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aBsTraCTs nature publishing group CONCLUSION: Trial results are highly sensitive to PK variability for compounds with potential inverted U shape response, hence it is challenging to develop a drug with such attributes. Response 0 1 2 3 4 5 6 Response 0 1 2 3 4 5 6 PK_CV=20%,∆/SD=200% True dose response Trial Result(90%PI) 10 20 30 40 Dose (BID mg) PK_CV=80%, ∆/SD=200% True dose response Trial Result (90%PI) 10 20 30 40 Dose (BID mg) Response 0 1 2 3 4 5 6 Response 0 1 2 3 4 5 6 PK_CV=20%,∆/SD=100% 10 20 30 40 Dose (BID mg) PK_CV=80%,∆/SD=100% 10 20 30 40 Dose (BID mg) Response 0 1 2 3 4 5 6 Response 0 1 2 3 4 5 6 PK_CV=20%, ∆/SD=50% 10 20 30 40 Dose (BID mg) PK_CV=80%,∆/SD=50% 10 20 30 40 Dose (BID mg) PI-81 CHARACTERIZATION OF GUINEA PIG MDR1/P-GP FUNC- TION. I. Hasibu, D. Patoine, S. Pilote, B. Drolet, C. Simard; Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, QC, Canada. I. Hasibu: None. D. Patoine: None. S. Pilote: None. B. Drolet: None. C. Simard: None. INTRODUCTION: We have previously shown that guinea pigs express MDR1/P-gp in small intestine. However, its function, as an efflux pump involved in drug transport, has not been characterized. The aim of this study was then to characterize MDR1 function and to determine its distribution in different tissues. METHODS: Molecular biology techniques (RNA extraction, RACE-PCR, RT-PCR and Western blot) were used. Western blot and RT-PCR analyses were performed using liver, small intestine, lung, kidney, atrium, ventricle, cerebellum, brain and adrenal gland protein extracts. Then, guinea pig MDR1 gene was cloned in pCI-neo vector and transfected in HEK293 cells. The functional transport studies were performed with the calcein assay (P-gp substrate) and using verapamil as a P-gp inhibitor. The degree of inhibition of P-gp activity was quantified by measuring the increase in intracellular calcein fluorescence. RESULTS: RACE-PCR analyses showed a 1279 amino acid sequence which is 85, 78, 81 and 78% homologous to human, mouse and rat MDR1a and MDR1b, respectively. Western blot studies showed a 170 kDa band, highly suggestive of MDR1/P-gp. MDR1 mRNA was found in liver, small intestine, atrium, ventricle, brain and adrenal gland. MDR1/ P-gp protein was found in liver, small intestine, atrium, ventricle, cerebellum, brain and adrenal gland. Calcein assay confirmed the MDR1/P-gp activity (84,76 ± 3,61 and 61,72 ± 5,29 FU for pCI-neo and guinea pig- MDR1 transfected in HEK293 cells respectively, p=0,0034). Moreover, a significant inhibition of guinea-pig/MDR1 transport activity was shown when using verapamil (61,72 ± 5,29 and 91,13 ± 2,34 FU, p=0,0009). CONCLUSION: These results suggest that guinea pigs express an active MDR1/P-gp which was detected in almost the same tissues as in humans. Considering the significance of this protein in drug transport, this is reinforcing the pertinence of using the guinea pig model for studying drug metabolism in a more “clinically relevant” context. PI-82 CHARACTERIZATION OF GUINEA PIG CYP2C FUNCTION. I. Hasibu, S. Pilote, D. Patoine, B. Drolet, C. Simard; Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, QC, Canada. I. Hasibu: None. S. Pilote: None. D. Patoine: None. B. Drolet: None. C. Simard: None. BACKGROUND: The guinea pig expresses drug-metabolizing enzymes such as CYP1A, CYP2B, CYP2D and CYP3A subfamilies. We previously showed that this animal also expresses CYP2C and CYP2E subfamilies. However, guinea pig CYP2C function has not been characterized. The aim of our study was to characterize the guinea pig CYP2C functional activity in order to use this animal for drug metabolism studies. METHODS: Molecular biology techniques (RNA extraction, RACE-PCR and Western blot) were used. The function was studied with ex vivo standard incubations using hepatic microsomes from guinea pig. A CYP2C9 probe drug (tolbutamide) was used. Inhibition studies were performed with CYP2C9 inhibitors (tienilic acid and fluconazole) and a CYP3A4 inhibitor (ketoconazole). Tolbutamide and its metabolite concentrations were analyzed by HPLC. RESULTS: RACE PCR allowed us to obtain a 1473 bp sequence which is 80, 82, 81% homologous to human CYP2C8, CYP2C9 and CYP2C19 cDNA respectively. Western blot allowed us to identify a 55 kDa band, highly suggesting CYP2C signature. Incubations of guinea pig hepatic microsomes revealed the formation of tolbutamide specific CYP2C metabolite and showed a K m and a V max of 387 μM and 195 pmol/min/mg proteins respectively. Inhibition assays revealed that p-tolbutamide hydroxylase activity is inhibited by tienilic acid (a mechanism-based inhibitor of CYP2C9), but not by fluconazole and ketoconazole, specific inhibitors of CYP2C9, CYP3A4 respectively. CONCLUSION: These results suggest that guinea pigs express an active CYP2C subfamily, which is quite different from the human CYP2C subfamily. However, when added to the confirmed expression of CYP1A, CYP2B, CYP2D, CYP2E and CYP3A subfamilies and considering the number of drugs metabolized by these hepatic subfamilies, this is reinforcing the pertinence of using the guinea pig model for studying drug metabolism in a more “clinically relevant” context. PI-83 A NEWLY DEVELOPED PEDIATRIC FORMULATION OF REVA- TIO FOR PEDIATRIC PULMONARY ARTERIAL HYPERTENSION PATIENTS IS BIOEQUIVALENT TO THE 1X20 MG REVATIO COM- MERCIAL TABLET AND TO THE 2X10 MG SILDENAFIL CITRATE CLINICAL TRIAL TABLETS IN HEALTHY ADULT VOLUNTEERS. X. Gao, L. Robert, M. O’Gorman, J. Cook; Pfizer, Inc, Groton, CT. X. Gao: 1. This research was sponsored by; Company/Drug; Pfizer, Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer, Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer, Inc. 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; Revatio formulation for pediatric use. L. Robert: 1. This research was sponsored by; Company/Drug; Pfizer, Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer, Inc. 5. I am a significant stockholder for; Company/ Drug; Pfizer, Inc. 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; Revatio formulation for pediatric use, which is not approved in US yet, but it is pending on approval from EU. M. O’Gorman: 1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder for; Company/Drug; Pfizer Inc. 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; the pediatric formulation of Revatio was not approved in US yet, but it was pending approval in Europe. J. Cook: 1. This research was sponsored by; Company/ Drug; Pfizer Inc. 2. I am a paid consultant/employee for; Company/Drug; Pfizer Inc. 5. I am a significant stockholder for; Company/ Drug; Pfizer Inc. 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; Revatio pediatric formulation which has not approved in US yet. BACKGROUND: Revatio is approved for pediatric pulmonary arterial hypertension (PAH) patients in EU based on the results of a large multicentre RCT (STARTS-1). Accordingly, a new pediatric formulation, 10 mg/mL sildenafil citrate powder for oral suspension (POS) was developed for the treatment of pediatric PAH patients. s38 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt
nature publishing group METHODS: A pivotal randomized, open-label, 3-way crossover study was conducted to demonstrate bioequivalence of the 20 mg (2 ml of 10 mg/ml) POS relative to the Revatio 1x 20 mg commercial tablet and the sildenafil citrate 2x10 mg clinical trial tablet in healthy adult volunteers under fasting conditions. Forty-two (42) subjects received three sildenafil treatments in a crossover manner as indicated above. Plasma samples were collected at the predefined series times and analyzed for sildenafil concentrations. Sildenafil PK parameters (C max , AUC last , and AUC inf ) were evaluated for bioequivalence of 20 mg POS relative to Revatio 1x 20 mg tablet and 2x 10 mg tablets. RESULTS: The statistical analyses demonstrated that 20 mg sildenafil POS formulation is bioequivalent to 1x 20 mg Revatio tablet and 2x10 mg sildenafil tablets, as the 90% confidence interval (CI) for the adjusted geometric means of C max , AUC last , and AUC inf , were all within 80% to 125%, the bioequivalence criteria specified by FDA and EMEA. In addition, these three formulations were well tolerated by the healthy volunteers in this study. CONCLUSION: 20 mg (10 mg/mL) sildenafil citrate POS, a newly developed pediatric formulation, is bioequivalent to 1x 20 mg Revatio tablet and 2x10 mg sildenafil tablets. PI-84 A PHASE 1 STUDY TO ASSESS THE EFFECT OF LU AA21004 ON THE STEADY-STATE PHARMACOKINETICS OF LITHIUM IN HEALTHY MALE SUBJECTS. G. Chen, R. Lee, Z. Zhao, M. Serenko; Takeda Global Research and Development Center, Deerfield, IL. G. Chen: 1. This research was sponsored by; Company/Drug; Takeda Pharmaceutical Company, Ltd, H. Lundbeck A/S. 2. I am a paid consultant/employee for; Company/Drug; Takeda Global Research and Development Center. 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; Lu AA21004. R. Lee: 1. This research was sponsored by; Company/Drug; Takeda Pharmaceutical Company, Ltd, H. Lundbeck A/S. 2. I am a paid consultant/employee for; Company/Drug; Takeda Global Research and Development Center. 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; Lu AA21004. Z. Zhao: 1. This research was sponsored by; Company/Drug; Takeda Pharmaceutical Company, Ltd, H. Lundbeck A/S. 2. I am a paid consultant/employee for; Company/ Drug; Takeda Global Research and Development Center. 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; Lu AA21004. M. Serenko: 1. This research was sponsored by; Company/Drug; Takeda Pharmaceutical Company, Ltd, H. Lundbeck A/S. 2. I am a paid consultant/employee for; Company/Drug; Takeda Global Research and Development Center. 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; Lu AA21004. BACKGROUND: Lu AA21004 is a multimodal antidepressant, currently in clinical development for the treatment of major depressive disorder. Lithium has a narrow therapeutic index and is often combined with antidepressants for treatment of refractory depression and bipolar disorders. The pharmacokinetics (PK), safety and tolerability of lithium when coadministered with Lu AA21004 are of clinical interest. METHODS: In this single-blind, multiple-dose, single sequence study, 18 healthy men (mean age 33.2 years) received lithium carbonate 450 mg extended release (ER) tablet twice daily (BID) and placebo capsule once daily (QD) on Days 1-14, followed by lithium carbonate 450 mg ER tablet BID and Lu AA21004 10 mg over-encapsulated tablet QD on Days 15-28. Blood and urine samples were obtained up to 12 hours postdose on Days 14 and 28 for the determination of lithium concentrations. Lithium PK parameters were estimated using noncompartmental methods. Statistical analysis to evaluate the effect of multiple doses of Lu AA21004 on the steady state pharmacokinetics of lithium was performed using ANOVA. Adverse events (AEs) were monitored throughout the study. aBsTraCTs RESULTS: A total of 16 subjects were included in the analysis. The 90% confidence intervals for the least square mean ratios of Lu AA21004 and lithium to placebo and lithium for AUC (0-12) , C max , and C min for lithium ranged from 91.0% to 110.7% (within the 80% to 125% no-effect boundary). Median T max values for Day 14 and Day 28 were identical. Urine PK parameters (A e [0-12], CLr, and Fe) of lithium on Day 14 and Day 28 were generally similar. Nasal congestion was the only AE reported more frequently with Lu AA21004 and lithium treatment (31.3%) than with placebo and lithium treatment (5.6%). All treatment emergent AEs were mild in intensity. CONCLUSION: Multiple doses of Lu AA21004 10 mg did not affect the steady state pharmacokinetics of lithium. Coadministration of Lu AA21004 10 mg QD with lithium 450 mg ER BID for 14 days was generally well tolerated. PI-85 A POPULATION ANALYSIS OF UNBOUND MYCOPHENOLIC ACID PHARMACOKINETICS AND PHARMACOGENETICS IN ADULT ALLOGENEIC HEMATOPOIETIC CELL TRANSPLAN- TATION. A. Frymoyer, 1 D. Verotta, 1 P. A. Jacobson, 2 J. Long-Boyle 1 ; 1 University of California, San Francisco, San Francisco, CA, 2 University of Minnesota, Minneapolis, MN. A. Frymoyer: None. D. Verotta: None. P.A. Jacobson: None. J. Long-Boyle: None. BACKGROUND: Unbound mycophenolic acid (MPA u ) pharmacokinetics (PK) in adult allogeneic hematopoietic cell transplantation (alloHCT) recipients displays large inter- and intrapatient variability, and lower exposure is associated with higher rates of acute graft vs host disease (aGVHD). The aim of this study was to evaluate patientspecific covariates, both genetic and non-genetic, as contributors to the variability of unbound MPA exposure and clinical outcomes in adult alloHCT recipients. METHODS: Intensive MPA u PK data obtained in 132 adult alloHCT recipients (38% female; mean [range] age 52 yrs [19-69 yrs]) from three previously completed clinical studies were used. A population-based PK model of MPA u was developed using nonlinear mixed-effects modeling (NONMEM). Clinical characteristics, concomitant medications and genetic polymorphisms (UGT1A8, UGT1A9, UGT2B7, and MRP2) were evaluated for their impact on MPA u PK. The relationship between daily MPA u AUC (AUC24) and aGVHD (grade II-IV and III-IV) was examined using a competingrisks survival regression analysis. RESULTS: MPA u concentration-time data was well described by a two-compartment model with first order absorption and linear elimination. Creatinine clearance was a small but significant predictor of MPA u CL. No other covariates tested were found to influence MPA u PK. Interpatient variability in CL, V central , and k a was 37%, 38%, and 73%, respectively. After oral dosing, bioavailability was low (0.56) and highly variable (CV 46%). Residual variability was 42%. The risk of aGVHD grade II-IV decreased 16% for every 200 ng*h/ml increase in AUC24 (p
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Poster Session I (PI 1-106)Displayed 8:00 am – 3:00 ... - Nature

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