maximum pain reduction (IC₅₀) was lower in patients with diabetes, indicating increased sensitivity to the drug. This model‐based approach provides valuable dosing guidance, suggesting once‐daily dosing treatments in patients with diabetes and twice‐daily dosing for patients with neuropathic pain secondary to nerve compression mechanisms.