therapeutic improvement by modified release dosage form通过改进释放剂型的治疗进展

1、.Dvidas Arquivo II International Workshop of Vascular II International Workshop of Vascular BiologyBiologySA Importncia da Farmacologia Clnica no desenvolvimento de novos conceitos para velhos produtosSimvastatin:therapeutic improvement by modified release dosage form ?Statines: improvement possible

2、 ?Efficacious, but not without problemsntherapeutic benefit proven in numerous studiesnAEs: gastro-intestinal disorders, myopathies critical risk factor: rhabdomyolysisPharmacodynamic/clinical backgroundnefficacy: determined by dose/extent of BA optimum efficacy requires sufficiently high concentrat

3、ions at the site of actionnsafety: primarily concentration determined goal: low concentrations in blood streamSimvastatin: therapeutic improvement by modified release dosage form ?Statins: propertiesPharmacokineticsnsignificant differences in absorption: from 30 % (lovastatin) up to 98 % (fluvastati

4、n)nextensive first-pass metabolism (gut, liver) relatively low (absolute) bioavailabilityAdvantage: substance specific targetingnselective/active uptake into hepatocytesnpredominant excretion via bile goal: high concentrations in the liver . at the same time low systemic exposureSimvastatin: therape

5、utic improvement by modified release dosage form ?Undesired side effects controllable ?Problem: non-linear pharmacokineticsncapacity of uptake into the liver limitednfirst-pass-metabolism (gut, liver) saturable over-proportional increase of BA with rising dosesDose proportionalitynhistorical compari

6、sonnhealthy subjects (n=24)nsingle dose, fastednestimation of AUC and Cmax in plasmaSimvastatin: therapeutic improvement by modified release dosage form ?01002003004005002 mg10 mg20 mg40 mgAUCCmaxng/mlhRationale for product optimisationClinical development rationalenpharmacokinetic/biopharmaceutical

7、 targetsnsufficiently high hepatic bioavailabilitynreduced systemic bioavailability/exposureGoal: Improvement of risk/benefit-relationshipnbetter efficacy not needed, .n. but reduction of undesired side effectsn significantly lower concentrations in plasma nquestion: achievable with modified release

8、 form ?Simvastatin: therapeutic improvement by modified release dosage form ?Simvastatin candidate for MR ?Compound propertiesnpro-drug and active metabolite (-hydroxy acid)nvery low (5 %) systemic (bio)availabilitynextensive first-pass metabolismnincomplete (ca. 30 %) oral absorption (?)Essential q

9、uestions for MR product developmentnlocalisation of first-pass metabolism (liver/gut) ?nsubstrate for efflux transporter P-gp ?nsufficient absorption throughout the entire GI tract (absorption window) ?Simvastatin: therapeutic improvement by modified release dosage form ?CYP 3A4luminal siteintestine

10、portal veinstomachCYP 3A4liver30%15%15%First-pass: hepatic or intestinal ?felodipine100%metaboliteIndicator grapefruit juiceninhibits CYP 3A4only in gut walln16-fold increase of BAP-gp substrate ?ninvestigations, e.g.in Caco-2 cell systemsnsimvastatin is aLP (ab) compound and P-gp substrateSimvastat

11、in: therapeutic improvement by modified release dosage form ?Development of MR dosage formDose proportionality 0300600900120006121824 80 mg (AUC: 334)160 mg (AUC: 876)320 mg (AUC: 1055)640 mg (AUC: 6966)ng/mlhMR form:nsignificantly lower BA (AUC and Cmax)nsaturation only with much higher doses Bioav

12、ailability 0300600900120003691240+40 mg IR80 mg ERng/mlhSimvastatin: therapeutic improvement by modified release dosage form ?Clinical surrogate study: 60 mg QPMStudy medication ntest: simvastatin modified release tablets, 60 mgnreference: Zocor IR tablets, 3x20 mgStudy conditionsnchangeover, 28 sub

13、jects (18-65 y)npatients with primary dyslipidaemia nfasting LDL: 130-250 mg/dlnfasting TG: 350 mg/dln after ambulatory dietary run-in of 4 weeksnprimary: LDL; second.: HDL, total cholesterol, TGSimvastatin: therapeutic improvement by modified release dosage form ?Primary parameter: LDL-cholesterolC

14、onclusion nsuperimposable effect vs. time curves n therapeutic equivalence proven (n=28!)Statistics88-10499Emaxconf. intervalpoint estim.85-10499EkumMean (n=28) effect curves5075100125150175200-1012345time (weeks)LDL cholesterol (mg/dl)testreferenceactive treatmentdietSimvastatin: therapeutic improv

15、ement by modified release dosage form ?Outcome of proof of concept studyFindings (for MR preparation)nsignificantly lower systemic exposure (Cmax)nnevertheless identical (equivalent) efficacy concept perfectly confirmed Potential benefit of MR form: risk reductionncertain trend towards less frequent

16、 AEs nbetter safety profile could not be proven so far however, improved safety margin very likelySimvastatin: therapeutic improvement by modified release dosage form ?Our conclusion(s)nproof of concept successfulnuseful MR form (the flatter the better)Open questionsnmodified release dosage form/for

17、mulationnfurther reduction of systemic exposure/extent of BA ?nefficacy of the MR formnequivalent efficacy even with lower dosage ?Simvastatin: therapeutic improvement by modified release dosage form ?AristoCon: 2005: Simvastatin project.Synthesis and structures of bis-phosphocholine compounds. Synt

18、hesis and structure of bis(phosphocholine)-hexane. .Synthesis and structures of bis-phosphocholine 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 CRP respo