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					임상약리학 협동과정 석사과정
            박혜윤
   Metabolic pathways most commonly
    involved
   The types of studies commonly used to
    identify human metabolites
   The analysis and interpretation of
    metabolite data
   A summary of clinically pertinent results
    from these studies
   Phase I metabolism
    (oxidation, hydrolysis, reduction)
    CYP 450 family

   Phase II metabolism
    (conjugation)
   Preliminary identification
    in vitro human microsomal or hepatocyte
    system
   Definite identification
    in vivo human study using radiolabeled drug
    1) Single-dose administration by the route of
       administration intended for clinical developmemt
    2) Collection of urine, feces, and blood/plasma until
       two consecutive nonquantifiable samples within a
       matrix are achieved
    3) Radiochemical profiling of samples
    => metabolic profiles & preliminiary assessments of
       systemic exposure( Cmax, AUC, Ae,u, Ae,f )
   Estimation of Cmax, Tmax, AUC, t1/2,Z
    ◦ Using an approach similar to that for parent drug
   t1/2,Z 는 rate-limited step을 반영하고,
    metabolism은 hydrophilicity를 높여서 clearance
    를 증가시키기 때문에, metabolite의 t1/2,Z 는 대체로
    elimination보다는 formation을 반영한다
   Metabolite의 t1/2,Z 는 parent drug의 t1/2,Z 보다 비
    슷하거나 길게 된다
   Metabolite의 t1/2,Z 가 parent drug보다 짧게 측
    정되었다면,
    ◦ sample quantitation의 기간이 metabolite plasma
      concentration-time profile 을 충분히 나타내지 못하
      거나,
    ◦ 데이터의 범위가 부적절했을 가능성

    ◦ One exception>
     Parent drug가 extensive first-pass metabolism를
     거치는 경우는 대부분의 metabolite가 parent drug
     이 systemic circulation에 도달하기 전에 형성된다
   the ratio of metabolite to parent AUC
     (molecular weight adjusted)

   the ratio of AUC p or m to AUC   14C
     (molecular weight adjusted)
    ◦ 특정 metabolite를 major metabolite로 간주할 것인
      지를 결정하는 basis로 이용됨
      (ex. the ratio of AUC m to AUC 14C ≥ 0.25)
Baillie et al, 2002
   Clearance



   Volume of distribution



        F : bioavailability of parent drug
        Fm: fraction of absorbed drug metabolized to metabolite”i”
        Vz,m: terminal VoD for the metabolite
        λz,m: terminal exponential rate constant for the metabolite
   Similar to parent drug
   The major difference: complexity
    ◦ a link btw parent and metabolite
    ◦ a component for formation of metabolite prior to
      the appearance of parent drug in systemic
      circulation
   Parent drug : an open two-compartment model
   One metabolite : formed systemically following an open one-
    compartment model
   Parent drug : an open two-compartment model
   One metabolite : formed presystemically and systemically
    following an open one-compartment model
   대개의 경우, exposure-response relationship 분석시
    parent drug의 혈장농도가 사용된다

   active metabolites가 유의미하게 response에
    기여할 경우
    ◦ metabolite가 parent drug plasma concentration –
      response relationship에서의 residual variability 를
      설명할 수 있다
   Hysteresis
    1. Counterclockwise hysteresis
         혈중약물농도가 최대치에 도달하는 시간보다 effect site에서의
          반응이 최대치에 도달하는 시간이 더 느리게 나타나는 경우
          -> agonism of metabolite
    2. Clockwise hysteresis
         Ex. Tolerance
          ->antagonism of metabolite

    ◦    May be also due to the “delayed” formation of an
         agonistic or antagonistic metabolite
1.   when the observed effect is the sum of response
     at two different sites




        E0 : the baseline effect
        Emax: the maximum change in effect
        C : free or total plasma concentration
        EC50: Emax의 50%에 해당하는 plasma concentration
2.   The observed effect of parent drug in the
     presence of a competitive antagonistic
     metabolite




        IC50,m: inhibition constant for the metabolite
   When the relationship exposure-response
    relationship is not well defined, Cavg is
    actually a more appropriate parameter
    ◦ Comparison across species
◦ Comparison within species
   The formation clearance ass. with each enzymes




    ◦ the amount of a primary metabolite formed :
    total recovery in excreta for the primary metabolite + any
    secondary metabolite(s) formed from the primary metabolite

   If metabolites formed via a single enzyme
       CL f, metabolite”i” via enzyme “n” = CL f, metabolite”i”
   When a metabolite is formed via multiple enzymes ,
    the fractional involvement of each enzyme in the
    formation of a metabolite can be estimated from
    the intrinsic clearance for each enzyme involved

                                                 CL   int   = Vmax/Km
CL    f, metabolite”i” via enzyme “n”   = CL   f, metabolite”i”   * FI



      Vmax,i : the maximum velocity for enzyme”i”
      Km,i : Vmax,i 의 50%에 대응하는 농도
      k : the number of different enzymes
◦ Estimation of formation clearance for each enzyme
  involved in the metabolism of drug X
   For enzyme inhibitors


      I : free (or total) plasma concentration of the inhibitor
      Ki : inhibition constant


   For enzyme inducers
   Changes in a parent drug plasma conc.



   Changes in a metabolite drug plasma conc.




      CLf : formation clearance for the metabolite
      CLm: total clearance for the metabolite
      CL: total clearance for the drug
   Drug X is co-administered
    with an inhibitor of Enzyme 3

   If 100% inhibition of Enzyme
    3-mediated metabolism
    ◦ Total clearance(parent) 25%⇓
    ◦ Parent drug conc. 33% ⇑
   If the active metabolite is
    formed 100% via Enzyme 3
    ◦ No formation
   If the active metabolite is
    formed 100% via Enzyme 2
    ◦ Metabolite conc. 33% ⇑
   “Important” active metabolites
   Estimation of a metabolite’s contribution to
    the overall desired pharmacological activity
    ◦ Relative systemic exposure
      ex. AUC    metabolite   / AUC   parent
    ◦ Relative potencies
      ex. in vitro IC50 parent / IC50 metabolite
    ◦ Relative activity < 10-25% : usually not considered
      clinically important
   Considerations
    ◦ The therapeutic index
    ◦ Potential changes with organ dysfunction
    ◦ Potential changes ass. with metabolic inhibition
      or induction within various subpopulations
   Baillie et al, 2002
   Systemic exposure for each individual
    metabolite relative to parent drug
   Relative potencies for each metabolite
   Pathway/specific enzymes involved with the
    formation of each metabolite
 • Individual relative activity =
       relative potency * AUCm/AUCp
 • Total relative activity

                70%




                             100%



135%
                                    12%
   To estimate the relative importance of each
    metabolite to the observed desired
    response(efficacy)
   To estimate changes in response when
    changes in total clearance occur
   To predict the potential for drug
    interactions mediated via coadministered
    drugs
   Metabolite data
    ◦ Provide more predictive PK & PD relationships
    ◦ Critical to understanding the potential for drug
      interactions mediated both via coadministered
      drugs & for the drug being developed
    ◦ Provide future candidates for subsequent
      development with an improved safety & efficacy
      profile

				
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posted:1/10/2013
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