3.1 Validation of the PBPK model’s predictive performance following intravenous administration
The structure of the full PBPK model was first externally validated by determining P/O ratios of AUC0–∞, CL, and Cmax following intravenous administration of buprenorphine in healthy volunteers. Twelve PK studies, spanning a dose range of 0.3–16 mg and including a total of 69 subjects (aged 20 to 66.8 years) with 89 concentration-time profiles, were used for intravenous model validation (Table 2 ).41,47-51 For all 12 PK studies, the P/O ratios of AUC0–∞, CL, and Cmax, fell within the 2-fold prediction error range. Geometric mean (95% CI) AUC0–∞, CL, and Cmax P/O ratios were 1.01 (0.90–1.13), 0.95 (0.84–1.08), and 0.91 (0.78–1.05), respectively, indicating adequate predictive performance of these PK parameters following intravenous administration across a wide dose range in healthy volunteers. All predicted vs . observed buprenorphine concentration-time profiles following intravenous administration are shown in Supplementary Figure 1 .