Erin H. Smeijsters1,3, Floris R. van Tol2, Alwin D.R. Huitema1,3,4, Aurelia H.M. de Vries Schultink1
1Department of Clinical Pharmacy, University Medical Center Utrecht, 2SentryX B.V., 3Princess Máxima Center for Pediatric Oncology, 4Department of Pharmacy & Pharmacology, Netherlands Cancer Institute
Objective Spinal surgery is a major intervention and postoperative pain management presents significant challenges. Currently, adequate pain relief during rehabilitation primarily relies on opioids. However, opioids are associated with several drawbacks, most notably systemic side effects like sedation, which can impede rehabilitation. Local anesthetics (LAs) may offer an alternative, particularly since postsurgical pain is typically localized at the surgical site; however, the short duration of LAs complicates long-term pain management [1,2]. Therefore, a local, sustained release system for the LA bupivacaine has been developed. Ring-shaped hydrogel implants, containing crystallized bupivacaine, were co-implanted with pedicle screws in sheep. Previous pharmacokinetic (PK) studies of bupivacaine are based on epidural administrations, which may vary from this formulation [3,4]. The objective of this study was to develop a preclinical PK model for the sustained-release formulation of bupivacaine in sheep in order to predict human exposure. Methods In total, six preclinical experiments were performed in 48 sheep and six ring types were evaluated. Rings differed in buffer, coating, molecular weight of the biopolymer, dose and degree of functionalization of the biomaterials. The experiments varied in types and combination of rings used and number of rings used (e.g. 4,6,8) per sheep [5]. The dose ranged from circa 25 to 90 mg per ring, depending on the type. The total amount ranged from circa 100 to 350 mg, which was due to the number and type of rings per sheep. Per sheep, 1 to 16 plasma samples were collected at different timepoints, ranging from 0.5 to 360 hours after implantation. In addition, six sheep received subcutaneous (s.c.) injections of 150 mg, whereafter samples were collected at 1, 4, 8, 20, 24, 32, 48, 72 and 96 hours. After a wash-out period of 14 days these sheep were included in one of the ring experiments. Non-linear mixed effects modelling in NONMEM (v7.5.1) was used to analyse the population PK. Results For the model development, a variety of common absorption models were evaluated. In short, the rings were defined as a depot compartment from where the absorption processes were tested. Dual, first- and zero-order absorption, saturable absorption, empirical absorption model through a Weibull function and transit compartment models were tested. Evaluation of the PK profiles showed flip-flop kinetics, where the slow absorption rate serves as the rate-limiting step, causing the absorption phase to govern the concentration-time profile rather than the elimination process. This phenomenon is well documented in modified-release formulations and has also been observed in other extended-release bupivacaine formulation [6,7]. The PK data of the s.c. bupivacaine administration was simultaneously modelled in order to correctly estimate the clearance parameter. The PK profiles were best described by a one-compartment model through first-order absorption with one transit compartment and linear clearance. For each experiment a different absorption rate constant (ka) was estimated, in order to account for the different types of rings used. The estimated clearance was 35.2 L/h (relative standard error (RSE) = 9.7%), which is comparable to previous studies. The volume of the central compartment (Vc) was 435 L (RSE = 10.6%), which is considerably higher compared to other studies evaluating (levo)bupivacaine [8]. This could be explained by the prolonged release and therefore an apparent higher Vc compared to direct-release formulations, possibly also interpreted due to the flip-flop kinetics. The ka varied among the ring compositions. The formulations of experiment 3 and 6, that are selected for further development, showed comparable ka of 0.797 h^-1 (RSE = 12.8%) and 0.596 h^-1 (RSE = 11.4%), respectively. Conclusions The novel sustained-release formulation of bupivacaine in a ring-shaped hydrogel implantation, combined with pedicle screws in sheep was well-described by a one-compartment model through first-order absorption with one transit compartment and linear clearance. This model provides new insights in the PK of this novel formulation, revealing a distinct profile compared to previously published formulations. These findings will facilitate further clinical development of bupivacaine in sustained-release hydrogel rings.
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Reference: PAGE 33 (2025) Abstr 11679 [www.page-meeting.org/?abstract=11679]
Poster: Drug/Disease Modelling - Other Topics