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1、.,Dvidas Arquivo II International Workshop of Vascular Biology Site ,A Importncia da Farmacologia Clnica no desenvolvimento de novos conceitos para velhos produtos,Simvastatin:therapeutic improvement by modified release dosage form ?,Statines: improvement possible ?,Efficacious, but not without prob
2、lems therapeutic benefit proven in numerous studies AEs: gastro-intestinal disorders, myopathies critical risk factor: rhabdomyolysis,Pharmacodynamic/clinical background efficacy: determined by dose/extent of BA optimum efficacy requires sufficiently high concentrations at the site of action safety:
3、 primarily concentration determined goal: low concentrations in blood stream,Statins: properties,Pharmacokinetics significant differences in absorption: from 30 % (lovastatin) up to 98 % (fluvastatin) extensive first-pass metabolism (gut, liver) relatively low (absolute) bioavailability,Advantage: s
4、ubstance specific targeting selective/active uptake into hepatocytes predominant excretion via bile goal: high concentrations in the liver . at the same time low systemic exposure,Undesired side effects controllable ?,Problem: non-linear pharmacokinetics capacity of uptake into the liver limited fir
5、st-pass-metabolism (gut, liver) saturable over-proportional increase of BA with rising doses,Dose proportionality historical comparison healthy subjects (n=24) single dose, fasted estimation of AUC and Cmax in plasma,ng/mlh,Rationale for product optimisation,Clinical development rationale pharmacoki
6、netic/biopharmaceutical targets sufficiently high hepatic bioavailability reduced systemic bioavailability/exposure,Goal: Improvement of risk/benefit-relationship better efficacy not needed, . . but reduction of undesired side effects significantly lower concentrations in plasma,question: achievable
7、 with modified release form ?,Simvastatin candidate for MR ?,Compound properties pro-drug and active metabolite (-hydroxy acid) very low (5 %) systemic (bio)availability extensive first-pass metabolism incomplete (ca. 30 %) oral absorption (?),Essential questions for MR product development localisat
8、ion of first-pass metabolism (liver/gut) ? substrate for efflux transporter P-gp ? sufficient absorption throughout the entire GI tract (absorption window) ?,First-pass: hepatic or intestinal ?,Indicator grapefruit juice inhibits CYP 3A4only in gut wall 16-fold increase of BA,P-gp substrate ? invest
9、igations, e.g.in Caco-2 cell systems simvastatin is aLP (ab) compound and P-gp substrate,Development of MR dosage form,Dose proportionality,Bioavailability,Clinical surrogate study: 60 mg QPM,Study medication test: simvastatin modified release tablets, 60 mg reference: Zocor IR tablets, 3x20 mg,Stud
10、y conditions changeover, 28 subjects (18-65 y) patients with primary dyslipidaemia fasting LDL: 130-250 mg/dl fasting TG: 350 mg/dl after ambulatory dietary run-in of 4 weeks primary: LDL; second.: HDL, total cholesterol, TG,Primary parameter: LDL-cholesterol,Conclusion superimposable effect vs. tim
11、e curves therapeutic equivalence proven (n=28!),Mean (n=28) effect curves,diet,Outcome of proof of concept study,Findings (for MR preparation) significantly lower systemic exposure (Cmax) nevertheless identical (equivalent) efficacy concept perfectly confirmed,Potential benefit of MR form: risk redu
12、ction certain trend towards less frequent AEs better safety profile could not be proven so far however, improved safety margin very likely,Our conclusion(s) proof of concept successful useful MR form (the flatter the better),Open questions modified release dosage form/formulation further reduction o
13、f systemic exposure/extent of BA ?,efficacy of the MR form equivalent efficacy even with lower dosage ?,AristoCon: 2005: Simvastatin project,.,.,Synthesis and structures of bis-phosphocholine compounds. Synthesis and structure of bis(phosphocholine)-hexane.,.,Synthesis and structures of bis-phosphoc
14、holine compounds. Structures of bis(phosphocholine) compounds with different linkers. See Supplementary Information for details.,.,Clinical treatment with a CRP inhibitor could be started immediately upon admission to hospital following acute myocardial infarction this would precede the acute phase
15、CRP response, which starts about 6 h after onset of pain and peaks at about 50 h (refs 8, 9).,.,Structure of the complex of CRP with 1,6-bis(phosphocholine)-hexane.,.,Structure of the complex of CRP with 1,6-bis(phosphocholine)-hexane,.,Structure of the complex of CRP with 1,6-bis(phosphocholine)-hexane,
