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22 Pharmaceutical Technology ® Trends in Formulation 2023 eBook PharmTech.com to commercial formulation were acceptable, thus providing a wider manufacturing space. This case demonstrated the utility of PBPK modeling in pro- viding justification for widening or setting up CRDS, demonstrating BE with the reference formulation. Case study #3: PBPK model expansion used to demonstrate VBE An expansion of case study #2, elagolix coadmin- istered with estradiol/norethindrone acetate (E2/ NETA) was approved under FDA's 505 (b) (2) for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. The commercial combination drug product consists of a morning dose (AM capsule) containing an elagolix tablet and an E2/NETA tablet as a fixed- dose combination and an evening dose (PM capsule) consisting of an elagolix tablet. In lieu of a costly and time-consuming clinical BE study and to avoid exposing healthy women to ad- ditional drug exposure for elagolix coadministered with hormonal add-back therapy, the sponsor was able to further leverage the PBPK model along with in-vitro dissolution data to test for VBE. As the in-vitro dissolution profiles were dissimilar for the tablet and capsule formulations, in-vivo BE studies or a waiver would have typically been required (5). Instead, the sponsor extended the previously verified PBPK model and performed external verification with elagolix 300 mg tablets and elagolix 300 mg AM and PM cap- sules where clinical data was available. This was a novel example where PBPK modeling was utilized along with in-vitro dissolution data to demonstrate VBE and achieve a waiver. This case study, along with the prior one, exempli- fies that once the PBPK model is developed it can be utilized throughout the drug's life cycle and support further modifications to the product, SUPAC changes, and com mercia l modif ications such as combina- tion therapies. Case study #4: Using PBPK to develop a pediatric formulation without requiring a BE study The sponsor was evaluating bempedoic acid, used to lower cholesterol in the blood, as a potential treat- ment for hy perlipidem ia in pediatrics. Ty pica l ly delivered as a solid tablet for adult subjects, an oral suspension dosing formulation was being evaluated for children with difficulty swallowing. Conducting a human BE trial in adults to assess the relative bioavailability of a new formulation is gener- ally required prior to its first use in pediatric subjects. However, FDA could grant a waiver if it was supported by a robust and validated PBPK modeling approach. Objectives of this study included the development of a PBPK model to simulate bempedoic acid plasma concentrations and predict oral absorption based on suspension and tablet dissolution determined under comparable in-vitro conditions. A final model was applied to evaluate the BE of oral suspension and immediate release tablet formulations of bempedoic acid 180 mg in a virtual population of healthy adults. The PBPK model was verified against obser ved be- mpedoic acid PK data from completed clinical studies. Model sensitivity to the potential impact of inter-in- dividual variability was explored with respect to GI physiology and differences between oral suspension and tablet formulations (6). With the PBPK model simulations, no clinical BE study was required to compare the pediatric suspen- sion and table formulations. This case study shows that PBPK can be leveraged to expand the formula- tion and drug delivery options from solid tablet to liquid suspension and support the medical needs of expanded patient types. Summary The use of biosimulation has had a profound impact on drug discovery and development. This paper fo- cuses of the use of MIFD to inform and guide decision making in formulation development for both new and existing drugs. Use of PBPK increases the speed and reduces the cost of formulation development and enables sponsors to ask 'what if' questions in advance of clinical testing. Example benefits of MIFD outlined in this paper include: • developing a biowaiver strategy, including demon- stration of VBE • predicting the outcome of a BE study comparing test and reference formulations • determining dissolution specification settings • supporting manufacturing site or process changes • bridging between different types of formulation, such as immediate to extended release • understanding food effects Drug De velopment The use of [physiologically based pharmacokinetics modeling] has had a profound impact on drug discovery and development.