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aBsTraCTs nature publishing group CONCLUSION: Teriflunomide was safe and well tolerated when given with Minidril ® . A modest increase (< 1.6-fold) in ETH and LEV exposure was observed when coadministered to teriflunomide; therefore, teriflunomide is not expected to adversely impact the efficacy of oral contraceptives. PI-61 GENOTYPE-BASED IN VITRO-IN VIVO EXTRAPOLATION (IVIVE) OF EFAVIRENZ PHARMACOKINETICS USING A PHYS- IOLOGICALLY-BASED PHARMACOKINETIC MODEL. C. Xu, 1 S. Quinney, 2 Y. Guo, 3 Z. Desta 1 ; 1 Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, 2 Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, 3 Drug Disposition, Lilly Research Laboratories, Indianapolis, IN. C. Xu: None. S. Quinney: None. Y. Guo: None. Z. Desta: None. BACKGROUND: The CYP2B6*6 allele is significantly associated with reduced efavirenz metabolism. We developed a physiologicallybased pharmacokinetic model (PBPK) for in vitro-in vivo extrapolation (IVIVE) of efavirenz pharmacokinetics using in vitro data. METHODS: Cl int for efavirenz 7- and 8-hydroxylation was estimated from human liver microsomes (HLMs) genotyped for CYP2B6*6 allele (n=5 for each genotype), expressed CYP2B6.1 and CYP2B6.6. Efavirenz pharmacokinetics of 1000 virtual healthy subjects was simulated using Cl int for individual HLMs and expressed enzymes by Simcyp ® Population-based Simulator (Version 11). Simulated efavirenz pharmacokinetics for individuals with each genotype were compared to the pharmacokinetics of a single 600 mg oral dose of efavirenz administered to healthy volunteers genotyped for CYP2B6*6 allele (n=20). RESULTS: The observed and predicted T max , C max , AUC 0-72h and CL po are shown in the Table. Most measured efavirenz concentrationtime profiles were within 5th and 95th percentile of concentrations simulated by a full PBPK model with compartmental absorption transit model for each genotype. All the predicted pharmacokinetic parameters were within 2-fold of observed values. CYP2B6*6/*6 was associated with lower CL po (40~70 %) and higher AUC 0-72h (10~20 %) compared to wild type. CONCLUSION: This PBPK model may be valuable for predicting the impact of CYP2B6 variants on pharmacokinetics from in vitro Cl int data. Further refinement of this model is ongoing. Table: Clinical and simulated pharmacokinetic parameters for a single 600 mg oral dose of efavirenz T max (h) C max (mg/L) AUC 0-72h (mg/L•h) CL po (L/h) In vitro System Observed Predicted Observed Predicted Observed Predicted Observed Predicted CYP2B6 *1/*1 HLM 2.3±1.0 2.0±0.4 2.3±0.7 1.79±0.39 45.9±16.7 35.0±15.8 8.5±3.4 9.65±23.3 CYP2B6.1 2.1±0.4 1.90± 0.3 37.2±13.2 4.4±3.3 CYP2B6 *1/*6 HLM 2.6±1.7 2.1±0.41 1.7±0.5 1.86±0.34 40.7±12.2 37.7±15.0 8.3± 2.8 5.3±9.1 CYP2B6 *6/*6 HLM 2.7±1.5 2.1±0.4 2.4±0.2 1.90±0.3 57.3±4.1 41.8±14.5 5.9± 0.5 2.2±2.1 CYP2B6.6 2.1±0.41 1.90±0.31 39.5±13.7 3.1±2.1 All the value presented as mean±S.D. PI-62 POPULATION PHARMACOKINETICS OF SM-26000, LIPO- SOMAL AMPHOTERICIN B, IN JAPANESE PEDIATRIC PATIENTS WITH INVASIVE FUNGAL INFECTION. Y. Ohata, 1 Y. Tomita, 1 K. Suzuki, 1 T. Maniwa, 1 Y. Yano, 2 K. Sunakawa 3 ; 1 Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan, 2 Kyoto Pharmaceutical University, Kyoto, Japan, 3 Kitasato University, Tokyo, Japan. Y. Ohata: 2. I am a paid consultant/employee for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. Y. Tomita: 2. I am a paid consultant/employee for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. K. Suzuki: 2. I am a paid consultant/employee for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. T. Maniwa: 2. I am a paid consultant/employee for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. Y. Yano: 2. I am a paid consultant/employee for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. K. Sunakawa: 2. I am a paid consultant/ employee for; Company/Drug; Dainippon Sumitomo Pharma Co., Ltd. BACKGROUND: SM-26000 was the encapsulation of Amphotericin B (AMB) into liposomes (L-AMB). Though antifungal efficacy of AMB encompasses a broad spectrum of medically important fungal pathogens, its toxicity was a great problem. The reduced toxicity of the liposomal formulation allows for the administration of much higher doses of AMB than can be safely administered when given as conventional AMB, leading to the expanding therapeutic potential of L-AMB. The objectives of this study were to develop a population pharmacokinetic (PK) model of AMB and to simulate PK profiles and to calculate C max,ss /MIC which is a pharmacokinetic/pharmacodynamic parameter. METHODS: The PK data at once-daily doses of L-AMB 1.0 mg, 2.5 mg, and 5.0 mg were available. L-AMB was administered by infusion for 60-120 min. In totality 159 serum concentrations from 39 pediatric patients with invasive fungal infection who were enrolled in a post-marketing clinical study conducted in Japan were used for population PK analysis. Model suitability for simulation was confirmed by visual predictive check based on the 95% prediction intervals which were calculated using highest posterior density (HPD) region method. RESULTS: The AMB plasma concentration - time data in Japanese pediatric patients was described by a two-compartment pharmacokinetics model with zero-order input and first-order elimination. Among the candidates for covariates, body weight showed a significant correlation with CL and Vc. The 95% prediction intervals of inter-individual variability of virtual patients were consistent with observed values. As bacterial strains were isolated from some patients, C max,ss /MIC was estimated as 0.7-33.8, using MIC of each isolate against L-AMB. CONCLUSION: The development of this population PK model for L-AMB supported individual subject exposure estimation for population PK/PD efficacy and safety analysis in the post-marketing clinical study. PI-63 LOW DENSITY LIPOPROTEIN (LDL-C) EXPOSURE- RESPONSE ANALYSIS FOR TOFACITINIB (CP-690,550) IN PATIENTS WITH RHEUMATOID ARTHRITIS. S. P. Riley, M. G. Boy, R. Riese, S. Krishnaswami; Pfizer, Inc, Groton, CT. S.P. Riley: 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; Tofacitinib (CP-690,550). M.G. Boy: 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; Tofacitinib (CP-690,550). R. Riese: 1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee 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; Tofacitinib (CP-690,550). S. Krishnaswami: 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; Tofacitinib (CP-690,550). BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus kinase (JAK) inhibitor currently in development for treatment of rheumatoid arthritis (RA). Objectives were to characterize the relationship between tofacitinib exposure and changes in LDL-c and explore covariate effects on the exposure-response (ER) relationship. s30 volume 91 supplemenT 1 | marCh 2012 | www.nature.com/cpt
nature publishing group METHODS: LDL-c data from 5 double-blind Phase 2 studies investigating the efficacy and safety of 1-30 mg BID tofacitinib and placebo in patients with RA were pooled and analyzed using NON- MEM 6.2. The ER relationship was described using a longitudinal, nonlinear mixed-effects model. The structural model form was an indirect response model with tofacitinib inhibiting the LDL-c elimination rate. Results were compared with observations from Phase 3 and long term extension (LTE) studies. RESULTS: The analysis included 1474 patients with 6106 LDL-c observations. The model estimated a steady-state ED 50 of 3.6 mg BID. Mean maximal LDL-c increases were predicted to be reached in approximately 5 weeks, with no evidence of a progressive increase for treatment durations of up to 3 years in LTE studies. Covariate analysis suggested that age, body weight, diabetic status, and race influenced baseline LDL-c. Subjects with hyperlipidemia at baseline showed smaller maximal increases (E max ) in LDL-c compared to patients with normal baseline. Subjects achieving ≥ 50% improvement in signs and symptoms of RA (American College of Rheumatology (ACR) 50) showed modestly larger E max compared to those who did not. Consistent with Phase 3 study observations, doses of 5 mg and 10 mg BID tofacitinib were estimated to have mean (90% CI) LDL-c increases from baseline of 13.4% (9.3-17.8) and 18.1% (12.9-24.9) respectively, at steady state. CONCLUSION: Model predictions based on Phase 2 study data suggest that the time course and magnitude of LDL-c increases following treatment with tofacitinib in RA patients are predictable and concordant with Phase 3 and LTE study observations. PI-64 A PHASE 1 STUDY TO ESTIMATE THE EFFECT OF KETO- CONAZOLE ON THE PHARMACOKINETICS OF TOFACITINIB (CP-690,550) IN HEALTHY VOLUNTEERS. P. Gupta, 1 R. Wang, 1 I. Kaplan, 1 C. W. Alvey, 1 M. Ndongo, 2 S. Krishnaswami 1 ; 1 Pfizer Inc, Groton, CT, 2 Pfizer Clinical Research Unit, Brussels, Belgium. P. Gupta: 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; Tofacitinib (CP-690,550). R. Wang: 1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee 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; Tofacitinib (CP-690,550). I. Kaplan: 1. This research was sponsored by; Company/Drug; Pfizer Inc. 2. I am a paid consultant/employee 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; Tofacitinib (CP-690,550). C.W. Alvey: 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 as part of my employee 401 (K) benefit. 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; Tofacitinib (CP-690,550). M. Ndongo: 1. This research was sponsored by; Company/ Drug; Pfizer Inc. 2. I am a paid consultant/employee 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; Tofacitinib (CP-690,550). S. Krishnaswami: 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; Tofacitinib (CP-690,550). BACKGROUND: Tofacitinib (CP-690,550) is an oral Janus kinase (JAK) inhibitor currently in development for the treatment aBsTraCTs of several inflammatory diseases including rheumatoid arthritis and psoriasis. The objective of this study was to estimate the effect of ketoconazole oral administration on the PK of a single 10 mg oral dose of tofacitinib. METHODS: This study was an open label, single fixed sequence study (A3921054; NCT01202240) in 12 healthy male subjects who received: (a) single dose oral tofacitinib 10 mg in Period 1 and (b) single dose oral tofacitinib 10 mg following 3 days of ketoconazole (400 mg qd) treatment in Period 2. Tofacitinib PK samples were collected prior to dosing (0 hours) and post-dose at 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours in Periods 1 (Days 1) and 2 (Days 3 and 4). PK parameters were calculated using noncompartmental analysis. The interactive effect on PK parameters was determined by analysis of variance which was used to calculate adjusted geometric mean ratios for test/reference (coadministration/tofacitinib alone) and the associated 90% confidence intervals. RESULTS: Coadministration with ketoconazole increased AUC inf and C max by 103%, and 16%, respectively. The ratio of adjusted geometric means was 203.23% (90% CI: 190.96%, 216.30%) for AUCinf and 116.24% (90% CI: 104.59%, 129.18%) for Cmax. Mean terminal t1/2 increased from 2.9 hours for tofacitinib alone to 3.9 hours for tofacitinib with ketoconazole. Median Tmax increased from 0.5 hours for tofacitinib alone to 1.0 hours with ketoconazole. CONCLUSION: The observed approximate doubling of tofacitinib AUCinf with ketoconazole is consistent with predictions from in-vitro data (~55% contribution by CYP3A4-mediated metabolism to total clearance) and suggests that tofacitinib dose may need to be adjusted or restricted when coadministered with ketoconazole. PI-65 NONLINEAR MIXED-EFFECTS MODELING OF THE INTER- SPECIES PHARMACOKINETIC SCALING OF CEFADROXIL AFTER ORAL AND INTRAVENOUS BOLUS ADMINISTRATION. M. M. Posada, D. Smith, M. Feng; University of Michigan, Ann Arbor, MI. M.M. Posada: None. D. Smith: None. M. Feng: None. BACKGROUND: The purpose of this study was to use an allometric scaling approach to predict human pharmacokinetic parameters of cefadroxil using animal pharmacokinetic data after oral and bolus I.V. dosing. Cefadroxil, a first generation cephalosporin, has high bioavailability and is excreted unchanged in urine. Its absorption and elimination are dependent on transporters, such as PEPT1 in the small intestine, and PEPT2 and OATs in the kidney. METHODS: The pharmacokinetic data used in this work were collected from the literature (mouse, rat, and horse) and from our own experiments performed in wild-type mice. The data were analyzed using different models, and the best one was chosen based on the goodness of fit. The data were pooled together and analyzed using mixedeffects modeling (NONMEM), and the results obtained were validated using a set of human data obtained from the literature. RESULTS: The pharmacokinetics of cefadroxil is best described by one-compartment model following I.V. or oral administration.. The allometry predicted human clearance (CL or CL/F), volume of distribution (V or V/F) and absorption rate constant (ka) were within 2-fold of the literature values. The maximum lifespan potential and/or body weight were used as covariates in the allometry model. Different error models were compared, and a proportional error model was selected based on the statistics. The predicted human CL and V are 101 ml/ min and 36.7 L, respectively, based on IV dose data from mice, rats, and foals. However, only the mouse data were used for the prediction of human oral PK because the absorption in rats and foals was significantly slower compared to humans and mice. The predicted human CL/F, V/F, and ka were 215 mL/min, 31.3 L, and 0.03min -1 , respectively. CONCLUSION: Our models allowed a good prediction of the pharmacokinetic parameters of cefadroxil in humans showing that interspecies scaling is a useful tool in the extrapolation from animals to humans. CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s31
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