Contact Information Comparison of Isavuconazole and Other with Respect to Physicochemical and Patrice Larger Poster No. International Ltd Pharmacokinetic Properties Affecting Tissue Penetration Grenzacherstrasse 487 P1734 PO Box 4005, Basel, Switzerland 1 1 1 Patrice Larger , Ulrike Wenzler and Anne Schmitt-Hoffmann Telephone: +41 61 606 1482 1Basilea Pharmaceutica International Ltd, Basel, Switzerland Email: [email protected]

Introduction and Purpose Methods/Results Methods/Results Methods/Results

• Isavuconazole is a broad-spectrum administered as the water-soluble , sulfate. • In a quantitative whole-body autoradiography (QWBA) study in healthy male Sprague-Dawley rats8, isavuconazole was: • Isavuconazonium sulfate has been approved by the U.S. Food and Drug Administration for the treatment of adults with invasive Comparison of physicochemical characteristics of isavuconazole and other azoles In vivo distribution characteristics of isavuconazole and other azoles (IA) and invasive , and by the European Commission for the treatment of adults with IA and those –– Widely distributed in all tissues, within 0.5 h after a single dose IV bolus administration. with mucormycosis for whom is inappropriate.1,2 • Physicochemical properties: • Permeability and lipophilicity (LogD at • Polar surface area (PSA): • Pharmacokinetic properties and information regarding drug distribution of antifungal azoles from human and animal –– Present in sanctuary sites, with concentrations higher than in blood, in absence of inflammation. pH 7.4*): studies: • A key determinant for clinically relevant efficacy of an antifungal drug is tissue penetration, which is dependent on its ––Calculated in silico from ––Calculated in • Brain (Cbrain:Cplasma = 1.86); Testes (Ctestes:Cplasma = 1.56); membrane permeability and is influenced by physicochemical parameters ( ).3 –Calculated in GastroPlus v9.0.005 Figure 1 their respective structures. – MarvinSketch 5.4.0.1 ––A literature search was conducted in EMBASE (Elsevier, Amsterdam, The Netherlands). Blood (Cblood:Cplasma = 1.07). using ADMET Predictor v7.2.0.0 ––Structures were drawn in (ChemAxon, Budapest, • In a study of Wistar rats, after a single oral dose of either isavuconazonium sulfate (25 mg/kg Figure 1. Free drug concept and distribution: drug penetration and distribution in tissues (Simulations Plus, Lancaster, USA). • Search terms used (without further restriction): isavuconazole, , , , Biovia Draw (Biovia, San Hungary). isavuconazole equivalent) or voriconazole (50 mg/kg), active drug concentrations were – Permeability coefficient (P ) prediction , pharmacology, pharmacokinetics, tissue, penetration, distribution, drug transporter, efflux pump, Diego, USA) and imported – eff measured in both brain and plasma using a validated liquid chromatography-mass spectrometry/ for intestinal permeability was used as a p-glycoprotein, and p-gp. as .mol files or .sdf files into mass spectrometry method.9 prediction software. general indicator of predicted • Articles and congress abstracts were considered. permeability. –– Concentrations of both drugs in the brain paralleled those in plasma, with the maximum *Note: all azoles are very weak bases and are neutral at physiological concentration in brain approximately twice as high as that in plasma. pH (7–7.4); therefore, LogD = logP. 7.4 • Given the plasma half-life of 115 h in humans (Table 2), once-daily maintenance dosing of isavuconazole is expected to produce tissue levels that remain high and are more constant over Table 1. Physicochemical properties of antifungal azoles Table 2. Pharmacokinetic properties of antifungal azoles in humans time versus those achieved with twice-daily administration of voriconazole, which has a 6-h half-life. Pgp Molecular Polarity Permeability P-gp Plasma protein Lipophilicity t a V , L/kg Drug Molecular structure weighta PSAa,b P a,c Drug 1/2 Substrate binding, % ss Evidence of efficacy against CNS fungal infections LogD a,c eff (h) [Reference] (g/mol) (Å2) 7.4 (10-4 cm/s) [Reference] [Reference] Good tissue penetration in the brain is associated with positive treatment outcomes of Pe central nervous system (CNS) infection both in vivo and clinically. ––Isavuconazole was effective in a non-clinical model of cryptococcal meningitis with good brain exposure measured in mice.10 Isavuconazole 437.5 88 3.6 4.0 Isavuconazole 110/115 No [4] 99.2–99.4 [5] 6 [5] ––Clinical case reports support the clinical efficacy of isavuconazole for treatment of CNS fungal infections.11-13 C C C C b, plasma u, plasma u, tissue b, tissue • The Infectious Diseases Working Party (AGIHO) of the German Society of fu, plasma fu, tissue Haematology and Medical Oncology (DGHO) recommends isavuconazole for salvage treatment of CNS mucormycosis.14 Cplasma Ctissue Itraconazole 705.7 101 4.9 1.9 Itraconazole 34–42 Yes [6] 99.8 [3] 11 [3] C f f tissue u plasma u plasma Conclusions ss plasma tissue Cplasma fu tissue fu tissue • Isavuconazole has physicochemical properties that favour high permeability. Posaconazole 29/27 Yes [7] >98 [3] 7–25 [3] Cb, plasma, bound plasma concentration; Cb, tissue, bound tissue concentration; Cplasma, total plasma concentration; Ctissue, total tissue concentration; Cu, plasma, unbound plasma concentration; Posaconazole 700.8 112 4.4 1.9

Cu, tissue, unbound tissue concentration; fu, plasma, fraction unbound in plasma; fu, tissue, fraction unbound in tissue; Pe, permeability (passive diffusion across membranes); • Isavuconazole is not a substrate of efflux pumps, which can limit penetration to certain Pgp, P-glycoprotein (efflux pump transporter); V , plasma volume; V , apparent volume of distribution at steady state (PK parameter); V , tissue volume. plasma ss tissue tissues, including the brain. • Isavuconazole is extensively distributed in most organs and tissues, and it penetrates • Drug activity is dependent on free (unbound) drug concentration at the site of action (Cu, tissue). • Tissue penetration is dependent on membrane permeability. sanctuary-site organs, such as the brain and testes. • Taken together, these data suggest that isavuconazole could have clinical efficacy against ––Physicochemical properties influence permeability. Voriconazole 349.3 76 2.1 4.5 Voriconazole 6 Nob 58 [3] 4.6 [3] • Lipophilicity increases permeability. fungal infections involving the CNS and other sanctuary sites. • Molecular weight and polarity decrease permeability.

––Disease-specific alterations of membrane physiology (e.g., infections and inflammation) can alter permeability. References ––Additional physiological factors can affect a drug’s ability to penetrate tissue, such as the tightness of the endothelium and 1. Astellas Pharma US Inc., CRESEMBA®. Cresemba (isavuconazonium sulfate) prescribing information. (Accessed 6 March, 2017 at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf). the action of efflux pumps (e.g., P-glycoprotein [P-gp]), which actively transport the drug back to the plasma and can thus ® Fluconazole 306.3 81 0.8 4.1 Fluconazole 30 Nob 12 [3] 0.7 [3] 2. European Medicines Agency. CRESEMBA (isavuconazole). (Accessed 6 March, 2017 at http://www.ema.europa.eu/ema/index. decrease Cu, tissue. jsp?curl=pages/medicines/human/medicines/002734/human_med_001907.jsp&mid=WC0b01ac058001d124). 3. Felton T, et al. 2014. Clin Microbiol Rev. 27:68–88. 4. Yamazaki T, et al. 2017. Clin Pharmacol Drug Dev. 6:66–75. 5. Desai A, et al. 2016. Antimicrob Agents ––Certain tissues (sanctuary sites, such as the brain or testes) combine a tight endothelium and high expression of efflux Chemother. 60:5483–5491. 6. Lestner J and Hope WW. 2013. Expert Opin Drug Metab Toxicol. 9:911–926. 7. Nagappan V and Deresinski pump transporters, which act as a significant barrier to drug penetration. S. 2007. Clin Infect Dis. 45:1610–1617. 8. Schmitt-Hoffmann A and Richter W. 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); London, United Kingdom; 31 March, 2012; abstr. P863. 9. Schmitt-Hoffmann A, et al. IDWeek™ 2016; a b c aTerminal half-life derived from MHRC SPCs and were measured under specific conditions; itraconazole oral/IV with repeated dosing; posaconazole oral/IV 300 mg; • Tissue/plasma concentration ratio and volume of distribution are dependent on permeability and relative affinity (Figure 1). Predicted from structure with (MarvinSketch 5.4.0.1) or (ADMET Predictor v7.2.0.0). New Orleans, LA; 29 October, 2016; abstr. 1952. 10. Wiederhold NP, et al. 2016. Antimicrob Agents Chemother. 60:5600–5603. P , permeability coefficient; PSA, Polar Surface Area. isavuconazole oral/IV 400 mg; voriconazole oral 200 mg; fluconazole oral/IV. eff 11. Everson N, et al. 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Copenhagen, Denmark; 25 April, b ––At equilibrium, a drug freely permeates across membranes and Cu, tissue = Cu, plasma or AUCu, tissue = AUCu, plasma; therefore: No definite information found, not likely to be good substrates. 2015; abstr. P0231. 12. Peixoto D, et al. 2014. J Clin Microbiol. 52:1016–1019. 13. Thompson GR, 3rd, et al. 2016. Clin Infect Dis. MHRA SPC, Medicines & Healthcare products Regulatory Agency Summary of Product Characteristics; P-gp, P-glycoprotein; t1/2, terminal half-life; Vss, volume of distribution at 63:356–362. 14. Schmidt-Hieber M, et al. 2016. Ann Oncol. 27:1207–1225. Ctissue fu plasma fu plasma steady state. and ss plasma tissue Disclosures Cplasma fu tissue fu tissue P. Larger, U. Wenzler, and A. Schmitt-Hoffmann are employees of Basilea Pharmaceutica International Ltd., and hold stock options in Basilea • Isavuconazole demonstrates a large volume of distribution (6 L/kg, 10-fold the total body water), despite its high Pharmaceutica International Ltd. • Physicochemical properties of isavuconazole included low molecular weight (<500 g/mol) and PSA, and intermediate ––High plasma protein binding (low f ) can lead to relatively low tissue/plasma concentration ratio and volume of plasma protein binding (Table 2). Acknowledgements u, plasma lipophilicity compared with the other azoles (Table 1). –Isavuconazole is extensively distributed in human tissues. This analysis was funded by Basilea Pharmaceutica International Ltd. Isavuconazole has been co-developed by Basilea Pharmaceutica distribution, without an impact on Cu, tissue and efficacy. – 4 International Ltd and Astellas Pharma Global Development, Inc. The authors wish to thank Gwen MacDonald, PhD, Basilea Pharmaceutica • The purpose of this work was to compare the physicochemical and pharmacokinetic drivers for tissue penetration of different • Isavuconazole had a comparable permeability prediction with voriconazole and fluconazole, and a higher permeability • Isavuconazole is not a substrate for P-gp , therefore will not undergo efflux from tissues with high expression of P-gp International Ltd, for her support in the development of this poster. Poster development support was provided by Barrie Anthony, PhD, marketed . prediction than itraconazole and posaconazole (Table 1). (e.g., at the blood-brain barrier). CMPP, and Suzanne M Douthwaite, BSc (Hons), CMPP, Envision Scientific Solutions, funded by Basilea Pharmaceutica International Ltd.

Presented at the 27th Annual European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Vienna, Austria; 22–25 April, 2017; P1734