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Pharmacokinetics and Therapeutic Drug Monitoring TDM Potential

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Pharmacokinetics and Therapeutic Drug Monitoring TDM Potential Powered By Docstoc
					Pharmacokinetics and Therapeutic
    Drug Monitoring (TDM):

Potential applications for developed and
          developing countries


    David M. Burger, PharmD, PhD
           UMC Nijmegen
           The Netherlands
     What is the rationale for TDM
 Current anti-HIV therapy is highly potent, but
  may become ineffective because of:
      toxicity
      low drug levels
      drug-drug interactions
      non-adherence
      resistance
 TDM may give solutions for these problems,
  thereby improving clinical outcome
   Review: “The role of TDM in treatment of HIV infection” by
    Back et al. British Journal of Clinical Pharmacology 2001; 51:
    301-8.
International Interlaboratory QC program
                                     (Aarnoutse et al., 8th CROI, Chicago 2001)

                      0,40



                      0,35
                                                                                     +/- 20% of nominal
                                                                                     concentration

                      0,30
  NFV concentration




                      0,25



                      0,20



                      0,15



                      0,10



                      0,05



                      0,00
                             1   2   3   4   5   6   7   8   9   10   11   12   13    14    15    16      17

                                                         Lab number


                                             NFV = 0.24 mg/L
                                             Nephrotoxicity and IDV
                                  10,0
                                                concentrations
                                                                                                 population data IDV
IDV plasma concentration (mg/l)




                                                                                                 800mg q8h


                                                                                                 patients with toxicity


                                   1,0




                                   0,1
                                         0   1   2   3          4          5   6      7      8

                                                     time post ingestion (h)


                                                                       Dieleman, AIDS 1999
                                           Nevirapine PK-PD
                               1



                              0,8
probability of VL < 20 c/mL




                              0,6                                                       [NVP] > 3.4 mg/L


                              0,4

                                                                   [NVP] < 3.4 mg/L
                              0,2

                                        P=0.02
                               0
                                    0            4            8            12             16       20      24
                                                             time after start therapy (weeks)


                                                     Veldkamp et al. AIDS 2001; 15: 1089-95
                           Efavirenz PK-PD
                              (Marzolini et al. AIDS 2001)
                  100



                   80
Probability (%)




                                                                % viral response
                   60                                           % CNS toxicity



                   40



                   20



                    0
                        < 1 (n=19)          1-4 (n=180)        > 4 (n=27)

                                     EFV plasma conc. (mg/L)
    Interventions and TDM (1)
   Six patients on IDV 800mg TID & Urological complaints
   IDV concentration ratios ranged 2.25 - 11.5
   IDV dose reduced to 600mg TID
   IDV concentration ratio ranged 0.63 - 1.37
   All patients remained free of urological complaints
   All patients continued to have VL < 500 copies/mL




               Dieleman et al. AIDS 1999
    Interventions and TDM (2)
   18 patients on NFV 1250mg BID & low drug levels
   Dose increase to 1500mg BID

        2, 5




        2, 0




        1, 5




        1, 0




         ,5




        0, 0

                 12 50 m g BID    1 50 0 m g BID
                   ATHENA: NFV
(Burger et al., 2nd PK Workshop, Noordwijk 2001 & 1st IAS, Buenos Aires, 2001)



         92 treatment-naive patients were randomized to a
          TDM-report group or a TDM-blind group
         All patients were using NFV 1250mg q12h + 2-3
          additional antiretroviral agents
         NFV plasma levels were determined at regular
          visits during 1 year of follow-up
         TDM rules:
             1st CR < 0.90: discuss intake with food
             2nd CR < 0.90: increase dose to 1500mg q12h
             3rd CR < 0.90: increase dose to 1750mg q12h or add low-
              dose RTV
                                      ATHENA: NFV
(Burger et al., 2nd PK Workshop, Noordwijk 2001 & 1st IAS, Buenos Aires, 2001)


                                     Discontinuations of Nelfinavir 1250mg BID
                40
                               in treatment-naive patients during 1 year of follow-up
                     P = 0.01                                                    TDM Report
                35

                                                                                 TDM Blind
                30



                25
% of patients




                20                    P = 0.02
                15



                10



                5



                0
                     overall           failure         patient        toxicity                unknown
                                                      request
                    ATHENA: NFV
(Burger et al., 2nd PK Workshop, Noordwijk 2001 & 1st IAS, Buenos Aires, 2001)


           Proportion of patients with successful response (VL < 500) on Nelfinavir
                                 1250mg BID (NC=F analysis)
  1
                                                                                TDM Report
 0,8
                                                                                TDM Blind
                               P = 0.06
 0,6

                                                     P = 0.03
 0,4


 0,2


  0
             0                       6                  12

                         time after start (months)
                                   % Patients with suboptimal nelfinavir level
          1s




                               0
                                    10
                                         20
                                              30
                                                   40
                                                        50
                                                             60
                                                                  70
                                                                                       80
                                                                                            90
                                                                                                 100
               ts
                    am
                         pl
                           e
1s
     tI
          nt
            er
              ve
                 nt
                   io
2n                    n
  d
      In
        te
           rv
             en
               tio
                   n
3r
                                                                       TDM group



  d
      In
        te
           rv
             en
               tio
                   n




          1s
               ts
                    am
                         pl
                           e
      2n
        d
                sa
                  m
                         pl
                           e
      3r
        d
                sa
                  m
                      pl
                        e
          4t
            h
                                                                       Control group




                sa
                  m
                         pl
                                                                                                       Effect of interventions in TDM group




                           e
                    ATHENA: IDV
(Burger et al., 2nd PK Workshop, Noordwijk 2001 & 1st IAS, Buenos Aires, 2001)

    TDM rules for IDV concentration ratio:
        IDV 800mg tid: 0.75 - 2.0
        IDV/rtv 800/100mg bid: 0.25 - 2.0
        IDV/rtv 400/400mg bid: > 0.50
    55 Patients were randomized (28 in TDM group; 27
     in control group)
        IDV 800mg tid: 16
        IDV/rtv 800/100mg bid: 20
        IDV/rtv 400/400mg bid: 19
    Follow-up of 1 year
                                             Discontinuations of Indinavir
                                 in treatment-naive patients during 1 year of follow-up
                60


                                                                                  TDM Report
                      P=0.07
                50
                                                                                  TDM Blind


                40
% of patients




                                                                                          P=0.17
                30


                                                                  P=0.21
                20




                10




                0
                     overall                failure                 patient                   toxicity
                                                                   request


                     Burger et al. 2nd PK workshop, Noordwijk, 2001& 1st IAS, Buenos Aires, 2001
                                     Discontinuation of IDV because of toxicity

                70
                                                                                  TDM Report
                       P=0.03
                60
                                                                                  TDM Blind

                50
% of patients




                                                                                     P=0.03
                40

                                         P=0.11                P=0.54
                30


                20


                10


                 0
                      800 tid           800/100 bid           400/400 bid           800 tid +
                                                                                   800/100 bid
                                                                                    combined
                N=       16                 20                   19                    36
                     Burger et al. 2nd PK workshop, Noordwijk, 2001& 1st IAS, Buenos Aires, 2001
             Proportion of patients with successful response (VL < 500) on Indinavir
                                         (NC = F analysis)

1,0

0,8
                                    P=0.06
0,6

0,4                        TDM Report
                                                                      P=0.04
0,2                        TDM Blind

0,0
                 0                             6                         12
                                    time after start (months)



      Burger et al. 2nd PK workshop, Noordwijk, 2001& 1st IAS, Buenos Aires, 2001
PharmAdapt: Proportion of patients with
plasma HIV-RNA below level of quantification
at W12 (PI-treated patients)

      %
 60


 50                                              48.5             52.3
                                                                  44.6
 40                                                     45.2
                        37.5
 30                                 34.1

 20


 10


  0
          Ba s elin e          W4                 W8           W1 2
                                     T DM   C on trol
                 PharmAdapt:
               Study limitations

   Interim analysis
   Limited number of possible interventions
   Choice of cutoffs for resistant viruses
   Turnaround time and delay for action and measure
   Systematic use of booster
   Monitoring of 1 drug in a multidrug combination
   Decision based on only one PI dosage
   Decision based on Ctrough
   Performance of genotypic algorythm
   Heterogenity of PI used
   Patients compliance to treatment
   Physicians adherence to genotypic/pharmacologic
    recommendations
           TDM for compliance
              monitoring
 „Contra‟
    PIs have short t1/2: only recent (non)-compliance will be detected
    Other causes for „abnormal‟ plasma levels


 Pro
    Objective method / Easy / Included in TDM
    Direct relation non-compliance, plasma level and effect
    Different kinds of non-compliance expressed in plasma level
    (ingestion, timing, food)
                                    Compliance Monitoring Indinavir
                       100,00
                                                                                population curve


                                                                                low er limit, ratio 0.23;
                        10,00                                                   upper limit, ratio 3.3
concentration (mg/l)




                                                                                actually last ingestion
                                                                                missed

                         1,00                                                   actual ingestion short
                                                                                before visit



                         0,10




                         0,01
                                0        2              4               6   8

                                             time after ingestion (h)
             Limitations of TDM
   Highly dependent on information from patient
   Only reflection of actual situation (+ few days before visit)
   We are measuring only one component of the combination
    regimen
   PIs are highly bound to protein; protein levels may vary within
    and between patients
   Virus is present in more compartments than the plasma
   No information of the virus
   Optimal frequency of sampling unknown
      example: wk 4, 8, 12, then every 12 weeks
        What can you do with 1,000 Euro?
                  50




                  40
number of tests




                  30




                  20




                  10




                   0

                       TDM   Viral load   Genotypic resistance
What about pharmacokinetics and
 TDM in developing countries?

 Topics relevant for local situation:
    minimum effective dose (saves money)
    bio-equivalence studies of generic products
    racial differences in PK
    influence of low body weight
    co-infections (TB)
    herbal products
8th CROI, Chicago 2001, poster 830

   Both Short-Term Virological Efficacy
   and Drug-Associated Nephrotoxicity
         Are Related to Indinavir
   Pharmacokinetics in HIV-1-infected
              Thai Patients
          D. Burger*a, M. Felderhof b, P. Phanupakc, C. Duncombec,d, A.
       Mahanontharitc , W. Yeamwanichnunc, S. Ubolyamc, D. Cooperd, M.
                            Steke, J. Langeb, P. Reissb
        a Univ. Med. Ctr. Nijmegen, b Acad. Med. Ctr/IATEC, Amsterdam,

          the Netherlands, c HIV-NAT, Thai Red Cross AIDS Res. Ctr.,
        Bangkok, Thailand, d NCHECR, Sydney, Australia, e Merck & Co,
                          Whitehouse Station, NJ, USA
IDV plasma concentration (medians) vs time curves
                                  10


                                   9
                                                                                             Caucasian

                                   8                                                         Thai
IDV plasma concentration (mg/L)




                                   7


                                   6


                                   5


                                   4


                                   3


                                   2


                                   1


                                   0
                                       0   1   2         3             4             5   6      7        8
                                                             time after intake (h)




                                                   Burger et al. CROI 2001
                                  AUC vs body weight (IDV 800mg TID)
                                        R-squared 0.19; p=0.06
                   45

                   40

                   35
IDV AUC (mg/L.h)




                   30

                   25

                   20

                   15

                   10

                    5

                    0
                        40   45   50    55    60      65      70   75   80   85   90
                                               Body weight (kg)



                                       Burger et al. CROI 2001
                                 Cmax vs. body weight (IDV 800mg TID)
                  16
                                       R-squared: 0.27; p=0.02

                  14


                  12
IDV Cmax (mg/L)




                  10


                   8


                   6


                   4


                   2


                   0
                       40   45     50   55      60      65      70   75   80   85   90
                                                 Body weight (kg)


                                             Burger et al. CROI 2001
    IDV/rtv BID in Thai patients
   12-h PK curve recorded 4 weeks after start of
    treatment in 17 patients
   Nephrotoxicity monitored during 12 weeks:
      flank pain
      hematuria
      increase in serum creatinine > 25%
   4/17 (24%) had signs of nephrotoxicity
   PK breakpoints:
      AUC 60 mg/L.h: 8 vs 60% (p=0.022)
      Cmax 13 mg/L: 8 vs 60% (p=0.022)
      Cmin: no breakpoint



           Burger et al. 2nd International Workshop on Clinical
           Pharmacology of HIV Therapy, Noordwijk, 2001
                        Cmax vs body weight (IDV/rtv 800/100 BID)
              20


              18


              16


              14


              12
Cmax (mg/L)




              10


              8


              6


              4


              2


              0
                   40   45         50         55          60           65    70     75   80
                                                    body weight (kg)



                             Burger et al. 2nd International Workshop on Clinical
                             Pharmacology of HIV Therapy, Noordwijk, 2001
      HIVNAT 001 Amd. 10:
     SQV bid +/- itraconazole

 Itraconazole is (like RTV) a strong
  inhibitor of CYP3A and PgP
 Itraconazole is less expensive than
  RTV
 Pharmacokinetic studies have shown
  that itraconazole can boost SQV levels
      HIVNAT 001 Amd. 10:
     SQV bid +/- itraconazole

 Patients were using SQV 1400mg bid + 2
  NRTIs and had VL < 50 copies/mL
 12h PK
 randomization to itraconazole 100mg +
  either SQV 800mg or 1200mg bid
 12h PK


           Cardiello et al. CROI 2002
                                      HIVNAT 001 Amd. 10:
                                     SQV bid +/- itraconazole
                          1.60



                          1.40

                                                                           1400mg BID
                                                                           800mg BID + ITRA 100mg
SQV plasma conc. (mg/L)




                          1.20
                                                                           1200mg BID + ITRA



                          1.00



                          0.80



                          0.60



                          0.40



                          0.20



                          0.00
                                 0   2    4             6              8                10          12

                                              time after intake (hr)
                                                                           Cardiello et al. CROI 2002
             HIVNAT 001.4
Pharmacokinetics of once-daily SQV-SGC and
SQV-HGC boosted with ritonavir in HIV-1 +
Thai patients

Peter Cardiello, Tarkika Monhaphol, Apicha Mahanontharit,
Rolf van Heeswijk, David Burger, Kiat Ruxrungtham,
Joep Lange, David Cooper, Praphan Phanupak

HIVNAT, Thai Red Cross AIDS Research Centre, Bangkok
    Rationale for studying
bioequivalence FTV/r vs. INV/r

 All initial studies with SQV plus low-dose
  ritonavir have been conducted with FTV
 INV may have some advantages over FTV
  when combined with low-dose ritonavir:
     less expensive (?)
     no need for refrigeration
     smaller pill size
     better tolerability (no capmul)
           Study design
  14 Thai HIV-1 + patients
  All patients were using SQV/r 1600/100mg
   once-daily + 2 NRTIs > 48 weeks
  All patients had VL < 50 c/mL and CD4 >
   350 cells/mm3



FTV     INV 1 week    FTV 1 week       FTV


                 PK            PK
                                     Results (medians)
                           10


                                                                            SQV - HGC



                                                                            SQ - SGC
SQV plasma level (mg/L)




                            1




                           0.1




                          0.01
                                 0   4    8            12             16   20           24
                                              time after intake (h)
      Results (medians)

             Inv     Ftv
AUC0-24     49.95   35.48   mg/L.h
CL/kg        0.65    0.89   L/h/kg
Thalf        3.72    3.63       h
Vd/kg        4.11    3.74     L/kg
Cmax         6.30    5.27    mg/L
Tmax         4.00    3.00       h
Cmin         0.21    0.07    mg/L
                      Results: Cmin
                 1
                       INV       FTV




                0.1               MEC = 0.1 mg/L
Cmin (mg/L)




                                  MEC = 0.05 mg/L




               0.01




              0.001
                                Results: Cmin
                                     INV        FTV
                10




                 1
Cmin (mg/L)




                0.1                               MEC = 0.1 mg/L

                                                  MEC = 0.05 mg/L




                      2 subjects < 0.05         4 subjects < 0.05
               0.01




              0.001
       PK lab at HIVNAT

 Training of technicians in the Netherlands
  and in Bangkok (Jan-March 2002)
 Installation of equipment (Feb 2002)
 First studies running (April 2002)
 Participation in external QC program
               Acknowledgements
   Dept of Clinical Pharmacy, UMC Nijmegen:
    Patricia Hugen, Rob Aarnoutse, Charles la Porte, Alina Bergshoeff
   Dept of General Internal Medicine, UMC Nijmegen:
    Peter Koopmans, Denise Telgt, Joep van Oosterhout, Monique
    Keuter, Hadewych ter Hofstede, Annemarie Brouwer
   Technicians and research nurses of UMC Nijmegen
   Patients, nurses and physicians of Dutch HIV clinics
   Dutch Study Group of Pediatric HIV infection
   IATEC/NATEC: Joep Lange, Peter Reiss
   HIVNAT, Bangkok: Praphan Phanupak, Kiat Ruxrungtham, Peter
    Cardiello, Mark Boyd, Chris Duncombe and others

				
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