Shuying Yang 1, Nena Mistry 2, Ahmed Nader 3
1 Clinical Pharmacology & Pharmacometrics, Systems and Tools, Platform Sciences, GSK (, UK), 2 Biopharmaceutics, Drug Product Development, GSK (, UK), 3 Clinical Pharmacology and Quantitative Medicine, Respiratory, Immunology, Inflammation Research Unit, GSK (, USA)
Objectives: Ibrexafungerp is a triterpenoid antifungal agent approved in the US in adult and post-menarchal pediatric females for the treatment of vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (rVVC). During the development, a potential cross-contamination of ibrexafungerp drug substance with a non-antibacterial β-lactam drug substance at the manufacturing site was identified, requiring change of drug substance manufacturing to a new site. Traditional regulatory requirements to support such change include in vitro comparability and clinical bioequivalence (BE) studies; however, this approach posed limitations due to the cross-contamination risk. The primary objective of this work was to demonstrate comparability in exposure of ibrexafungerp between the proposed new commercial supply and the previous commercial supply, and the impact of any potential difference in the exposure of ibrexafungerp, using a model-informed drug development (MIDD) approach, in lieu of clinical PK and/or efficacy data.
Methods: An innovative MIDD strategy using physiologically based pharmacokinetic (PBPK) and exposure–response (ER) modelling, together with the in vitro testing data, was proposed as follows: 1) A PBPK model was developed using a milled-out approach in Simcyp™ simulator version 23 and Simcyp™ In-Vitro Data Analysis Toolkit (SIVA™) version 5 (Certara – Simcyp, Sheffield, UK.); the model was validated with a range of Phase 1 studies, including intravenous (IV) infusion, oral solution, and formulations of different salts; 2) An ER model was derived and evaluated using clinical data from two Phase 2 studies where both exposure and clinical endpoints (clinical cure and mycological eradication) were available in VVC patients; 3) The PBPK model was used to define a dissolution safe space using virtual BE simulations [1, 2]; 4) The systemic exposure following the clinical dose/regimen was simulated based on the two boundaries of the safe space under fasted and fed states from the PBPK model; 5) The simulated exposure data were then applied to the ER model to predict the probability of clinical responses at the exposure corresponding to the two safe space boundaries under fasted and fed conditions to compare with the previous clinical results.
Results: A PBPK model was successfully developed and validated with clinical PK data (IV infusion [2 studies], oral solution [5 studies]). The dissolution safe space was defined using virtual BE simulations. Two boundaries were identified and obtained. Subsequently, the systemic exposure following the clinical dose (two doses of 300 mg ibrexafungerp under fasted and fed states) was simulated based on the two boundaries of the safe space. The simulations showed about -14% or +16% change in area under the curve (AUC) at the two boundaries when compared to the previous supply, respectively. The logistic regression modelling with clinical data indicated that the systemic exposure as total AUC during the treatment period was well correlated with the clinical response, in particular mycological eradication response at the time of cure assessment time. Based on the ER model, the predicted probability of mycological eradication response given the exposure at the two safe space boundaries showed only about 2-3% difference when compared with the previous supply.
Conclusions: The simulations and predictions showed that the potential variation in dissolution due to manufacturing change had minimal impact on the clinical efficacy. The results supported the comparability evaluations of ibrexafungerp without a need for clinical PK and efficacy data in patients.
References:
[1] Loisios-Konstantinidis I, et al. Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen. Eur J Pharm Sci. 2020;143:105170
[2] McAllister M, et al. Developing clinically relevant dissolution specifications for oral drug products—industrial and regulatory perspectives. Pharmaceutics. 2020;12(1):19
Reference: PAGE 34 (2026) Abstr 12169 [www.page-meeting.org/?abstract=12169]
Poster: Drug/Disease Modelling - Absorption & PBPK