PIII-71NXY-059, a novel neuroprotectant, causes a limited and clinically insignificant reduction in the elimination of cefuroxime by competing for the organic anion transporter

P78 American Society for Clinical Pharmacology and Therapeutics CLINICAL PHARMACOLOGY & THERAPEUTICS FEBRUARY 2006 PIII-71 PIII-73 NXY-059, A NOVEL NEUROPROTECTANT, CAUSES A LIMITED AND CLINICALLY INSIGNIFICANT REDUCTION IN THE ELIMINATION OF CEFUROXIME BY COMPETING FOR THE ORGANIC ANION TRANSPORTER. I. Reinholdsson, D. Nilsson, G. Huledal, N. Åsenblad, Y. Cheng, M. Kågedal, O. Borgå, AstraZeneca R&D, Borga PK Consulting, Södertälje, Sweden. BACKGROUND: NXY-059 is a novel, free-radical trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke (AIS). In an initial Phase III study (SAINT I) NXY-059 has shown efficacy in AIS by reducing functional disability. Approximately 30% of NXY-059 is eliminated by active tubular secretion by an organic anion transporter (OAT) in the kidneys. Cefuroxime is eliminated renally, partially (45%) by OAT. This study explored whether co-administration of cefuroxime reduced the elimination of NXY-059, and vice versa. METHODS: This was an open, single-center, randomized, threeperiod, crossover study. Twenty-three healthy subjects completed the study. NXY-059 / placebo was infused over 10 h. Doses were similar to those used in the Phase III program. A clinically recommended cefuroxime dose (1.5g iv), or placebo, was infused over 30 min, 4 h after the start of the NXY-059 / placebo infusion. Blood and urine were collected for 10 h for determination of NXY-059 and cefuroxime. RESULTS: NXY-059 reduced the renal clearance (CLR) of cefuroxime by 27% (p0.001) causing the area under the concentration-time curve of cefuroxime to increase by 27%. There was no evidence of any effect of cefuroxime on the CLR of NXY-059. No safety concerns were raised. CONCLUSIONS: NXY-059 reduced the elimination of cefuroxime due to competitive inhibition of OAT. The reduction is limited in relation to the wide therapeutic window of cefuroxime and thus of no clinical significance. PHARMACOKINETICS AND PHARMACODYNAMICS OF CERA, AN INNOVATIVE ERYTHROPOIESIS STIMULATING AGENT, ARE INDEPENDENT OF THE SITE OF SUBCUTANEOUS ADMINISTRATION. A. Pannier, PharmD, X. Liogier D’Ardhuy, PhD, P. Jordan, PhD, A. Brown, MB, BS, B. G. Reigner, PharmD, PhD, F. Hoffmann La Roche, Roche Products Ltd, Basel, Switzerland. BACKGROUND/AIMS: Continuous Erythropoietin Receptor Activator (CERA), an innovative erythropoiesis stimulating agent, acting differently at the receptor level and with prolonged half-life, is in development to provide correction of anemia at extended administration intervals. The study objectives were to describe and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of CERA after subcutaneous (SC) administration using 3 different sites (abdomen, arm and thigh). METHODS: An open-label, randomized, single-center, singledose, 3-way crossover study in 42 healthy volunteers (HV) examined the PK and PD of CERA. Each subject received 3 single administrations of CERA 3.0 g/kg (one at each site: abdomen, arm and thigh) with a 7-week washout period between each injection. RESULTS: The AUClast (primary PK parameter) was similar for the 3 sites of administration and the ratios of the geometric least square means [90% Confidence Interval] were 1.01 [0.9 - 1.13], 1.11 [1.01 - 1.22] and 1.1 [1.02 - 1.18] when comparing abdomen to arm, thigh to arm and thigh to abdomen. For Cmax, the ratios and their 90% CI were 1.09 [0.95 - 1.25], 1.21 [1.07 - 1.37] and 1.11 [1.02 - 1.22], respectively. The increase in mean reticulocyte count was similar for the 3 sites of SC injection. For AUE1-50days, mean values were similar for the 3 sites (ratios between 1.00 and 1.05). CONCLUSION: The site of subcutaneous injection (abdomen, arm or thigh) has no clinically relevant effect on the pharmacokinetics and pharmacodynamics of CERA. PIII-72 PIII-74 POTENT INHIBITION OF CYTOCHROME P450 (CYP) 2B6 CATALYZED EFAVIRENZ 8-HYDROXYLATION BY TICLOPIDINE AND CLOPIDOGREL. W. Huh, MD, D. R. Jones, PhD, D. A. Flockhart, MD, Z. Desta, PhD, Division of Clinical Pharmacology, Indiana University, Indianapolis, IN. BACKGROUND: Ticlopidine (TCL) and clopidogrel (CLP), a widely used thienopyridine antiplatelet drugs have been reported to inhibit CYP2B6 in vitro and in vivo. We have previously shown that the antiretroviral drug efavirenz is primarily metabolized by hepatic CYP2B6 and is proposed as probe of activity for this enzyme. We tested the ability of TCL and CLP to inhibit efavirenz metabolism in vitro. METHODS: Enzyme reactions were carried out with human liver microsomes (HLMs) or expressed CYP2B6 and appropriate cofactors. A range of efavirenz concentrations was coincubated with HLMs with and without multiple concentrations of TCL and CLP to estimate Ki values. In addition, other mechanisms of inhibition were tested by preincubating the test inhibitors of different times with HLMs and expressed CYP2B6. Similar inhibition experiments with bupropion (50 M) served as positive controls. RESULTS: CLP and TCL were potent noncompetitive inhibitors of efavirenz 8-hydroxylation with HLMs (Ki values: 2.6 M and 1.1 M respectively). Preincubation experiments showed that CLP was a reversible inhibitor of efavirenz 8-hydroxylation and a mechanismbased inhibitor of bupropion hydroxylation, while TCL inhibited both substrates reversibly. CONCLUSIONS: CLP and TCL are potent CYP2B6 inhibitors, but the mechanisms of inhibition might be substrate dependent. TCL and CLP may decrease efavirenz elimination in HIV patients and as a result increase its adverse effects. POPULATION PHARMACOKINETICS OF PROPOFOL IN KOREAN POPULATIONS. S. Jang, BS, T. Han, MD, PhD, FAAFP, K. Park, PhD, MD, Yonsei University College of Medicine, Dept of Pharmacology, Hangang Sacred Heart Hospital, Department of Anesthesiology and Pain Medicine, Seoul, Republic of Korea. BACKGROUND: To analyze propofol pharmacokinetics in Koreans and to examine the covariate effects. METHODS: Propofol pharmacokinetics was studied in 19 healthy Koreans (21-54 years, 44-86 kg, ASA(American Society of Anesthesiologists) class I or II) who received a single intravenous dose of 2mg/kg within10 sec. Arterial blood samples were taken at 0, 15, 30, 45, 60 sec, 2, 3, 5, 10, 15, 30, 45, 60 min, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 hr after dosing. Pharmacokinetic modeling including covariate effects was performed using NONMEM. RESULTS: Propofol pharmacokinetics was best described by a 3 compartment pharmacokinetic model, where the effects of age, body weight, and the ASA class were found significant for elimination rate and central volume, with body weight most significant (p0.0001). The estimates of pharmacokinetic parameters for a typical individual were 1.8, 3.2, and 1.8 L/min for systemic, intercompartmental 1, and intercompartmental 2 clearance, respectively, and 2.0, 7.7, and 102 L for central, peripheral 1, and peripheral 2 volume, respectively, somewhat different from literature values obtained from long infusion. CONCLUSIONS: Our results show that propofol pharmacokinetics in Koreans need to be described incorporating clinically important covariates. The results also show that, for short infusion, propofol pharmacokinetic parameter values may be found different from those for long infusion, and a care must be taken for an unbiased dosage individualization in Korean populations.