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aBsTraCTs nature publishing group effects of multiple oral doses of glimepiride (1 mg/day for 5 days) on the PK and PD of a single dose of ipragliflozin (150 mg). The plasma PK parameters of ipragliflozin, glimepiride, and its active metabolite 5-hydroxy-glimepiride were determined throughout the study. RESULTS: The PK parameters of glimepiride obtained in the presence and absence of ipragliflozin were similar. Geometric mean ratios (GMRs) [90% CI] for AUC inf (ipragliflozin + glimepiride/glimepiride) were 1.051 [1.013-1.090] for glimepiride and 0.998 [0.966-1.031] for 5-hydroxy-glimepiride. GMRs for C max (ipragliflozin + glimepiride/glimepiride) were 1.100 [1.019-1.188] for glimepiride and 1.008 [0.941-1.079] for 5-hydroxy-glimepiride. The PK parameters of ipragliflozin were comparable between ipragliflozin + glimepiride versus ipragliflozin alone: GMRs [90% CI] of AUC inf and C max were 0.991 [0.966-1.016] and 0.973 [0.892-1.062], respectively. No difference was observed in the PD of ipragliflozin after ipragliflozin + glimepiride versus ipragliflozin alone: GMR [90% CI] of UGE was 0.919 [0.876-0.963]. CONCLUSION: Concomitant administration of ipragliflozin and glimepiride to healthy subjects did not result in a PK or PD interaction between these two drugs. PI-11 ETHNIC SENSITIVITY ASSESSMENT DURING DRUG DEVELOPMENT: PAST, PRESENT AND FUTURE IN A LARGE PHARMACEUTICAL COMPANY.C. S. Weber, 1 Y. Fukushima, 1 A. Guenther, 1 Q. Jiang, 2 S. Kim, 3 R. Li, 2 Y. Lim, 3 P. Lu, 4 R. Peck, 5 C. Rayner, 6 S. Zhai, 2 J. Zhi 4 ; 1 Fa. Hoffmann-La Roche Ltd, Basel, Switzerland, 2 Roche R&D Center, Shanghai, China, 3 Roche Korea Company Ltd, Seoul, Korea, Republic of, 4 Hoffmann-La Roche Inc, Nutley, NJ, 5 Roche Products Ltd, Welwyn Garden City, United Kingdom, 6 Roche Products Pty. Ltd, Dee Why, Australia. C.S. Weber: 2. I am a paid consultant/employee for; Company/Drug; F. Hoffmann-La Roche Ltd, Switzerland. Y. Fukushima: 2. I am a paid consultant/ employee for; Company/Drug; F. Hoffmann-La Roche Ltd, Switzerland. A. Guenther: 2. I am a paid consultant/employee for; Company/ Drug; F. Hoffmann-La Roche Ltd, Switzerland. Q. Jiang: 2. I am a paid consultant/employee for; Company/Drug; Roche R&D Center Shanghai. S. Kim: 2. I am a paid consultant/employee for; Company/ Drug; Roche Korea Company Ltd, Seoul. R. Li: 2. I am a paid consultant/employee for; Company/Drug; Hoffmann-La Roche Inc, Nutley. Y. Lim: 2. I am a paid consultant/employee for; Company/Drug; Roche Korea Company Ltd, Seoul. P. Lu: 2. I am a paid consultant/ employee for; Company/Drug; Hoffmann-La Roche Inc, Nutley. R. Peck: 2. I am a paid consultant/employee for; Company/Drug; Roche Products Ltd, Welwyn Garden City. C. Rayner: 2. I am a paid consultant/employee for; Company/Drug; Roche Products Pty. Ltd, Dee Why. S. Zhai: 2. I am a paid consultant/employee for; Company/ Drug; Roche R&D Center, Shanghai. J. Zhi: 2. I am a paid consultant/ employee for; Company/Drug; F. Hoffmann-La Roche Inc, Nutley. BACKGROUND: The question on ethnic differences in drug response has received more attention in recent years, likely because more clinical trials are performed and included for registration in emerging markets. We investigated how this has been addressed during drug development in Roche/Genentech in the past. Having identified changes over time and lessons learned, the objective was to propose improved future strategies. METHODS: US labels of Roche/Genentech marketed drugs since 1995 and corresponding labels in selected Asian countries were reviewed for information on ethnic sensitivity. Clinical development plans of all Roche projects in Phases 1-3 were analyzed for activities assessing ethnic sensitivity. The more recent activities were evaluated for their value and impact on later development phases. RESULTS: >50% of Roche/Genentech drugs registered in the US don’t contain any label statement in relation to findings on ethnic/racial differences or similarities. This is true even in cases where a large data base in Asian subjects exists. For those drugs registered more recently, ethnicity label statements are found more frequently but are mostly limited to differences/similarities in PK. Of the drugs in late-phase development ≥50% generated some early PK data in Asians and Caucasians that enabled global studies including US/EU and Asian countries. Exploratory PK data and, in few cases PD, in Asians and Caucasians are available for 90% of drugs currently in Phase 2. For most drug candidates in Phase 1 no concrete plans exist for studying ethnic sensitivity until proof of concept is established. Case studies are presented to exemplify the limitations/risks of past strategies and their impact on drug development. CONCLUSION: Today, more and earlier ethnic sensitivity assessments are being performed. The assessment could be improved in the future taking into account innovative methods, the growing science in this field and the clinical trial opportunities in Asia. PI-12 APPLICATIONS OF EXPLORATORY CLINICAL TRIALS IN DRUG DEVELOPMENT- REVIEW OF EXPLORATORY TRIAL USER GROUP MEETING, WASHINGTON, JUNE 2011. I. Shaw, 1 L. Stevens, 1 P. Mudd, 2 M. Young, 2 P. Y. Muller, 3 D. Boulton, 4 D. Spracklin, 5 C. Lambert, 6 E. Helmer, 7 M. Rizk 8 ; 1 Quotient Clinical Ltd, Ruddington, United Kingdom, 2 Glaxo SmithKline, Research Triangle Park, NC, 3 Novartis Institutes for BioMedical Research, Cambridge, MA, 4 Bristol-Myers Squibb Co, Princeton, NJ, 5 Pfizer, Groton, CT, 6 Astra Zeneca R&D, Alderley Park, United Kingdom, 7 Takeda Global Research & Development Centre (Europe), London, United Kingdom, 8 Merck Research Laboratories, West Point, PA. I. Shaw: None. L. Stevens: None. P. Mudd: None. M. Young: None. P.Y. Muller: None. D. Boulton: None. D. Spracklin: None. C. Lambert: None. E. Helmer: None. M. Rizk: None. BACKGROUND: Requirements for exploratory trials are defined by ICH M3 R2 and clinical data derived from such studies is recognized by regulatory authorities worldwide. Examples in current drug development were reviewed at a meeting in June 2011. METHODS: 16 case studies highlighted by the following examples were discussed at the meeting. IV microtracer use was described by a study to generate absolute bioavailability data. The study with a DPP-4 inhibitor resulted in regulatory approval and the abbreviated approach to IV formulation development brought the product to the market quicker than traditional approaches would have enabled. Exploratory FIH (eFIH) studies were exemplified by a study with a drug targeting an anti-inflammatory receptor. The study established human PK of the drug prior to phase IIa to justify progression of development. Microdose utility was demonstrated through a study screening a lead candidate for DDI liability with and without the presence of a potent CYP3A4 inhibitor. Increases in AUC at both micro and therapeutic dose were confirmed supporting progression/termination decisions for back-ups and informing concomitant medication advice for subsequent studies. RESULTS: IV tracer applications deliver cost and time savings over conventional methods for generating IV data. ‘Piggybacking’ tracer doses onto other studies in the development portfolio limits the impact on program budgets. eFIH studies at pharmacologic dose have significant utility, particularly given the ability to add other study objectives such as food effect, and IV tracer to the design. Microdosing applications are viewed as a ‘fit for purpose’ rather than as a routine development strategy. CONCLUSION: Exploratory trials are challenging conventional drug development paradigms by generating data earlier to inform key development decisions with the potential to bring new medicines to market quicker. PI-13 LACK OF EFFECT OF IPRAGLIFLOZIN, A SELECTIVE SODIUM GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBI- TOR, ON CARDIAC REPOLARIZATION IN HEALTHY MALE AND FEMALE SUBJECTS. W. Zhang, 1 R. Smulders, 2 A. Abeyratne, 1 A. Dietz, 3 J. Keirns 1 ; 1 Astellas Pharma Global Development, Inc, Deerfield, IL, 2 Astellas Pharma Global Development, Leiderdorp, Netherlands, 3 Spaulding Clinical Research, West Bend, WI. W. Zhang: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am s12 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt
nature publishing group a paid consultant/employee for; Company/Drug; Astellas Pharma. 6. I will be discussing the following product, which is not labeled for the use under discussion, or the product is still investigational; Company/ Drug; Ipragliflozin. R. Smulders: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. 6. I will be discussing the following product, which is not labeled for the use under discussion, or the product is still investigational; Company/Drug; Ipragliflozin. A. Abeyratne: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. A. Dietz: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. 6. I will be discussing the following product, which is not labeled for the use under discussion, or the product is still investigational; Company/Drug; Ipragliflozin. J. Keirns: 1. This research was sponsored by; Company/ Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. BACKGROUND: Ipragliflozin (ASP1941), a novel, potent selective SGLT2 inhibitor, is under development by Astellas Pharma for the treatment of type 2 diabetes mellitus. This study assessed the effects of repeated, oral single-dosing of ipragliflozin (100 mg and 600 mg) on cardiac repolarization as measured by QTcF interval in healthy subjects. METHODS: This was a randomized, double-blind, placebo and active controlled, four-way crossover study. Eighty-eight subjects were randomized into one of four sequences, with 22 subjects (10 male and 12 female) in each sequence. Each sequence included: Treatment A, placebo for 7 days; Treatment B, ipragliflozin 100 mg/day for 7 days (therapeutic dose); Treatment C, ipragliflozin 600 mg/day for 7 days (supratherapeutic dose); and Treatment D, moxifloxacin 400 mg on day 7 only. The washout period was at least 7 days. An analysis of covariance (ANCOVA) was used to assess the effect of ipragliflozin on QTcF interval with sequence, period, treatment, and treatment by time as fixed effects; subject (sequence) as a random effect; and baseline QTcF as a covariate. RESULTS: The upper bound of the one-sided 95% confidence interval (CI) for the mean QTcF treatment difference from placebo, between ipragliflozin 600 mg and placebo at each time point, was less than 10 msec in all subjects and also by sex. The largest upper bounds of the 95% CIs of mean treatment differences from placebo were 4.44 msec and 2.88 msec for ipragliflozin 600 mg and 100 mg in all subjects, respectively. No subjects showed QTcF intervals > 480 msec, nor time-matched change from baseline > 60 msec. No significant ipragliflozin-related electrocardiogram changes were noted. Moxifloxacin demonstrated assay sensitivity for QTcF prolongation with the lower bound of the one-sided 95% CI > 5 msec. CONCLUSION: Ipragliflozin did not show clinically meaningful or statistically significant effects on cardiac repolarization in healthy subjects at doses up to 600 mg/day. PI-14 EFFECT OF HEPATIC IMPAIRMENT ON THE PHARMACOK- INETICS OF IPRAGLIFLOZIN, A NOVEL SODIUM GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITOR. W. Zhang, 1 W. Krauwinkel, 2 J. Keirns, 1 R. Townsend, 1 K. C. Lasseter, 3 L. Plumb, 1 R. Smulders 2 ; 1 Astellas Pharma Global Development, Inc, Deerfield, IL, 2 Astellas Pharma Europe BV, Leiderdorp, Netherlands, 3 Clinical Pharmacology of Miami, Inc., Miami, FL. W. Zhang: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. 6. I will be discussing the following product, which is not labeled for the use under discussion, or the product is still investigational; Company/Drug; Ipragliflozin. W. Krauwinkel: 1. This research was sponsored by; Company/ Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. J. Keirns: 1. This research was sponsored by; Company/ Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. R. Townsend: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid aBsTraCTs consultant/employee for; Company/Drug; Astellas Pharma. K.C. Lasseter: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/ Drug; Astellas Pharma. L. Plumb: 1. This research was sponsored by; Company/Drug; Astellas Pharma. 2. I am a paid consultant/ employee for; Company/Drug; Astellas Pharma. R. Smulders: 1. This research was sponsored by; Company/ Drug; Astellas Pharma. 2. I am a paid consultant/employee for; Company/Drug; Astellas Pharma. 6. I will be discussing the following product, which is not labeled for the use under discussion, or the product is still investigational; Company/Drug; Ipragliflozin. BACKGROUND: Ipragliflozin (ASP1941), a novel potent selective SGLT2 inhibitor, is undergoing development by Astellas Pharma for the treatment of type 2 diabetes mellitus. It is mainly metabolized by the liver primarily via glucuronidation. This study evaluated the effect of moderate hepatic impairment (HI) on the pharmacokinetics (PK) of ipragliflozin and its metabolites (M1, M2, M3, M4 and M6). METHODS: This was an open-label, single dose study. Sixteen subjects were enrolled (n = 8 healthy subjects and n = 8 with moderate HI [Child-Pugh score 7-9]; groups were gender, age and body weight matched) and received a single oral dose of ipragliflozin 100 mg. Serial blood samples were collected for up to 144 h to determine plasma concentrations of ipragliflozin and its metabolites. Adverse events (AEs) were monitored during the study. RESULTS: All subjects completed the study. Mean C max and AUC inf values of ipragliflozin were 27% and 25% higher, respectively, in those with moderate HI versus healthy subjects (Table). No changes in half-life and protein binding of ipragliflozin were observed in moderate HI subjects. Mean C max and AUC inf values of M2, the major metabolite, were similar in both populations. AEs were mild in severity and their incidence similar in both populations. CONCLUSION: Moderate HI had no clinically meaningful effects on the single-dose PK of ipragliflozin and its major metabolite M2. A single oral dose of ipragliflozin 100 mg was well tolerated both in healthy subjects and those with moderate HI. Ipragliflozi n AUC inf = area under the plasma concentration-time curve from time of dosing to infinity; C max = maximum plasma concentration; CI = confidence interval. CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s13 Analyte M1 M2 M3 M4 M6 Table: Summary of statistical comparisons for ipragliflozin and its metabolites. Parameters (unit) AUCinf (ng.h/mL) Cmax (ng/mL) AUCinf (ng.h/mL) Cmax (ng/mL) AUCinf (ng.h/mL) Cmax (ng/mL) AUCinf (ng.h/mL) Cmax (ng/mL) AUCinf (ng.h/mL) Cmax (ng/mL) AUCinf (ng.h/mL) Cmax (ng/mL) Least squares geometric means Healthy subjects 8950.95 1334.69 616.11 77.95 6186.58 904.48 1453.66 149.01 1361.70 180.36 781.90 53.91 Moderate HI subjects 11,178.27 1691.91 455.73 45.36 6177.15 858.63 1812.78 165.60 2584.40 312.95 1251.11 75.38 Ratio 124.8 8 126.7 6 73.97 58.19 99.85 94.93 124.7 0 111.1 3 189.7 9 90% CI for ratio 93.84–166.19 92.79–173.17 35.23–155.30 25.50–132.81 76.82–129.78 67.53–133.44 92.80–167.58 77.83–158.67 122.72–293.53 173.5 114.77–262.33 2 160.0 1 139.8 4 101.14–253.14 87.97–222.28
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