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.