DISCUSSION
This is the first study to describe dose- and formulation-dependent sublingual buprenorphine absorption across a wide dose range through PBPK modeling. The developed model will serve as a foundation to build a fetomaternal PBPK model for buprenorphine on, which can be used to explore the relationship between fetal buprenorphine exposure and the severity of NOWS postnatally. By integrating a novel description of nonlinear sublingual buprenorphine absorption, the model adequately predicted PK following administration of sublingual tablets and solution. First, the full PBPK model structure was successfully externally validated using published intravenous PK data. Subsequently, a total of 23 published PK studies not used for model development, in which 371 healthy volunteers received buprenorphine as either sublingual tablet or solution across a dose range of 2–32 mg, were used to validate the final PBPK model. Geometric mean P/O ratios of AUC, CL/F, Cmax, and Tmax were close to unity and fell within the 1.25-fold prediction error range. Goodness-of-fits plots indicated unbiased prediction of all PK parameters, except for Cmax, which suggested a moderate trend towards overprediction, especially for high doses.
Previous studies have demonstrated nonlinear PK of sublingually administered buprenorphine (either as tablet or solution) across the entire dose range used for the management of OUD [26, 28, 29]. PK following intravenous administration, in contrast, is linear [51], which strongly suggests that nonlinearity observed under sublingual dosing is driven by varying bioavailability, rather than by changes in clearance. Various mechanisms have been proposed to explain nonlinear bioavailability, including varying dissolution degrees and times between tablet strengths [26], where high-dosed formulations may need to be kept in situ longer to allow maximal absorption, thereby increasing the risk of swallowing relatively more of the dose. In addition, buprenorphine sequesters in oral tissues [55], which decreases the concentration gradient that drives sublingual absorption of buprenorphine. The absorption model proposed in this study captures nonlinear bioavailability observed clinically. It is, however, important to note that the model was developed using PK data across a dose range of 2–32 mg [23, 26, 28]. We caution against applying the absorption model outside this dose interval.
The developed model has a few limitations. Kp values used to describe distribution of buprenorphine across various organs were obtained from rat data [38, 40] and may therefore not capture human physiology in all respects. More importantly, distribution in rats was not measured under strict steady-state conditions [38, 40], which limits the robustness of the Kp values estimated in this study. Nevertheless, using these Kp values, observed concentrations were well-captured by the PBPK model and the volume of distribution at steady-state (Vss) was furthermore calculated at 6.23 L/kg in Simcyp, which approximates 4.95 L/kg observed clinically [41]. We explored using the Rodgers and Rowland [56] method as an alternative to predict tissue distribution (method 2 in Simcyp), but this resulted in an estimated Vss of 23.0 L/h, which would necessitate the application of an empirically identified Kp scalar to recover the observed Vss. Instead, we deemed distribution estimated from rat data, albeit not measured under ideal steady-state conditions, to be more in line with the physiological rationale of PBPK modeling.
Another limitation is that the present model overestimates Cmax modestly following sublingual administration of buprenorphine tablets and solution (geometric mean P/O ratios of 1.20 and 1.34, respectively). Manual parameter estimation of ideal proportion would preferably have yielded one and the same value to recover both observed AUC and Cmax simultaneously for each dose, but ideal proportion values for AUC and Cmax diverged, especially at the lower and upper limits of the dose spectrum (Figure 3). This indicates an oversimplification of sublingual absorption in the current PBPK model. The model accounts for differences in the total transfer of buprenorphine across oral mucosa, but the rate of this process is likely variable across dose and formulation. Absorption rate differences were not integrated into the PBPK model, and AUC- and Cmax-optimized nonlinear absorption models were instead averaged, leading to a modest overestimation of Cmax overall. To understand the implication of this overestimation, it is worthwhile to briefly review the PK/PD relationship of buprenorphine, and, specifically, the degree by which its PD effect is explained by Cmax compared to AUC. Yassen et al. [57] characterized the PK/PD relationship of buprenorphine in healthy volunteers with respect to its respiratory depressant effect, which is an unambiguous marker for buprenorphine’s penetration into the central nervous system (CNS) and its receptor association/dissociation kinetics at the μ-opioid receptor [58]. They estimated the time required for concentration at the effect site to reach 50% of the plasma concentration (t1/2,ke0) for buprenorphine at 75.3 minutes [57], which, relative to other opioids, indicates a slow onset of action, but a longer duration, where its effect is only marginally driven by Cmax [59]. Since the developed PBPK model adequately predicts AUC following sublingual administration of buprenorphine, we believe the implications of modestly overestimating Cmax are therefore limited.
CONCLUSION
The full PBPK model developed in this study is the first to adequately capture buprenorphine PK following sublingual administration (either as tablet or solution) across a wide dose range. The model provides valuable insights into the mechanisms that underly complex sublingual buprenorphine PK. Potential applications of the model include using it to optimize the treatment of OUD with buprenorphine, but for our group specifically, the model forms the basis for planned fetomaternal PBPK modeling endeavors. Improving the treatment of NOWS requires tailoring of pharmacotherapy based on the expected severity of withdrawal symptoms. Fetomaternal PBPK modeling of buprenorphine facilitates estimation of prenatal buprenorphine exposure throughout gestation based on the maternal intake, which opens the way for examining the likely link it has with postnatal withdrawal severity. This, in turn, could enable fetomaternal PBPK model-informed precision dosing of buprenorphine, which is expected to improve the clinical outcomes of neonates affected by NOWS. The thoroughly validated PBPK model for buprenorphine developed in this study forms the fundament for this task.