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PII-123IMPACT OF PHARMACOGENETICS ON DRUG INTERAC-
TIONS. C. Collins, MD, I. Ragueneau, MD, H. Hachad, PharmD, R.Levy, PhD, University of Washington, Seattle, WA.
BACKGROUND: Subjects classified as poor metabolizers (PMs)of a polymorphic enzyme must rely on nonpolymorphic enzyme(s)for clearance of agents metabolized by those isoforms. The aim ofthis study was to quantify the effect of inhibition of the nonpolymor-phic enzyme in term of maximal drug exposure in PMs.
METHODS: The M & T Drug Interaction DatabaseTM was usedto identify published studies including pharmacokinetic results fromextensive (EMs) and PMs in which an enzyme inhibitor of thenonpolymorphic metabolic pathway was introduced.
RESULTS: Six studies were identified that met these criteria: fivestudies involved CYP2C19, one involved CYP2D6, and all involvedCYP3A4 as the nonpolymorphic enzyme. The effects of CYP3Ainhibitors on omeprazole, citalopram and diazepam PK in CYP2C19EMs and PMs was reviewed and the maximal drug exposure of PMswas defined as PMi/EMc (PMi� AUC during inhibition in PMs;EMc� control AUC in EMs). This ratio was 9.2, 13.5 and 34.1 whenomeprazole was inhibited by ketoconazole (200 mg QD), clarithro-mycin(400 mg BID) and troleandomycin (500 mg QD), respectively,1.6 for citalopram (with troleandomycin 250 mg) and 1.8 for diaze-pam (inhibited by diltiazem 200 mg QD). The effect of a CYP3A4inhibitor (ketoconazole 100 mg) on venlafaxine exposure in CYP2D6EMs and PMs produced a ration of 3.6.
CONCLUSIONS: For poor metabolizers of CYP2C19 andCYP2D6, introduction of an inhibitor of the alternate pathway(s) candrastically increase drug exposure.
PII-124PHARMACOKINETICS (PK) AND PHARMACODYNAMICS
(PD) OF DAILY LASOFOXIFENE (LASO) IN JAPANESE (J)AND CAUCASIAN (C) POSTMENOPAUSAL (PM) WOMEN. R.Fountaine, PharmD, Y. Nishizawa, PhD, M. J. Gardner, PhD, Pfizer,Inc, Groton, CT.
BACKGROUND: LASO, a next generation selective estrogenreceptor modulator (SERM), is in late development for the treatmentof osteoporosis. It is oxidatively and conjugatively metabolized.Since ethnic differences in drug metabolism exist, potential PK/PDdifferences for LASO in J and C PM women were explored.
METHODS: Two randomized, investigator blind, parallel-groupstudies were run in PM women. The study in J subjects was placebo-controlled, whereas the study in C subjects was not. Daily 0.25, 0.5mg or placebo tablets were given for 14 days, with loading doses of8-times the daily dose given on day 1. Nine subjects were treated ateach active dose level, with six J subjects treated with placebo.Plasma/serum samples were collected during and following treatmentfor PK/PD evaluations.
RESULTS: The PK/PD of LASO were similar in J and C subjects.Exposure increased predictably with dose, with a mean T1/2 ofapproximately 150 hours. LDL concentrations generally decreasedwith LASO treatment, whereas HDL was not consistently affected.LASO was well-tolerated.
CONCLUSIONS: Following daily dosing for 14 days, there donot appear to be significant differences in LASO PK/PD/safety be-tween J and C populations at clinically relevant doses.
PII-125OSMOTIC PSEUDOEPHEDRINE TABLET: IN VITRO/IN
VIVO CORRELATION STUDY. M. Befumo, BS, E. Feleder, MD,PhD, M. Coppari, BS, M. Ricci, PharmD, J. Faour, PhD, OsmoticaArgentina S.A., Buenos Aires, Argentina.
BACKGROUND: A preliminary linear IVIVC was suggestedfrom a previous bioavailability study of Pseudoephedrine osmotictablets. Our objective was to develop and validate a full IVIVC andbuild a PK model to predict the entire time-course of plasma con-centrations, in order to support adjustments of the PSE release profile.
METHODS: Dissolution was carried out on 12 units (USP app.II37°C, water, 100 rpm). A single dose of 3 osmotic tablets (PSE240mg) with different release profiles and Children’s Sudafed® (20ml, 60mg PSE, Warner-Lambert) as IR reference were administeredto 8 healthy subjects using a randomized William’s crossover design.PSE (0–72hr) was assayed in plasma by GC-MS. Pharmacokineticand statistical calculations were carried out in WinNonlin Pro 4.0.
RESULTS: Relative bioavailability was 100.0%, 92.4 % and94.5% (fast, medium and slow release rate respectively). 90%CIswere within 80.00%-125.00%. A linear IVIVC was observed, withslopes (�95%CI limits) 1.0239�0.0438, 1.0467�0.0470 and1.0303�0.0498. Model internal prediction errors for Cmax and AUCwere under 10%.
CONCLUSIONS: A linear 1:1 IVIVC was demonstrated forosmotic PSE tablets, which presented similar bioavailability to thereference IR product. The resulting pk model is able to predict the invivo impact of eventual formulation changes.
PII-126THE PHARMACOKINETICS AND PHARMACODYNAMICS
OF THE ORAL DIRECT THROMBIN INHIBITOR XIMELAGA-TRAN WHEN ADMINISTERED WITH AZITHROMYCIN ANDCEFUROXIME. H. Dorani, K. Schutzer, T. Sarich, U. Wall, L.Ohlsson, U. Eriksson, AstraZeneca R&D Molndal, AstraZeneca LP,Molndal, Sweden.
BACKGROUND: Ximelagatran is bioconverted to its active formmelagatran. It has a low potential for drug interactions as its metab-olism is independent of CYP450 enzymes.
METHODS: Healthy volunteers (n�32) received ximelagatran36 mg as a single oral dose and, after a �2-day washout period, eitherazithromycin 500 mg on Day 1 and 250 mg qd on Days 2 to 5, orcefuroxime 250 mg bid on Days 1 to 4 and 250 mg on Day 5, witha 36 mg dose of ximelagatran on Days 1 and 5.
RESULTS: The least squares mean estimates for melagatranexposure (AUC) ratios with:without antibiotic were 1.60 (90% CI,1.40–1.82) and 1.41 (90% CI, 1.24–1.61) on Days 1 and 5 of theazithromycin period. For cefuroxime, the corresponding ratios were1.23 (90% CI, 1.07–1.42) and 1.16 (90% CI, 0.972–1.38). The meantime to Cmax, elimination half-life, and renal clearance of melagatranwere not affected by administering ximelagatran with either antibi-otic. Plasma antibiotic concentrations were not affected by coadmin-istration of ximelagatran. Neither antibiotic affected melagatran-dependent prolongation of activated partial thromboplastin time.Ximelagatran given with the antibiotics was well tolerated.
CONCLUSION: Melagatran exposure was increased by coad-ministration with azithromycin and to a lesser extent with cefu-roxime, but the pharmacodynamics and tolerability of ximelagatranand the plasma concentrations of the antibiotics were unaffected.
CLINICAL PHARMACOLOGY & THERAPEUTICS2005;77(2) American Society for Clinical Pharmacology and Therapeutics P83