(M1030-01-03) A Case Study on the Applicability of the Refined Developability Classification System to Identify Compounds Suitable for Biowaivers: Voriconazole

Purpose: Waivers of the regulatory requirement for human bioequivalence studies have become widespread since the Biopharmaceutics Classification System (BCS) was introduced [1]. Replacing comparative pharmacokinetic (PK) trials with reliable outcomes i) is ethically important, ii) ensures faster access to medicines, and iii) improves medicine affordability. Nevertheless, patient risks regarding safety and treatment success must be taken into account. The BCS adopts a conservative strategy of assessing biopharmaceutical risks and was implemented in the ICH M9 guideline to justify biowaivers if certain criteria are met [2]. In this work we compared the BCS-based approach with guidance provided by the refined Developability Classification System (rDCS) for the antifungal voriconazole. Being further adapted to human physiology and tailored to the drug’s properties, the rDCS offers different perspectives than the BCS.

Methods: For BCS classification, equilibrium solubility of voriconazole in three pharmacopeial (Ph.Eur.) dissolution media (hydrochloric acid medium pH 1.2, acetate buffer solution pH 4.5, and phosphate buffer solution pH 6.8) was measured with the shake-flask methodology. For rDCS purposes, equilibrium solubility was measured in FaSSGF (pH 1.6) and FaSSIF-V1 (pH 6.5). The study protocols followed the ICH M9 guideline [2]. Samples were taken at suitable time intervals up to 24 hours, filtered and diluted for analysis via HPLC-UV or UPLC-UV. The dose-to-solubility (D/S) ratios were calculated based on the recommended oral loading dose (400 mg). Dissolution of voriconazole tablets (VFEND® 200 mg film-coated tablets) was tested at 37°C in 900 mL dissolution media using USP Apparatus 2 at 50 rpm. Samples were taken at suitable time intervals up to 60 minutes and the removed volume was replaced with fresh medium. Samples were filtered, diluted, and analyzed via HPLC-UV. The disk intrinsic dissolution rate (IDR) in FaSSIF-V1 and FaSSGF at 37°C was determined using the µDISS Profiler. Compressed disks were rotated at 100 rpm and dissolution curves were recorded with UV fiber optic dip probes. All studies were performed in triplicate. Permeability was assessed using Caco-2 cell monolayers, applying a pH gradient (pH 6.5⟹7.4). Apparent permeability (P_app) values were calculated for apical to basolateral transport (A⟹B) after incubation of 120 minutes (n = 2). Samples from both compartments were analyzed via LC/MS-MS. Averaged P<sub>app values were converted to effective human permeability (P_eff) values using Simcyp Version 21 software. Reference compounds of known permeability (atenolol, propanolol and antipyrine) were screened alongside voriconazole. rDCS calculations and classifications were performed according to Rosenberger et al. and Beran et al. [3, 4].

Results: Results are summarized in Table 1. Voriconazole was assigned to BCS class II, based on its solubility at pH 6.8 and the highest recommended single dose of 400 mg [5, 6]. High permeability of the compound was inferred from human bioavailability studies, which reported values > 85% [7, 8]. The originator (VFEND®) displayed very rapid in vitro dissolution in all tested media with ≥ 85% dissolution within ≤ 15 minutes (Figure 1). The rDCS classified voriconazole as class I at the same dose, with a solubility limited absorbable dose (SLAD) of 1810 mg. Dissolution rate analysis resulted in target particle size estimates of ≤ 516 µm to ensure complete dissolution of the dose within the intestinal transit time, and ≤ 118 µm to ensure higher intestinal dissolution than permeation rate.

Conclusion: Our results suggest that voriconazole immediate release dosage forms (200 mg) would not be eligible for BCS-based biowaivers. In line with this classification, a product-specific guidance for generic drug development (FDA) recommends a single-dose, two-way crossover in vivo study in fasting healthy subjects for the same tablets [9]. In the USA 11 generic drug products are marketed (Table 2) [10]. By contrast, rDCS analysis indicated a low absorption risk for voriconazole doses up to the SLAD of 1810 mg, in line with clinical data demonstrating high oral bioavailability of 400 mg voriconazole [7], and dose proportional increases in AUC and c_max for single oral doses between 800-1600 mg [11]. Similar studies and application of the rDCS to a larger set of compounds with diverse structures and properties, especially those classified as BCS II but rDCS I, will assist in establishing its potential to identify appropriate compounds for biowaivers and stimulate discussions about biowaiver extensions, including review of eligibility criteria and class boundaries [12].

References: 1. Amidon, G.L., et al., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res, 1995. 12(3): p. 413-20.
2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Biopharmaceutics classification system-based biowaivers M9. 2019.
3. Rosenberger, J., J. Butler, and J. Dressman, A Refined Developability Classification System. J Pharm Sci, 2018. 107(8): p. 2020-2032.
4. Beran, K., et al., Application of the refined Developability Classification System (rDCS): Approaches to assess dissolution rate limitations of voriconazole and lemborexant, in 4th European Conference on Pharmaceutics 2023: Marseille, France.
5. Aristo Pharma GmbH, Fachinformation, Voriconazol Aristo® 50 mg/100 mg/200 mg Filmtabletten. 2021.
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7. Hohmann, N., et al., Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole. Clinical Pharmacokinetics, 2016. 55(12): p. 1535-1545.
8. Pfizer, Full Prescribing Information, VFEND® (voriconazole) tablets, for oral use. 2022.
9. U.S. Food and Drug Administration (FDA), Product-Specific Guidances for Generic Drug Development: Guidance on voriconazole. 2011.
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Acknowledgements:This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 955756.

Table 1. Details of the BCS and rDCS classification of voriconazole

Figure 1. Dissolution profiles of VFEND® 200 mg tablets in media with pH 1.2, 4.5 and 6.8

Table 2. Therapeutic equivalent voriconazole IR solid oral drug productsa with a marketing authorization in the USA [10]