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					 Drug Transfer into Milk:
Clinical Methods & Issues
    Patrick J. McNamara

     University of Kentucky
      College of Pharmacy
                Outline
   Clinical Study Design Issues
   Models
   Active Transport Issues
   Neonatal Exposure Issues
   Conclusions
      Neonate Exposure via Milk
   SS serum conc.                             neonate
                                            FDserum
    in the neonate
                                 neonate
                                Cserum      neonate
                                            Clsystemic

                                   M       maternal  Vmilk 
                                  F        Cserum          
                      neonate
                     Cserum        S                  
                                               neonate
                                            Clsystemic
   Neonatal factors
          bioavailability (F), volume of milk consumed (V),
           nursing interval () and systemic clearance (Cl)
   Maternal factors
          bioavailability (F), dosing rate, milk to serum
           ratio (M/S) and systemic clearance (Cl)
Clinical Study Design Issues
   Single Time Point vs AUC Approach
   Milk Concentration vs M/S
   M/S & Neonate Concentrations
   Single Time Point vs AUC Approach
       Time dependence in M/S (Wilson, 1985)
                Hydrochlorothiazide, single dose
                Nadolol, multiple dose
       Observation of cimetidine in rabbits
       100                                      20
                                      Serum
                                      Milk
                                                15
       10
 Conc                                         M/S
(ug/ml)                                         10
         1
                                                    5

                                                                    AUCm/AUCs
        .1                                          0
             0      100   200   300     400             0   100    200    300
                      Time (min)                             Time (min)
    Clinical Study Design Issues
   Milk Concentration vs M/S
       Milk concentrations sufficient for exposure est.
       M/S provides greater societal/scientific value
          PK estimate in lactating mother
          Insight into mechanism (passive vs active)

          Overall modeling of drugs (& chemicals) into milk

   M/S & Neonate Concentrations
       Neonatal concentrations - very valuable
       Logistical and ethical issues make these
        studies difficult to carry out
               Models
   Physiochemical Model Predictions
   Animal Models
   Cell Culture Models
Physiochemical Predictive Models
   Unbound distribution model [Rasmussen, 1958
    & 1959; Sisodia and Stowe, 1964]
       pH partition hypothesis
   Membrane diffusion model [Meakin, 1985]
       molecular weight, log P, degree of dissociation
   Phase distribution model [Fleishaker, 1987]
       physicochemical factors & distribution into milk
        components
   log-transformed distribution model [Atkinson
    and Begg, 1990]
       stepwise multiple linear regression
   Genetic neural network model [Agatonovic-
    Kustrin, 2000]
       60 drug compounds - 61 est. structural features
                                                                                                                                      f sun
         Factors
                                                                                M/S due to Ionization                                    un
                                                                                                                                      fm
                                                                       4



    Influencing M/S
                                                                                                                                  Cations: Milk pH=6.8
                                                                       3                                                          Cations: Milk pH=7.2




                                                               m
                                                                                                                                  Anions: Milk pH=6.8




                                                               /f
                                                                       2                                                          Anions: Milk pH=7.2




                                                               s
                                                               f
                                   un
                  M   f                      fs W
                    
                                                                       1
                                  s
                                   un
                  S   f           m          f m Sk                    0
                                                                           0     2        4       6         8       10       12     14
                                                                                                      pKa


                                            fs
                M/S due to Protein Binding                                      M/S due to Fat Partitioning
                                           fm
          1.0                                                         20

          0.8
                                                                      15
fs / fm




                                                               W/Sk
          0.6
                                                  M to S              10
          0.4                                  Protein Ratio
                                                      0.05                                                                                    fu = .1
          0.2                                                          5
                                                      0.5                                                                                     fu = .001
          0.0                                                          0
                0.0   0.2   0.4        0.6    0.8    1.0                   -3   -2   -1       0       1         2        3    4      5        6
                                  fs                                                                  Log D
               Physiochemical Model Prediction
                                                                              Agatonovic-Kustrin,
                       Log Phase
                                                                              Analytica Chimica Acta 418:181 (2000)
                       Model 26
               6                                                    10.0
                       Model 18
               5
Observed M/P




                                                     Observed M/P
               4

               3                                                     1.0

               2

               1

               0                                                     0.1
                   0   1     2     3    4    5   6                      0.1                 1.0               10.0
                             Predicted M/P                                            Predicted M/P

                          Good overall prediction
                          Obtained with no experimental parameters (e.g.,
                           binding, partitioning, etc)
                          Data analysis still only as good as the data sets used
                           to generate the relationships
                                                                                                         Flux of 14C-Nitrofurantoin in

    Cell Culture                                                                               250
                                                                                                                  CIT3 Model

                                                                                                                                                        B to A


      Models




                                                                          Transferred (pmol)
                                                                                               200                                                      B to A, NF




                                                                            Nitrofurantoin
                                                                                                                                                        A to B
                                                                                               150                                                      A to B, NF

                                                                                               100

   Nitrofurantoin Flux                                                                        50


    across CIT3 Cells                                                                            0
                                                                                                     0         20   40     60    80    100   120
                                                                                                                    Time (minutes)



                                         14C-Nitrofurantoin
                                                          Transport                                                      Influence of Dipyridamole on
                                           across CIT3 Monolayers                                                          Nitrofurantoin M/S in Rats
                         90
    Nitrofurantoin Transfer




                               Dipyridamole
       Ratio cm/hr*10^3




                                                                                                           40
                         80

                         70                                                                                30

                         60                                                                              M/S
                                                                                                           20                                 *
                         50                                     Nitrofurantoin
                                                                                                           10
                         40
                              -2    -1      0       1     2     3     4
                                                                                                               0
                                          Log [Ligand(uM)]                                                               Control         Treatment
                                       Animal Models
   Nitrofurantoin M/S in Rats [Kari, 1997]
                  Nitrofurantoin in milk and plasma of 10-day lactating
                   rats gavage-fed 50mg/kg nitrofurantoin

                          100
        Concentration, ug/ml




                               10
                                                           M/P predicted = 0.31
                                                           M/P observed = 23.1
                               1


                               0.1
                                   0   100     200   300
                                         Time, min
                   M/S          Predicted
                                          M f sun f s W
                                               un
                Prediction                S     f m f m Sk
                                   M Css ,milk     AUCss ,milk
                         Observed             or
                                   S Css ,serum AUCss ,serum
                          Rabbit      100
                                                          Rat                             Human
           10                                        NF         CM              10
                                                                                              CM
                                                                                         NF
                                                                 RN
                                       10                 AC
M/S Obs




            1

                                        1                                        1

          0.1
                                       0.1



          0.01                        0.01                                      0.1
             0.01   0.1          1   10 0.01   0.1         1         10   100      0.1        1      10
                          M/S Pred                    M/S Pred                            M/S Pred
    Active Transport Issues
   Clinical evidence
   Carriers
   Substrate / Drug Database
               Cimetidine in Human Milk
                                                                                              (Oo, et al, 1995)
 CONC (ug/ml)
100                                      100                                        100
                                                                   Serum
                                                                   Milk
10                                       10                                         10


 1                                        1                                          1


 .1                                       .1                                         .1

          100 mg                                   600 mg                                     1200 mg
.01                                      .01                                        .01
      0    5   10    15   20   25   30         0    5   10    15    20    25   30         0    5   10   15   20   25   30
                   Time (h)                                 Time (h)                                Time (h)

                                            Parameter
                      Dose (mg)    100        600       1200
                    MRTs (h)    3.8 (1.0) 3.6 (1.0) 3.7 (0.9)
                    MRTm (h) 6.8 (1.5) 6.8 (1.3) 6.8 (1.3)
                    M/S obs     5.7 (1.8) 5.8 (1.2) 5.8 (1.4)
                    M/S pred    1.0 (0.2) -           -
Nitrofurantoin
                                                        3.5
                                                                                                milk




                                Concentration (g/ml)
                                                        3.0                                     serum




                                   Nitrofurantoin
in Human Milk                                           2.5

                                                        2.0

                                                        1.5

                                                        1.0

                                                        0.5
 (Gerk, et al, 2001)
                                                        0.0
                                                              0   2       4       6     8    10    12
                                                                              Time (hours)




                                                         Parameter
               Subject    1    2                          3           4        Mean SD
            M/S pred 0.25 0.27 0.34 0.24                                        0.28     0.05
            M/S obs      4.34 5.25 10.14 5.04                                   6.19     2.66
                  Transporters
   Candidate genes expressed (RT-PCR) in cells
    isolated from human milk (Ito and McNamara
    Labs)

Positive   OCT1   OCT3   PGT   OCTN2 OATP-B OATP-D
           CNT1   ENT1   SVCT1 MDR1 MRP2 MRP5

Negative   OCT2   OCTN1 OAT1   OATP-A ENT2    MRP3

   Protein Expression – Structural studies
   Functional studies
   Substrate / Drug Database
    Neonatal Exposure Issues
   Route of Drug Clearance
   Nursing vs Dosing Interval
   Mechanism of Toxicity
   Lactation vs Developmental Stage
    Route of Drug Clearance
   Developmental patterns vary
   GFR normalized to body weight
    appears comparable to adult
   Metabolic pathways vary
       CYP-450 and most Phase II reactions are
        inefficient at birth
       Sulfate conjugation is the exception
Developmental Expression of
     Cytochrome P450
                 50
% of Adult In Vitro


                                                                       1A2
                 40                                                    2C
    Activity



                                                                       2D6
                 30
                                                                       2E1
                 20
                                                                       3A4

                 10

                      0
                          1            10                 100

                                     Age, Days
Stage                         Isozyme
Fetal                         2E1
                                                 [Vieira, 1996;Treluyer, 1997; Sonnier,
Early Neonatal                2D6, 1A2, 3A4
                                                 1998]
Neonatal                      2C
  Nursing vs
Dosing Interval




                                Conc
   Chronic vs Acute
    Dosing
    Generalizations
                                 0     4   8      12     16   20   24
                                              Time, h

       Longer t 1/2 longer 
       Longer  less able to
        “control” exposure      Conc




                                  0    4   8      12     16   20   24
                                               Time, h
                                                                             Cls,        Cls,       Dose      Conc
            Neonatal                                               M/S      mother
                                                                           ml/min/kg
                                                                                       neonate
                                                                                       ml/min/kg
                                                                                                    Ratio
                                                                                                    % of
                                                                                                              Ratio
                                                                                                               % of

            Exposure
                                                                                                   Maternal   Maternal

                                                                    10        20          20       0.10% 5.56%

                                      S ) V                       1        20          20       0.01% 0.56%
                            F maternal M                   
                                                    milk
                neonate
DoseRate
                                                                 0.1       20          20       0.001% 0.06%
         maternal                      maternal
DoseRate                             Clsystemic                              Cls,        Cls,       Dose      Conc
                                                                   M/S      mother     neonate      Ratio     Ratio

C neonate                           S ) V
                F neonate F maternal M   
                                         
                                                  milk     
                                                          
                                                           
                                                                           ml/min/kg   ml/min/kg    % of
                                                                                                   Maternal
                                                                                                               % of
                                                                                                              Maternal
  ss
 maternal
                                neonate
Css                            Clsystemic                            1        20          20       0.01% 0.56%
                                                                     1        2           2        0.10% 5.56%
       Higher exposure
                                                                             Cls,        Cls,       Dose      Conc
                Higher M/S                                        M/S      mother     neonate      Ratio     Ratio
                Lower Cls                                                 ml/min/kg   ml/min/kg    % of       % of
                                                                                                   Maternal   Maternal
                         Maternal
                         Neonate                                    1         2          2        0.09%      5.56%
                                                                     1         2         0.2       0.09%      55.6%
                Lower First Pass?                               assuming a milk volume consumption of 800 /ml day
                                                                           or 0.11 ml/kg/min for a 5 kg infant
                      Conclusions
   Diffusion accounts for appearance of most drugs
    in milk
       M/S can be predicted
       unbound, cationic lipophilic drugs favor higher M/S

   Transporter gene expression in lactating
    mammary epithelial cells – limited number of
    drugs

   Neonate exposure assessment should include:
       Maternal clearance: higher clearance less exposure
       Neonatal clearance: lower clearance more exposure
       Active metabolites should be considered

				
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posted:10/19/2011
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