Abstracts: 2012 American College of Clinical Pharmacology Annual Meeting, Annual Meeting, September 23-25, 2012, San Diego, California

Abstract

Clinical Pharmacology in Drug DevelopmentVolume 1, Issue 4 p. 175-175 Free Access 2012 American College of Clinical Pharmacology Annual Meeting September 23rd–25th San Diego, California Correction(s) for this article ERRATUM Volume 2Issue 1Clinical Pharmacology in Drug Development pages: 99-99 First Published online: March 11, 2013 First published: 10 January 2013 https://doi.org/10.1177/2160763X12454673Citations: 3AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat 1381007 Population Model-based Estimates of Genotype-dependent CY-P2C9 Mediated Flurbiprofen Oral Clearance and In Vivo Inhibition Constants (Ki) For Fluconazole Inhibition Jia Kang1, Vikas Kumar2, Richard Brundage1, Timothy Tracy3 1Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA; 2Clinical Pharmacology, Pfizer Worldwide R&D, Groton, CT, USA; 3College of Pharmacy, University of Kentucky, Lexington, KY, USA Statement of Purpose, Innovation or Hypothesis: Reports of genotype-dependent (CYP2C9*1*1, CYP2C9*1*3 and CYP2C9*3*3) inhibition of flurbiprofen (FLB) metabolism by fluconazole have been demonstrated both in vitro and in vivo. The goal of the present study was to determine estimates of the in vivo Ki of fluconazole for CYP2C9 using a population pharmacokinetic (PPK) approach. Description of Methods and Materials: A PPK model was developed incorporating the pharmacokinetics of both FLB and its primary metabolite 4'-hydroxyflurbiprofen in the absence and presence of fluconazole. The Ki of fluconazole was estimated assuming a competitive inhibition model on the CYP2C9-mediated clearance pathway. Inhibitor concentrations were estimated in each individual as the median of 5 steady-state fluconazole concentrations. The PPK analysis was performed in NONMEM 7 using ADVAN5 TRANS1. Data and Results: 21 subjects (CYP2C9*1/*1, n=11; CYP2C9*1/*3, n=8; and CYP2C9*3/*3, n=2) were administered a single oral 50 mg dose of FLB either alone or after 7 daily doses of 200 or 400 mg of fluconazole in a randomized crossover design. Blood samples were collected over 24 hours and analyzed for FLB and fluconazole concentrations, and urine samples were collected for the analysis of FLB and its 4'-hydroxyflurbiprofen metabolite. The intrinsic clearances (L/hr; mean ± standard error) of FLB hydroxylation by CYP2C9 decreased as expected across CYP2C9*1*1 (1.22 ± 0.0885), *1*3 (0.485 ± 0.112) and *3*3 (0.0474 ± 0.00626) genotypes. The estimates of in vivo Ki (μM; mean ± standard error) for fluconazole inhibition of FLB metabolism were 16.1 ± 2.85 for CYP2C9*1/*1, 18.0 ± 2.81 for *1/*3, and 34.9 ± 3.56 for *3/*3. The differential fluconazole Ki values resulted in a lowered degree of drug interaction in individuals with one or two CYP2C9*3 alleles. The population estimates of FLB renal clearance and residual clearance through unknown pathways were 0.193 ± 0.0174 L/hr and 0.177± 0.0262 L/hr for all three groups. Interpretation, Conclusion or Significance: The proposed PPK model has demonstrated the impact of CYP2C9 genetic polymorphism on drug interaction of fluconazole on FLB metabolism. The model-based estimates of in vivo Ki for fluconazole inhibition within the three CYP2C9 genotypes are comparable to those inferred from previous in vitro and in vivo studies. 1381869 Studies of Potential Drug-Drug Interactions Between Azilsartan Medoxomil and Either Amlodipine or Digoxin Caroline Dudkowski1, Aziz Karim2, Zhen Zhao1 1Takeda Global Research and Development, Deerfield, IL, USA; 2FCP; AzK Consulting Inc (formerly at Takeda), Skokie, IL, USA Statement of Purpose, Innovation or Hypothesis: Azilsartan medoxomil (AZL-M) is an angiotensin-II receptor blocker approved to treat hypertension. After oral administration, it is rapidly hydrolyzed to azilsartan (AZL). Potential clinical uses may involve coadministration of AZL-M with the antihypertensive agent amlodipine (AML) or the cardiac glycoside digoxin (DIG). Two studies were conducted to assess how coadministration of AZL-M with either AML or DIG affected the steady-state pharmacokinetics of AZL and the respective coadministered drug. Description of Methods and Materials: Each open-label, multiple-dose, crossover study enrolled 24 healthy adults (age 18–45 years). Each subject received each of three regimens in random sequence 1) AZL-M 80 mg, 2) AML 10 mg or DIG 200 mcg, or 3) AZL-M plus AML or DIG. Each regimen was administered in multiple, once-daily doses sufficient to achieve steady-state, followed by washout. Steady-state pharmacokinetic (PK) parameters and safety were assessed. Data and Results: Ratios of mean steady-state PK values (coadministered drugs relative to monotherapy) are shown in the Table expressed as percentages. Coadministration of AZL-M with AML or DIG had no significant effect on the steady-state PK of AZL, or on the steady-state PK of AML or DIG. The most common adverse events during coadministration of AZL-M with either AML or DIG were dizziness and headache. All adverse events were of mild or moderate intensity. No new safety concerns were observed during any period of drug coadministration relative to single-drug treatment. Table 1. 1381869: Ratios (90% CI of ratios) of mean steady-state PK values expressed as percentages. Analyte AZL-M+AML/AZL-M alone AZL-M+AML/AML alone AZL AUC0-tau Cmax 102.2 (98.4, 106.2) 94.4 (88.4, 100.8) AML AUC0-tau Cmax 98.8 (96.6, 101.0) 100.0 (97.0, 103.0) AZL-M+DIG/DIG alone AZL-M+DIG/AZL-M alone AZL AUC0-tau Cmax 102.9 (97.8, 108.2) 94.3 (85.4, 104.2) DIG AUC0-tau Cmax 98.4 (94.4, 102.7) 100.3 (92.0, 109.4) tau, duration of dosing interval (24 hours). Interpretation, Conclusion or Significance: Coadministration of either the CYP3A4 substrate AML or the P-glycoprotein substrate DIG with AZL-M did not alter the systemic exposure to AZL or either coadministered drug relative to single-drug administration at steady-state. 1384434 A Phase 1 Study Evaluating the Effect of Eliglustat on the Pharmacokinetics, Safety and Tolerability of Digoxin in Healthy Subjects Marjie L. Hard, Ana Cristina Puga, Leorah Ross, Fanny O'Brien, Cheryl Delacono, Lisa von Moltke Genzyme - A Sanofi Company, Cambridge, MA, USA Statement of Purpose, Innovation or Hypothesis: Eliglustat is in development as an oral treatment for Gaucher disease type 1. In vitro studies suggest eliglustat has potential for inhibition of P-glycoprotein (P-gp). The purpose of this study was to determine the effect of repeated oral doses of eliglustat on the pharmacokinetics of orally administered digoxin in healthy adult subjects. Safety and tolerability of digoxin administered alone and with eliglustat also were assessed. Description of Methods and Materials: Twenty-eight subjects (12 males and 16 females) were enrolled in this study consisting of two treatment periods. In Period 1, a single dose of digoxin 0.25 mg was administered on Day 1. In Period 2, eliglustat 150 mg BID, or 100 mg BID for CYP2D6 poor metabolizers (PMs), was administered on Days 11–17, and a single dose of digoxin 0.25 mg was coadministered on Day 15. Serum digoxin concentrations were determined over 72 hours on Days 1 and 15. Linear mixed-effects models were used to compute the difference in means for Ln-transformed AUC and Cmax. Linear contrasts were used to estimate the least square mean difference between treatments and 90% confidence interval (CI) of the difference. The geometric least square mean ratio (GMR) and 90% CIs of the test/reference ratio were computed by exponentiation of the difference and 90% CI. Data and Results: Nineteen subjects were extensive CYP2D6 metabolizers. Four subjects were PMs, 4 were ultra-rapid, and 1 was an intermediate CYP2D6 metabolizer. The GMR for digoxin exposure was 149% (90% CI: 133%-166%) in the presence of eliglustat. A similar result was observed for digoxin peak exposure, where the GMR for Cmax was 170% (90% CI: 156%-184%). Coadministration of one dose of digoxin with eliglustat was generally safe and well tolerated. Interpretation, Conclusion or Significance: Coadministration of eliglustat with digoxin increased total and peak exposure to digoxin by 49% and 70%, respectively, suggesting that eliglustat is an inhibitor of P-gp. 1386718 A Pharmacokinetic Drug-Drug Interaction Study Between Rosuvastatin and CS-866 in Healthy Male Korean Volunteers Hyerang Roh, Hankil Son, Donghwan Lee, Kyungsoo Park Brain Korea 21 Project for Medical Science, Yonsei University college of Medicine, Seoul, Republic of Korea Statement of Purpose, Innovation or Hypothesis: This study is to investigate the pharmacokinetic (PK) profiles and drug-drug interaction(DDI) between rosuvastatin and CS-866(olmesartan) in healthy male korean volunteers. Description of Methods and Materials: A randomized, open-label, 3-period, cross-over, and multiple-dose study was conducted with 36 healthy male subjects. The subjects were randomly assigned to six groups of equal number and received one of the following three formulations once a day for 7 days at each period with a 8-day washout period between the formulations; 20 mg rosuvastatin tablet, 40 mg CS-866 tablet, and the co-administration of 20 mg rosuvastatin and 40 mg CS-866 tablet. Blood samples were collected up to 72 hours after dosing and plasma concentrations of rosuvastatin, its active metabolite (N-desmethyl rosuvastatin) and CS-866(olmesartan) were analyzed by a LC-MS/MS method. Pharmacokinetic parameters at steady state, AUCtau (24-hr interval), AUCss,last, AUCss,inf, Css,max, Css,min and t1/2, were obtained by a non-compartment method using WinNonlin. Data and Results: The geometric mean ratios(GMR) (90% CI) of the pharmacokinetic parameters for the co-administration of the two drugs to the mono-administration of each drug were 90.44% (85.14 ∼ 96.08%) for AUCtau and 89.08 % (81.41 ∼97.48%) for Css,max for rosuvastatin, and 83.30 % (77.55 ∼ 89.48%) for AUCtau and 82.55 % (75.62 ∼90.12%) for Css,max for N-desmethyl rosuvastatin, whereas those were 99.03 % (95.61 ∼ 102.57%) for AUCtau and 97.19 % (91.73∼102.98%) for Css,max for CS-866. Formulation effects of AUCtau and Css,max were significant (p < 0.05) in both rosuvastain and N-desmethyl rosuvastatin. All adverse events (AEs) were mild to moderate, except two severe ones. There was no significant difference in AE frequency between co- and mono-administration. Interpretation, Conclusion or Significance: This study shows that the pharmacokinetics of rosuvastatin and its active metabolite are affected by CS-866 due to drug-drug interaction when the two drugs are co-administered while the pharmacokinetics of olmesartan are not affected by such drug-drug interaction. 1389866 Green Tea Extract Reduces the Bioavailability of the OATP Probe Fexofenadine Melonie Stanton1, Mark Segal2, Jonathan Shuster3, Reginald Frye1 1Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA; 2Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, FL, USA;3Health Outcomes and Policy, University of Florida, Gainesville, FL, USA Statement of Purpose, Innovation or Hypothesis: The aim of this study was to determine the effect of single-dose administration of green tea extract on the pharmacokinetics of the OATP probe fexofenadine in healthy volunteers. We hypothesized that green tea extract administration would alter fexofenadine exposure due to decreased OATP-mediated uptake. Description of Methods and Materials: This was a randomized open-label crossover study consisting of two phases, a control phase and the green tea phase. Healthy men (n=4) and women (n=4) aged 18 years or older were enrolled. The mean (SD) age and body mass index of study participants were 30.9 (16.2) years and 25.0 (2.2) kg/m2, respectively. Participants received a single oral dose of fexofenadine hydrochloride 60 mg either alone or 1-hour after a single oral dose of green tea extract (EGCG 800 mg). Blood samples were drawn before and over 24 hours after fexofenadine administration. Fexofenadine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. Fexofenadine pharmacokinetic parameter values were estimated from the plasma concentration-time data using standard noncompartmental methods (WinNonlin, PharSight Corp., Mountain View, CA, USA). A two sample method for crossover studies was used to compare the fexofenadine pharmacokinetics between the two phases. Differences were considered statistically significant if p was less than 0.05. Data was analyzed with SAS version 9.3 (SAS Institute, Cary, NC). Data and Results: Green tea extract significantly decreased fexofenadine mean AUC by 66% from 872 to 294 ugxh/L (p = 0.0058) and mean Cmax by 65% from 146 to 50.2 ug/L (p = 0.0154) as compared with the control phase. There were no significant differences in tmax, or t½ between the control and green tea phases. Interpretation, Conclusion or Significance: To our knowledge, this is the first time the in vivo effects of green tea extract on OATP-mediated transport have been characterized. This study indicates that green tea extract decreases the bioavailability of fexofenadine, most likely through inhibition of OATP-mediated intestinal uptake. Future research to investigate the role of green tea extract in transporter-mediated interactions and the resulting clinical implications is warranted. 1389928 Effect of a Proton Pump Inhibitor or an Antacid on Pharmacokinetics of Betrixaban, a Novel Oral Factor Xa Inhibitor Athiwat Hutchaleelaha1, Joseph L. Lambing1, Kevin Romanko2, Daniel D. Gretler2 1Drug Metabolism and Pharmacokinetics, Portola Pharmaceuticals Inc., South San Francisco, CA, USA; 2Clinical Development, Portola Pharmaceuticals Inc, South San Francisco, CA, USA Statement of Purpose, Innovation or Hypothesis: Betrixaban is a once daily oral Factor Xa inhibitor being investigated in a Phase 3 clinical trial to prevent venous thromboembolism in acute medically ill patients. A proton pump inhibitor (PPI) or antacid are extensively used for the treatment of gastric acid-related disorders. Besides the potential drug-drug interaction with pH-sensitive drugs, PPIs may affect pharmacokinetics of other drugs via inhibition of CYP2C19 and/or Pgp. This study determined the effect of a PPI (esomeprazole) or an antacid on the pharmacokinetics of a 40 mg betrixaban capsule administered as a single oral dose to healthy subjects. Description of Methods and Materials: This was a single center, open-label, 3-period crossover, period randomized study. There were three treatment regimens: betrixaban by itself (Treatment A), betrixaban after 5 days of pretreatment with esomeprazole (Nexium® Delayed-Release capsule, 40 mg) (Treatment B), and betrixaban after the administration of 5 mL Maalox® (Treatment C). Data and Results: Betrixaban in combination with esomeprazole produced a 12.8% higher Cmax and 15.3% higher AUC(0-∞) relative to that of the betrixaban alone. Betrixaban in combination with antacid produced a 14.0% lower Cmax and 7.6% lower AUC(0-∞) than the betrixaban alone. Neither difference was statistically significant (p ≥ 0.3060). Interpretation, Conclusion or Significance: While formal bioequivalence was not demonstrated with 90% confidence intervals (CI) for geometric least square (LS) mean ratios fully contained within the 80 to 125% of control, the effect of an antacid or esomeprazole on the PK of betrixaban is small and not considered clinically meaningful. These results indicate that co-administration of betrixaban and PPI or antacid was safe and well tolerated and that no dose adjustment is needed. Table 2. 1389928: Table Geometric LS Mean Pairwise Comparisons Parameter Treatment n Pair Ratio (%) 90%CI p-value Cmax (ng/mL) A 12 12.8 B 12 14.4 B/A 112.8 (75.3, 169.0) 0.6132 C 12 11.0 C/A 86.0 (57.4, 128.9) 0.5287 AUC(0-∞) (ng*h/mL) A 12 267.4 B 12 308.3 B/A 115.3 (91.3, 145.7) 0.3060 C 12 247.2 C/A 92.4 (73.2, 116.8) 0.5675 1390253 Lack of Pharmacokinetic Interaction Between a Novel Oral Factor Xa Inhibitor, Betrixaban and Digoxin Athiwat Hutchaleelaha1, Joseph L. Lambing1, Kevin Romanko2, Daniel D. Gretler2 1Drug Metabolism and Pharmacokinetics, Portola Pharmaceuticals Inc, South San Francisco, CA, USA; 2Clinical Development, Portola Pharmaceuticals Inc, South San Francisco, CA, USA Statement of Purpose, Innovation or Hypothesis: Betrixaban is a once daily oral Factor Xa inhibitor being investigated in a Phase 3 clinical trial to prevent venous thromboembolism in acute medically ill patients. Digoxin is a commonly prescribed cardiac glycoside that has a narrow therapeutic index. Because both betrixaban and digoxin are Pgp substrates, this study evaluated the pharmacokinetic interaction between these two drugs. Description of Methods and Materials: This was a single-center, open-label, sequence-randomized, 3-period crossover study of betrixaban and digoxin, where each drug was administered orally alone or in combination for 7 days in 18 healthy subjects. Treatment A was 80 mg betrixaban alone once daily. Treatment B was a loading dose of 0.5 mg digoxin, followed by 0.25 mg administered 6 hours later and then once daily on Days 2–7. Treatment C was the combination of Treatments A and B. Each period was separated by a 12- to 14-day washout period. All doses were taken after an overnight fast. Data and Results: After achieving steady-state for both drugs on Day 7, the mean Cmax and AUC(0–24) of betrixaban, when administered alone or in combination with digoxin, were similar (92.5 vs. 92.6 ng/mL and 943.9 vs. 935.5 ng*hr/mL, respectively). The % mean ratios (90% confidence intervals) for the Cmax and AUC(0–24) were 90.8 (75.6, 109.1) and 92.9 (83.4, 103.5), respectively. There was no change in percent dose excreted as unchanged betrixaban in the urine (7.63% vs. 7.54%). The mean Cmax and AUC(0–24) of digoxin when administered alone or in combination with betrixaban were also similar (1.76 vs. 1.61 ng/mL and 16.2 vs. 15.3 ng*hr/mL, respectively). The % mean ratios (90% confidence intervals) for the Cmax and AUC(0–24) were 112.1 (102.3, 122.9) and 107.1 (102.1, 112.3), respectively. There was no change in percent dose excreted as unchanged digoxin in the urine (52.1% vs. 52.4%). Interpretation, Conclusion or Significance: These results indicate that co-administration of betrixaban and digoxin was safe and well tolerated by the healthy male and female subjects and that no dose adjustment is needed. 1391862 A QT/QTc Study of Quinine Sulfate in Young and Elderly Volunteers Robert D. Faulkner1, Lawrence Satin2, Suman Wason1 1Mutual Pharmaceutical Company, Inc., Philadelphia, PA, USA; 2Cardiocore, Bethesda, MD, USA Statement of Purpose, Innovation or Hypothesis: Cardiotoxicity is a potential concern during treatment with the antimalarial quinine sulfate (QS). Studies show varying effects of QS on cardiac rhythm and pharmacokinetic (PK) differences between young and the elderly. A definitive QT/QTc study was conducted in healthy, young and elderly participants to assess effects of QS on cardiac repolarization, measured by QT interval prolongation in accordance with the ICH E14 guidance. Description of Methods and Materials: Randomized, double-blind, placebo (PBO) and positive-controlled, 3-way crossover study (31 healthy male and female, young [mean 26.8 yrs; 50% male] and elderly [mean 70.5 yrs; 47% male]. Subjects received 648 mg of QS or PBO tid for 6 days and a single dose on day 7, or PBO tid for 6 days and a single 400 mg moxifloxacin on day 7. ECGs were collected by 12-lead Holter monitoring on Day 7. Plasma samples for QS and major metabolite 3-hydroxyquinine (3-HQ) were obtained on Days 1 and 7. The primary end-point was the largest time-matched period-specific, baseline-adjusted, placebo-corrected individual QT interval (ΔQTcI). Data and Results: PK for QS and 3HQ on Days 1 and 7 were comparable between young and elderly. QTc study sensitivity was confirmed by a lower 95% confidence limit (CI) in QTcI >5 msec for moxifloxacin. QTcI was positively correlated with QS concentrations >3.5 mcg/mL. Maximal mean ΔQTcI was 30 msec and occurred between 1–3 hours post-dose. Mean ΔQTcI of >10 msec were observed out to 6 hours post-dose with upper 95% CIs >10 msec out to 24 hours post-dose. No increases from baseline QTcI >60 msec or absolute QTc >500 msec were observed in any subject. No clinically meaningful gender differences in PK or ΔQTcI were seen. There were no serious AEs reported and no discontinuations due to safety reasons. Interpretation, Conclusion or Significance: QTc prolongation was correlated with plasma QS with maximal ΔQTcI of 30 msec. There were no meaningful differences in QTc prolongation or QS pharmacokinetics by age or gender. 1392377 Empagliflozin Has No Effect on the Steady-state Pharmacokinetics of Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers Sreeraj Macha1, Michaela Mattheus2, Sabine Pinnetti3, Hans J. Woerle2, Uli C. Broedl2 1Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 3Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Statement of Purpose, Innovation or Hypothesis: The effect of multiple oral doses of empagliflozin 25 mg once daily (qd) on the steady state pharmacokinetics of the combined oral contraceptive ethinylestradiol (EE) 30 μg/levonorgestrel (LNG) 150 μg qd was investigated. Description of Methods and Materials: This was a Phase I open-label, two-period, fixed-sequence study in 18 healthy premenopausal female volunteers. There was a mandatory run-in period in which participants received EE 30 μg/LNG 150 μg qd for 21–48 days followed by a treatment-free interval of 7 days. Participants then received EE 30 μg/LNG 150 μg qd for 14 days (reference; period 1), followed by EE 30 μg/LNG 150 μg qd plus empagliflozin 25 mg qd for 7 days (test; period 2). Data and Results: The pharmacokinetics of EE and LNG were not affected by co-administration with empagliflozin. Geometric mean ratios (90% CI) of area under the steady state plasma concentration-time curve over a uniform dosing interval τ at steady state (AUCτ,ss) and maximum measured steady state plasma concentrations (Cmax,ss) for EE were 102.82% (97.58, 108.35) and 99.22% (93.40, 105.39), respectively. For LNG, these values were 101.94% (98.54, 105.47) and 105.81% (99.47, 112.55), respectively. The 90% CIs were within the standard bioequivalence boundaries of 80–125%. There were no relevant changes in the time to reach peak levels and terminal elimination half-life of both EE and LNG between test and reference treatments. Ten women in each treatment had at least one adverse event (AE), all of which were mild or moderate in intensity. Severe AEs were reported by three women in the reference group and one woman in the test group. There were no serious AEs or premature discontinuations. Interpretation, Conclusion or Significance: The combination of EE 30 μg/LNG 150 μg and empagliflozin 25 mg was well tolerated. Based on standard criteria, empagliflozin had no effect on the pharmacokinetics of EE and LNG, indicating that no dose adjustment of EE 30 μg/LNG 150 μg is required when empagliflozin is co-administered. 1392497 Effect of CYP3A4 Inhibitor Coadministration on the Pharmacokinetics of Avanafil, a New, Potent, Selective PDE-5 Inhibitor Toni M. Grant1, Mohammad Obaidi1, Peng Chai1, Katrina E. Canonizado1, Christine M. Brandquist1, Elliot Offman2, Alfred Spivack3, Shiyin Yee3 1Clinical Pharmacology Sciences, Celerion, Lincoln, NE, USA; 2Clinical Pharmacology Sciences, Celerion, Montreal, QC, Canada; 3VIVUS, Inc., Mountain View, CA, USA Statement of Purpose, Innovation or Hypothesis: Avanafil is an oral, potent, and highly-specific phosphodiesterase type 5 (PDE-5) inhibitor, being developed for treatment of erectile dysfunction. Cytochrome P45 (CYP) 3A4 catalyzes formation of the main metabolites of avanafil. This study assessed the effect of coadministration of strong (ketoconazole, ritonavir) and moderate (erythromycin) CYP3A4 inhibitors on the pharmacokinetics of avanafil. Description of Methods and Materials: This was an open-label, randomized, one-sequence, parallel group, single-center study. Subjects were randomized into 3 groups and received one dose of avanafil on Day 1 and Day 6 (Groups 1 and 2) or Day 8 (Group 3), and multiple doses of ketoconazole (Group 1; N = 15) or erythromycin (Group 2; N = 15) on Days 2–6 or ritonavir (Group 3; N = 14) on Days 2–8. Serial blood samples drawn on avanafil administration days were quantified for plasma avanafil using a validated LC/MS/MS method. Pharmacokinetic parameters were derived using noncompartmental analysis. Analysis of variance was performed on ln-transformed Cmax, AUC0-t, and AUCinf using SAS® Proc Mixed. Nonparametric comparisons of tmax and t½ were conducted using Wilcoxon Signed Ranks Test. Data and Results: The statistical comparisons of plasma avanafil pharmacokinetic parameters demonstrated peak and overall avanafil exposures increased by approximately 2- to 3-fold and 13- to 14 fold, for Cmax and AUC respectively, following avanafil + ketoconazole or ritonavir, and by 2- to 3-fold following avanafil + erythromycin compared to avanafil alone. Nonparametric statistical comparisons demonstrated statistically significant differences in tmax following avanafil + ketoconazole or ritonavir, but not following avanafil + erythromycin, compared to avanafil alone, and statistically significant differences in t½ following avanafil + ketoconazole or erythromycin compared to avanafil alone. Ritonavir t½ values were not compared, due to small N. Interpretation, Conclusion or Significance: Coadministration of moderate or strong CYP3A4 inhibitors increases plasma avanafil exposure. For subjects taking known CYP3A4 inhibitors, avanafil dose-adjustment is recommended. 1392639 Effect of Multiple Doses of Ketoconazole or Pioglitazone on the Single-dose Pharmacokinetics of TAK-875 Ronald Lee1, Sai Nudurupati1, Miyako Sudo2, Junzo Takahashi2, Minh Vo1 1Clinical Pharmacology, Statistics and Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company, Deerfield, IL, USA; 2Clinical Pharmacology, Statistics and Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company, Sho-nan, Japan Statement of Purpose, Innovation or Hypothesis: TAK-875 is a potent and highly selective agonist of GPR40 being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. In vitro results demonstrated that TAK-875 is metabolized primarily by CYP3A to an inactive TAK-875 M-I metabolite (M-I). Two studies evaluated the effect of multiple doses of ketoconazole (CYP3A inhibitor) or pioglitazone (CYP3A inducer) on the pharmacokinetics (PK) of TAK-875 and M-I. Description of Methods and Materials: Twenty-four healthy male and female subjects in each study were administered a 25 mg dose of TAK-875, and serial blood samples obtained for 192 or 168 hours post-dose in the ketoconazole or pioglitazone study, respectively. Multiple 400 mg doses of ketoconazole or 45 mg pioglitazone were administered, and on the fifth or eighth dose, respectively, a 25 mg dose of TAK-875 was coadministered and blood samples collected for 192 or 168 hours postdose. PK was assessed by point estimates and 90% confidence intervals (CIs) for the ratios (TAK-875+ketoconazole or pioglitazone to TAK-875 alone) of the central values for TAK-875 and M I Cmax and AUCs. A conclusion of no-effect of ketoconazole or pioglitazone on TAK-875 and M-I was made if the 90% CIs were between 0.80–1.25. Data and Results: After multiple doses of 400 mg ketoconazole or 45 mg pioglitazone with TAK-875 compared to TAK-875 alone, the 90% CIs for TAK-875 Cmax and AUCs were within the 0.80–1.25 range. In contrast, the 90% CIs for M-I Cmax and AUCs were below 0.80 when TAK-875 was coadministered with ketoconazole and slightly above 1.25 when coadministered with pioglitazone. Exposures of M-I were 62–94% lower and 16–25% higher when TAK-875 was administered with ketoconazole or pioglitazone, respectively, compared to TAK-875 alone. Treatment in both studies was well tolerated. Interpretation, Conclusion or Significance: Multiple doses of ketoconazole or pioglitazone had no effect on the PK of TAK-875 but had an effect on M-I. 1392677 Effect of Multiple Doses of TAK-875 on Single-dose Pharmacokinetics of Repaglinide and Single-dose Pharmacokinetics/Pharmacodynamics of Warfarin Michael Kukulka1, Ronald Lee1, Hinamshu Naik1, Sai Nudurupati1, Miyako Sudo2, Junzo Takahashi2 1Clinical Pharmacology, Statistics, and Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company, Deerfield, IL, USA; 2Clinical Pharmacology, Statistics, and Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company, Sho-nan, Japan Statement of Purpose, Innovation or Hypothesis: TAK-875 is a potent and highly selective agonist of GPR40 being developed to improve glycemic control in patients with type 2 diabetes mellitus. In vitro results demonstrated that TAK-875 is a potential inhibitor of CYP2C8 and CYP2C9. Two separate studies evaluated the effect of multiple doses