2.3 PBPK model validation and evaluation
Following an extensive literature search for buprenorphine PK data in healthy volunteers, the PBPK model’s predictive performance was assessed for intravenous and sublingual administration successively by determining the ratio between predicted and observed (P/O ratio) AUC, clearance (CL) or apparent clearance (CL/F), Cmax, and, in case of sublingual administration, time to reach Cmax(Tmax). All data used for model validation were independent (test data), i.e. , not used in the development of the PBPK or sublingual absorption model.
Predicted PK parameters were obtained by running virtual trials in Simcyp and represented the geometric mean of the virtual trial’s population. The population’s age (preferably age range, but mean age if no range was reported), proportion of females (50% was assumed for studies that did not report the participants’ sex), and administered buprenorphine dose and formulation were matched to that in the clinical study. For virtual trials in which buprenorphine was sublingually administered, a coefficient of variation (CV) of 33.9% was applied to the administered dose to reflect variability in bioavailability, which is consistent with the average variation observed by Bullingham et al .47 The virtual cohort consisted of 100 individuals (10 individuals × 10 trials) for each simulation. The virtual trial duration was set to the time associated with the last reported observable concentration in the clinical study.
For clinical studies in which buprenorphine was intravenously administered, observed PK parameters were defined as those reported in the trial; missing values were calculated through noncompartmental analysis using Edsim++ (v2.0.4; Mediware Incorporated, Prague, Czech Republic). Clinical studies rarely determined a true Cmax following intravenous administration. Instead, Cmax generally represented the first concentration (Cfirst) measured few minutes after completion of a bolus injection (Tfirst). Therefore, to match predicted and observed Cmax, predicted Cmax was defined as the modeled concentration at Tfirst.
For clinical studies in which buprenorphine was sublingually administered, observed PK parameters were, similarly to described for linear regression modeling, obtained through Bayesian estimation by fitting the buprenorphine population PK model reported by Moore et al .46 to concentration-time data extracted from publications using WebPlotDigitizer. Reported PK parameter values were not used, as some studies employed limited sampling strategies, which limited the robustness of time-associated (i.e. , Tmax and Cmax) and exposure-dictated (i.e. , AUC and CL/F) PK parameters. In the interest of consistency, all concentration-time profiles of sublingually administered buprenorphine for each clinical study were digitized and used to estimate PK parameters through Bayesian estimation.
Potential bias in the PBPK model’s prediction following sublingual administration was evaluated using predicted vs . observed AUC, CL/F, Cmax, and Tmax and dose vs . respective P/O ratio goodness-of-fit plots.