`
`ABSTRACTS
`
`PIII-86
`THE INFLUENCE OF RENAL IMPAIRMENT ON THE
`PHARMACOKINETICS OF VILDAGLIPTIN. Y. L. He, PhD,
`B. Flannery, BS, Y. Wang, J. Campestrini, PhD, M. Ligueros-Saylan,
`MD, W. P. Dole, MD, D. Howard, PhD, Novartis, Novartis, Novartis,
`Cambridge, MA.
`BACKGROUND: Vildagliptin is a potent and selective DPP-4
`inhibitor in clinical development for the treatment of type 2 diabetes.
`The major elimination pathway is hydrolysis and 23% of an oral dose
`is excreted as parent in the urine. Kidney is also demonstrated to be
`one of the major organs that contributes to the hydrolysis metabolism.
`The objective of this study was to investigate the influence of renal
`impairment (RI) on the pharmacokinetics (PK) of Vildagliptin.
`METHODS: The PK of Vildagliptin was determined in subjects
`
`with mild (GFR ¼ 50–80mL/min), moderate (GFR ¼ 30–50 mL/min),
`severe (GFR < 30 mL/min) renal impairment (RI), and subjects with
`end stage renal disease (ESRD), compared to subjects with normal
`renal function (HV) matched for age, gender and body weight. Each
`group consisted of 6 subjects. Each subject received a single oral
`dose of 100 mg Vildagliptin. Blood samples were collected to deter-
`mine plasma concentrations of Vildagliptin and its major inactive
`metabolite (LAY151) with LC-MS/MS.
`RESULTS: Compared to HV, exposure to vildagliptin in subjects
`with various degrees of RI and ESRD was increased (Cmax:8–66%;
`AUC0-1:32–134%). There was considerable variability in the Cmax and
`AUC0-1 among groups. Renal clearance (CLR) in HV was 12.4 L/h, and
`a reduction in CLR was observed in subjects with RI, which also corre-
`lated with the GFR (R2 ¼ 0.75). In contrast, the increase in exposure
`(AUC0-1) or CL/F of vildagliptin in RI (average 70% for all subjects
`with RI) did not correlate with the GFR. Exposure to the inactive
`metabolite (LAY151) increased in subjects with RI and the magnitude
`of increase in the exposure was correlated with the severity of RI.
`CONCLUSION: The changes in exposure to vildagliptin does not
`correlate with GFR, and the average increase was less than 2-fold
`when pooled all subjects with RI. Dose adjustment for vildagliptin is
`not considered necessary for subjects with RI, and this is further
`supported by the clinical safety data in long term trials.
`
`PIII-87
`PHARMACOKINETIC COMPARISON OF EXTENDED-AND
`I M M E D I A T E - R E L E A S E O R A L F O R M U L A T I O N S O F
`SIMVASTATIN IN HEALTHY KOREANS. S. Jang, BS, J. Choi,
`MD, PhD, M. Park, MD, K. Kim, MD, PhD, K. Park, PhD, MD,
`Yonsei University College of Medicine, Seoul, Republic of Korea.
`Supported by Brain Korea 21 Project for Medical Science, Yonsei
`University.
`BACKGROUND: An extended-release (ER) formulation of sim-
`vastatin would be expected to have more efficient hepatic uptake by
`sustained delivery of the drug to the liver. This study compared the
`pharmacokinetics of ER and immediate-release (IR) formulations of
`simvastatin after multiple-dose given in healthy subjects.
`METHODS: This was designed as a randomized, multiple-dose,
`parallel study. 29 subjects were randomly assigned to the newly-
`
`developed test-formulation (ER, n ¼ 15) and reference-formulation
`(IR, n ¼ 14) of simvastatin. Each subject received an oral dose of
`
`40 mg every morning for 8 consecutive days. Blood samples were
`collected at 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 13, 17, 24
`hours after dosing on day 1 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 13, 17,
`24, 36 and 48 hours after dosing on day 8. Plasma concentrations were
`analyzed by the LC/MS/MS method, and AUClast (AUC from dosing
`to the last sample time), Cmax, tmax, and t1/2 were determined by a non-
`compartment method using WinNonlin, for both simvastatin and
`simvastatin acid.
`RESULTS: For simvastatin acid, which is the active compound of
`the drug, for day 1, AUClast, Cmax, tmax for ER vs IR formulation were
`on the average 23.2 vs 31.2 ng hr/ml, 2.2 vs 4.5 ng/ml, and 8.7 vs 4.0
`hr, respectively, and for day 8, AUClast, Cmax, tmax, t1/2 for ER vs IR
`formulation were on the average 57.6 vs 41.4 ng hr/ml, 3.4 vs
`
`5.2 ng/ml, 8.4 vs 4.6 hr, 13.1 vs 4.5 hr, respectively. These results
`show that the ER formulation has smaller Cmax, later tmax and longer
`t1/2 compared with the IR formulation, reflecting the ideal charac-
`teristics of slow-release formulation. Although not statistically
`significant (p ¼ 0.2256), AUClast for the ER formulation for day 8
`
`was larger than IR while it was smaller for day 1, which may be caused
`by a parallel design of using different subjects for two groups, yielding
`considerable interindividual variation. The results with simvastatin
`were similar with simvastatin acid.
`CONCLUSION: This study shows that the new ER formulation of
`simvastatin may have ideal characteristics of slow-release formulation
`in most of the noncompartmental pharmacokinetic measures in
`Korean populations. To better evaluate the characteristics of the ER
`formulation, integrated results including more subjects’ kinetic data
`as well as dynamic data may be needed.
`
`PIII-88
`P H A R M A C O K I N E T I C I N T E R A C T I O N S B E T W E E N
`RANOLAZINE AND HMG-CoA REDUCTASE INHIBITORS IN
`VITRO AND IN VIVO. M. Jerling, MD, PhD, CV Therapeutics, Palo
`Alto, CA.
`BACKGROUND/AIMS: Ranolazine is approved by the FDA
`for the treatment of chronic angina in combination with amlodipine,
`beta blockers or nitrates, in patients who have not achieved adequate
`response with other antianginals. It is a CYP3A and P-glycoprotein
`(Pgp) substrate. The kinetic interactions with the HMG-CoA
`reductase inhibitors atorvastatin, cerivastatin, fluvastatin, lovastatin,
`pravastatin and simvastatin was evaluated in vitro, and the interaction
`with simvastatin in healthy volunteers.
`METHODS: HMG-CoA reductase inhibitors were incubated
`with human liver microsomes with quantification of parent compound
`and metabolites. Inhibition constants for ranolazine in these assays
`were determined. In the clinical study 18 healthy volunteers received a
`single 80 mg simvastatin dose on Day 1, ranolazine 1750 mg in the
`morning of Day 3 followed by 1000 mg bid up to Day 9, and
`
`simvastatin 80 mg qd Days 6–9. AUC0-1 after the first simvastatin
`dose and AUCt on Day 9 at steady-state were compared for simvas-
`0
`0
`tatin lactone, simvastatin acid, 6
`-exomethylenesimvastatin, 3
`-hydro-
`xysimvastatin, and HMG-CoA reductase inhibitor activity.
`RESULTS: In the microsomal assays ranolazine weakly inhibited
`CYP450-dependent metabolism of all statins except pravastatin with
`Ki values >20 mM and IC50 values >46 mM. Simvastatin had the
`highest intrinsic clearance. All statins except pravastatin were Pgp
`substrates where the difference between basal-to-apical and apical-to-
`basal transport was lowest for atorvastatin and similar for the other
`statins. Ranolazine inhibited Pgp-mediated transport of all statins
`except pravastatin across MDCK-MDR1 cell monolayers with
`the lowest IC50 value of 39.5 mM for simvastatin. In humans ranola-
`zine increased AUC 1.59-fold for simvastatin lactone (90% CI
`1.37–1.84), 1.39-fold for simvastatin acid (1.14–1.71), 1.32-fold for
`0
`6
`-exomethylenesimvastatin (1.04–1.67), and 1.59-fold for HMG-
`CoA reductase inhibitor activity (1.45–1.74). AUC decreased for
`0
`3
`-hydroxysimvastatin.
`CONCLUSION: In vitro results indicate that simvastatin is the
`statin most sensitive to interactions with ranolazine through CYP3A
`and Pgp inhibition. Ranolazine at
`the maximum labeled dose
`increased AUC for simvastatin compounds and HMG-CoA reductase
`inhibitor activity less than 1.6-fold in humans.
`
`PIII-89
`EARLY MORNING SPOT URINE VOID IS AN IDEAL
`ALTERNATIVE TO 24 HOUR URINE COLLECTION FOR
`DETERMINATION OF BIOMARKERS OF EXPOSURE IN
`ADULT SMOKERS. S. Kapur, S. Mohamadi, R. Muhammad,
`R. Serafin, Q. Liang, S. Feng, H. Roethig, PM USA, Richmond, VA.
`BACKGROUND: Cigarette smoke exposure in adult smokers
`(SM) can be determined by measuring urinary excretion of selected
`smoke constituents or metabolites. Complete 24-hour urine (24H)
`
`CLINICAL PHARMACOLOGY & THERAPEUTICS j VOLUME 81 SUPPLEMENT 1 j MARCH 2007
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