Effect of ezetimibe on serum concentrations of lipid-soluble vitamins

Effect of ezetimibe on serum concentrations of lipid-soluble vitamins

Posters II. Lipid Lowering Drugs/Novel 90 IPI73 BAYESIAN ANALYSIS OF LIPID-LOWERING POTENTIALS OF ROSWASTATIN AND ATORVASTATIN ‘M.D. Anderson Canc...

174KB Sizes 2 Downloads 28 Views

Recommend Documents

No documents
Posters II. Lipid Lowering Drugs/Novel

90

IPI73

BAYESIAN ANALYSIS OF LIPID-LOWERING POTENTIALS OF ROSWASTATIN AND ATORVASTATIN

‘M.D. Anderson Cancer Center: University of Texas, Houston, Texas, USA

D.A. Berry’, S.M. Berry, J. M&&r.

Rosuvastatin (ROS) is a new HMG-CoA reductase inhibitor (statin). A doseranging programme was conducted to evaluate the ability of once-daily doses of double-blind ROS against ‘placebo to modify low-density lipoprotein cholesterol (LDL-C) in hyperlipidaemic patients; open-label atorvastatin (ATV) was included as a benchmark. Initially, a 6-wk, randomised, placebocontrolled, parallel-group, multicentre trial (4522IL/OOO8)was conducted with ROS 1, 2.5, 5, 10, 20 and 40 mg and ATV 10 and 80 mg; ROS dose range was extended to 80 mg in a follow-up trial (4522IL/OO23),yielding a total of 210 patients. Using a standard frequentist statistical analysis (ANOVA), combined results of these trials showed that ROS produced clinically and statistically significant dose-related changes in LDL-C over placebo (-34% [l mg] to -65% [80 mg]; p < 0.001); results for ATV were -44% (10 mg) and -59% (80 mg). To compare the dose-response of ROS with ATV on percentage reduction in LDL-C from baseline we used a Bayesian hierarchical model. Published results from 17 trials (n = 4315 patients) were used to supplement the ATV results; trials were included if patients had recognised hyperlipidaemia but were not severely ill, if they received once-daily ATV doses for 26 wks, and if LDL-C was a primary efficacy measurement. In the Bayesian model, trials were the Iirst level of experimental unit in the hierarchy and patients were the second. Using the Bayesian model, the dose-response relationships were fitted well by a loglinear model for both statins. The ROS response is greater than that of ATV over the range of doses considered [Figure]. The estimated additional reduction in LDL-C with ROS at the same dose of ATV was 14 percentage points (95% probability interval [PI]: 11%17%) at 10 mg and 10 points (95% PI: 7%13%) at 80 mg. These results suggest that ROS is more potent than ATV in lowering LDL-C across the examined dose range.

..... Ato-

-----Upper

6 l.ower 65%

Cl

,RoslNasbwl

-upper

0

10

20

30

40

a Lower

50

Dose (mgldw) PI74 El

60

65% Cl

70

60

ROSWASTATIN IS A HIGH AFFINITY SUBSTRATE OF HEPATIC ORGANIC ANION TRANSPORTER OATP-C

C.D.A. Brown A. Wiidass, K. Bleasby, B. Lauffart. Department of Physiological Sciences, Medical School, University of Newcastle, NE2 4HH, UK Rosuvastatin is a new addition to the statin class of HMG-CoA reductase inhibitors; others include atorvastatin, pravastatin and simvastatin. The effectiveness of these drug molecules in the treatment of hyperlipidemia is thought to arise from inhibition of cholesterol synthesis in the liver. Central to this action, is the efficient uptake of statins into hepatocytes that may be partly mediated by specific transporters located on the basolateral membrane

rosuvastatin and OATP-C was of high aBinity with an apparent Km of 7.3f0.3 uM (n = 6). in addition, cis-inhibition studies of r3H]- rosuvastatin uptake suggested that the aflinity of rosuvastaun for OATP-C was significantly higher than for either pravastatin (30.3f3.2 PM, P < 0.001, n = 6) or simvastatin (43.1f02 yM, P < 0.001, n = 6); the atIinity of the lipophilic statin atorvastatin (2.5f0.3 PM, P > 0.5, n = 6) for OATP-C was not significantly different to that of rosuvastatin. In summary, we conclude that the relatively hydrophilic property of rosuvaatatin together with its high affinity for the liver specific OATP-C suggest that it will be effectively and selectivity delivered to the liver in human subjects. References [l]

HamelinB.A. er nl (1998)TIPS. 19: 2636. [2] TamaiI. et al (2000)B&hem. Biophys.Res. Common.273: 251-260.

IPI?5

EFFECT OF EZETIMIBE ON SERUM CONCENTRATIONS OF LIPID-SOLUBLE VITAMINS

R.H. Knopp’, H. Bays*, C.V Manion3, L.J. Lipka4, L. Melani4, AI? LeBeaut4, R Suresh4, E.P. Veltri4. The Ezetimibe Study Group; ‘Northwest Lipid Research Clinic, Seattle, WA; 2L-MARC Research Center, Louisville, KX 30klahoma Medical Research Foundation, Oklahoma City, OK; 4Schering-Plough Research Institute, Kenilwotih, NJ, USA

Purpose: To determine the effect of the novel selective cholesterol absorption inhibitor ezetimibe (EZE) on serum concentrations of lipid-soluble vitamins. Methods: In a randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of EZE, serum concentrations of vitamins A, D (25-hydroxy vitamin D and 1,25-dihydroxy vitamin D), the two major components of vitamin E (a- and y-tocopherol), and the a- and S-carotenoids were measured at baseline and after 12 weeks of once-daily therapy with either EZE 10 mg (n = 85) or placebo (PBO; n = 28) at a subset of the study centers. Prothrombin time (PT), an indicator of vitamin K, was also assessed. Results: For all subjects, levels of vitamin A, a-tocopherol, and 1,25dihydroxy vitamin D were 3 normal levels at baseline and remained 2 normal after 12 weeks of therapy. All PBO subjects had normal a- and p-carotene levels at baseline and at 12 weeks. a- and p-carotene levels were normal at baseline and at 12 weeks for 82 (97%) and 78 (92%) EZE subjects, respectively; 2 and 4 EZE subjects, respectively, had < normal levels at baseline with 2 and 1, respectively, normalizing at 12 weeks; 1 and 3, respectively, had normal levels at baseline and < normal at 12 weeks. Twenty-three (82%) PBO subjects had normal y-tocopherol levels at baseline and at 12 weeks, 3 had < normal at baseline normalizing at 12 weeks, and 2 had normal levels at baseline and < normal at 12 weeks. Seventy-two (85%) EZE subjects had normal y-tocopherol levels at baseline and at 12 weeks, 10 had < normal levels at baseline with 5 normalizing at 12 weeks, and 3 had normal levels at baseline and < normal at 12 weeks. One PBO and 1 EZE subject had 25-hydroxy vitamin D levels c normal at baseline. Both had normal levels at 12 weeks. PT was unatfected by EZE treatment. Conclusions: EZE does not alter lipid-soluble vitamin status. Ip1761 ROSWASTATIN (20,40 AND 80 MG) REDUCES LDL-C, RAISES HDL-C AND ACHIEVES TREATMENT GOALS MORE EFFECTIVELY THAN ATORVASTATIN (20,40 AND 80 MG) IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLAEMI

PI.

E. Stein’ K.L. Strutt, E. Miller, H. Southworth. For the HeFH Study -3 Group; ‘Metabolic and Atherosclerosis Research Center Cincinnati, Ohio, USA

Recently a family of polyspecilic organic anion transport proteins (OATPs) have been cloned from human tissue [2]. OATP-A and OATP-C are abundantly expressed on the basolateral membrane of hepatocytes [2]. OATPA is expressed widely in tissues whereas OATP-C is predominantly liver specific. To test whether rosuvastatin is a substrate for OATP-A or OATP-C, we measured the uptake of [3H]-rosuvastatin into Xenopus Zaevis oocytes expressing either OATP-A or OATP-C under a number of experimental conditions. Initial experiments showed that the uptake of [3H]-rosuvastatin was 20fold greater in oocytes expressing OATP-C than in either HzO-injected control oocytes or oocytes expressing OATP-A, suggesting that rosuvastatin is a substrate for OATP-C but not for OATP-A. The interaction between

Heterozygous familial hypercholesterolaemia (HeFH) is a common genetic disease leading to premature ischaemic heart disease. Rosuvastatin is a new statin that has shown mean reductions in low-density lipoprotein cholesterol (LDL-C) of up to 65% in a dose-ranging programme. This randomised, double-blind, parallel-group, forced-titration, multicentre trial (4522IL/OO30) in HeFH patients compared the efficacy of rosuvastatin (ROS) with that of atorvastatin (ATV) in modifying lipoproteins and apolipoproteins (Apo) and achieving a target LDL-C goal (~3 mmol/L). (1) Entry criteria included: patients with HeFH (clinical and/or genetic criteria) B 18 yrs with mean fasting LDL-C levels > 5.69 but ~12.93 mmol/L and triglycerides (TG) < 4.52 mmol/L. A 6-wk dietary run-in, preceded a weighted randomisation to

72nd EAS Congress