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9/28/2010 1 Pharmacodynamics in practice Eric Nuermberger, MD Center for TB Research Johns Hopkins University September 23, 2010 A case CC/HPI : 61 yo F with new dx of sm+ pulmonary TB Past medical hx : obese (110 kg) ; poorly controlled DM; HIV negative Rx : predominantly twice-weekly, DOT, standard “maximum” doses Response : still Cx+ at 4 mo. TDM : INH 8.84 μg/ml (goal = 9 -15) RIF 5.85 μg/ml (goal = 8 -24) Intervention : restart 4-drug therapy with INH 400 mg, RIF 900 mg Outcome : cured with an additional 6 months of daily therapy Diagnosis : Pulmonary tuberculosis with sub-therapeutic rifampin exposure resulting in treatment failure resulting in treatment failure

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  • 9/28/2010

    1

    Pharmacodynamics in practice

    Eric Nuermberger, MD

    Center for TB ResearchJohns Hopkins University

    September 23, 2010

    A caseCC/HPI: 61 yo F with new dx of sm+ pulmonary TB

    Past medical hx: obese (110 kg) ; poorly controlled DM; HIV negative

    Rx: predominantly twice-weekly, DOT, standard “maximum” doses

    Response: still Cx+ at 4 mo.

    TDM: INH 8.84 μg/ml (goal = 9 -15)RIF 5.85 μg/ml (goal = 8 -24)

    Intervention: restart 4-drug therapy with INH 400 mg, RIF 900 mg

    Outcome: cured with an additional 6 months of daily therapy

    Diagnosis: Pulmonary tuberculosis with

    sub-therapeutic rifampin exposure resulting in treatment failureresulting in treatment failure

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    Dose-response curve for a TB drugef

    fect

    Sub-therapeutic

    Clinical failure probable

    Resistance to i d

    Sub-optimal

    Long

    ExposureExposure

    Ant

    i-TB

    e companion drug possible

    Long treatment duration

    Failure or relapse possible

    Optimal

    Short treatment duration

    Clinical failure

    improbable

    Susceptibility testing

    • Critical concentration: the drug concentration “breakpoint” which defines whether a bacterial isolate is susceptible or resistant – if bacteria grow, they are considered “resistant”– if not, they are considered “susceptible”

    • Minimum inhibitory concentration (MIC): the lowest drug conc. to prevent growth

    • Minimum bactericidal concentration (MBC): the lowest drug conc. to kill ≥99% of bacteria

    Drug susceptibility is not uniform and resistance is not absolute

    Susceptibility to rifampin Susceptibility to streptomycin

    Jureen et al, J. Clin Micro (2010)

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    Pharmacokinetics (PK)• What the body does to the drug

    – Absorption, Distribution, Metabolism, Excretion

    • Describes time course of drug in the body

    Cmax

    Pharmacodynamics (PD)

    • What the drug does to the body (or the bug)

    • Describes the relationship between drug exposure and effect

    Cmax

    PD and dose optimization

    The parameter AUC/MIC correlates best with the bactericidal activity of RIF in the mouse model

    Jayaram et al, AAC (2003)

    W.A. Craig, Clin Infect Dis (1998)

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    Population PK variability

    McIlleron et al, AAC (2006)

    One determinant of PK variability:Genetic differences in drug transporters

    Weiner et al, AAC (2010)

    “The probability that one and only one dose (e.g., rifampin 600 mg) is the correct dose for every human on the planet is approximatelyevery human on the planet is approximately

    ZERO.”

    C. Peloquin, Pharm.D.

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    Rifampin is typically used at or near its minimally effective dose

    • Early bactericidal activity1RIF dose n EBA0-2

    300 mg 3 0.06600 mg 8 0 19

    • In DAILY combination therapy with INH2– Pts receiving

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    Low drug exposures are linked to emergence of resistance

    • Among HIV+ pts receiving twice-weekly RBT-based Rx:– Failure/relapse in 5 3%– Failure/relapse in 5.3%– 8 of 9 with acquired

    rifamycin resistance (ARR)

    • Low RBT and INH exposures were associated with ARR

    Weiner et al, Clin Infect Dis (2005)

    Pharmacodynamics of daily rifapentine and rifampin in mice

    15

    cin /M

    IC

    15

    cin /M

    IC

    Rifapentine (10mg/kg) Rifampin (10mg/kg)AUC/MIC = 899 μg-h/mL AUC/MIC = 311 μg-h/mL

    0 24 48 72 96 120 144 1680

    5

    10

    Time (hrs)

    Free

    rifa

    myc

    Con

    cent

    ratio

    n/

    0 24 48 72 96 120 144 1680

    5

    10

    Time (hrs)

    Free

    rifa

    myc

    Con

    cent

    ratio

    n/

    Interim summary

    • Low rifamycin and INH exposures have been associated with adverse outcomes

    • Esp. for rifamycins, peculiarities in dosing and variable absorption results in sub-therapeutic p pexposures for some pts, sub-optimal exposures for most pts

    • Optimizing rifamycin exposures, whether with rifapentine or rifampin, may result in shorter, more effective regimens for TB

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    babi

    lity

    (%)

    Toxicity

    50

    100Response

    Prob

    Drug Concentration (µg/ml)

    10 20 30 40

    Evans, 1986

    AUC/MIC is the PD driver for the bactericidal effects of PZA in mice

    T>MIC Cmax/MIC

    AUC/MIC

    Divorcing efficacy from toxicity

    • In vitro & mouse studies show AUC/MIC predicts PZA’s bactericidal effects1,2

    • Re-analysis of clinical data reveals that hyperuricemia is correlated with the duration of yptime that serum pyrazinamide concentrations exceed a toxic threshold3

    • Therefore, dosing PZA intermittently (with proper dose multiplication) may alleviate arthralgias without sacrificing efficacy

    1Gumbo et al, AAC (2009) 2Ahmad et al, ICAAC (2010) 3Pasipanodya et al, AAC (2010)

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    Therapeutic drug monitoring

    • May help determine the “right” dose for the patient in front of you

    • Routine TDM may be cheaper than re-treatment in selected groupstreatment in selected groups

    • Still, there are no prospective studies addressing whether routine TDM would improve outcomes

    Cautionary tales

    • In a cross-over PK study among HIV-TB pts1:– Reducing the thrice weekly dose of RBT from 300

    to 150 mg maintained similar drug levels upon addition of LPVr

    – But, 9 (90%) of 10 pts had low RBT conc. – 1 (10%) of 10 developed ARR

    • Using routine TDM in pts with advanced HIV2:– 18 (86%) of 21 pts had rifamycin conc. below the

    recommended minimum values

    1 Boulanger et al, CID (2009) 2 Holland, Pharmacotherapy (2009)

    Patients for whom TDM may be considered

    • Advanced HIV disease– esp. if receiving RBT and ART

    • GI co morbidity with risk of malabsorption• GI co-morbidity with risk of malabsorption• Severely ill • Obesity• Slow response to therapy (+ cx at 3 mo.?)

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    4

    5

    6

    Patterns of Absorption with Oral Drugs

    0

    1

    2

    3

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

    Delayed

    Malabsorpt

    Normal

    “Targets” for first-line drugs

    • Isoniazid (300 mg) ≥ 3 µg/ml(900 mg) ≥ 9 µg/ml

    • Rifampin ≥ 8 µg/mlRif b ti 0 3 / l• Rifabutin ≥ 0.3 µg/ml

    • Pyrazinamide (25 mg/kg) ≥ 35 µg/ml• (50 mg/kg) ≥ 70 µg/ml

    Peloquin, Drugs (2002) Chideya et al, CID (2008) Boulanger et al, CID (2009)

    Depending on the clinical scenario, higher minimum concentrations may be warranted

    Take-home points

    1. The effect of TB drugs is proportional to the exposure achieved at the infection site

    2. A single dose size does not fit all TB pts3 Adverse treatment outcomes are3. Adverse treatment outcomes are

    associated with low drug exposures4. TDM should be considered for some pts

    to ensure adequate drug exposure5. More data relating PK/PD of TB drugs to

    clinical outcomes are needed

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    Risk factors for Relapse in USPHS Study 22

    21 8% 6.2%

    Cavity?

    Yes

    Culture (+) at 2 months?Yes No

    21.8%

    2.1%5.0%No

    Lancet, 2002

    Lower rifabutin AUC linked with ARR versus cure

    P-Value

    *

    AUC0-24Med (IQC)

    Dose mg/kgMed (IQC)

    No.

    Group

    * P for RBT AUC ARR vs. cure, Mann-Whitney

    0.045.1(4.0 - 7.4)

    4.8(4.2 – 6.2)

    82CURE

    3.1(2.0 - 3.8)

    4.6(3.5 - 5.7)

    6ARR(IQC)

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    TDM with Oral TB Drugs

    Two hour post dose blood draws generallycapture the “peak” concentration.

    Six hour post dose blood draws generallyseparate delayed absorption from malabsorption.p y p p

    Peloquin CA. Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs 2002; 62: 2169 -2183.

    Clinical trials planned or underwayPhase III study of intermittent P- and M-containing continuation phase regimensSponsor (PI) Location(s) Test regimens Primary outcomes

    St. George’s U. (A. Jindani)

    S. Africa 2RMZE + 4P20M (1/7)2RMZE + 2P15M (2/7)

    RelapseRifamycin resistance

    Phase II studies of daily P- +/- M-containing initial phase regimensPhase II studies of daily P / M containing initial phase regimensSponsor (PI) Location(s) Test regimens Primary endpointsCDC TBTC(S. Dorman)

    29 sites in NAm, Africa, Brazil, Spain

    2P10HZE Sputum Cx conversionTolerability

    JHU(S. Dorman)

    South Africa 2P7.5HZE2P10HZE

    Sputum Cx conversionTolerability

    JHU(S. Dorman)

    Brazil 2P10HZM Sputum Cx conversionTolerability

    Q. How high of a dose can you give?A.As high as necessary

    Actual examples :

    INH 900 d il RIF 2100 d il

    TDM

    INH 900 mg daily, RIF 2100 mg dailybecause most of the doses were ending upin the patient’s stool.

    Otherwise, if you keep doing what you have been doing, you will keep getting what you have been getting.

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    Clinical courseRapid tests: smear-positive w/ heavy AFB, MTD positive

    HIV-negative

    Treatment: INH 300mg, RIF 600mg, PZA 2g, EMB 2g (5/7) x 3w,began INH 900mg, RIF 600mg, PZA 4g, EMB 4g (2/7) x 6w,9/15 INH 900mg, RIF 600mg (2/7)

    Sputum culture: positive for M. tuberculosis, pan-susceptible

    Response: 1/11: still symptomatic, slight improvement in CXR smear-neg., culture-pos. w/ pan-susceptible Mtb

    Intervention: 2/1: Dosing frequency increased to (3/7)2/23: Drug levels: INH 8.84 μg/ml (goal = 9 -15)

    RIF 5.85 μg/ml (goal = 8 -24)3/7: restarted 4-drug Rx w/ INH 400mg, RIF 900mg;

    completed 6 mo. of daily therapy at these doses

    45678

    R10HZR15HZR20HZR40HZU

    per

    Lun

    g

    Bactericidal effect of escalating RIF doses

    0 2 4 6 8 10 1201234

    P10HZ

    Treatment duration (weeks)

    Log 1

    0 C

    FU

    Pharmacodynamics of INH activity

    0

    0.2

    0.4

    0.6

    0.8

    1

    0 2 0 5 0 8 1 1 1 4 1 7

    Log

    kill

    afte

    r 5 d

    oses

    Mouse

    -0.20.2 0.5 0.8 1.1 1.4 1.7

    Log dose of isoniazid (mg/kg)

    Jayaram et al, AAC 2004

    Donald et al, AJRCCM 1997

    Human

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    Conclusions II

    • Both rifamycins display dose-dependent sterilizing activity in mice

    • The best rifamycin for daily therapy is the y y pyone best tolerated at highest exposure level

    Objectives of talk

    1. Review the role of the rifamycins in TB therapy 2. Briefly discuss factors associated with sub-

    therapeutic rifampin exposure3 Posit that rifampin exposure is sub optimal in3. Posit that rifampin exposure is sub-optimal in

    most patients with TB4. Convince you that optimizing rifamycin

    exposures could significantly shorten the duration of treatment for TB

    Rifampin

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    Effect of dose and frequency on RIF activity in chronic mouse infection

    Lung CFU counts after 6 wks treatment with rifampin at the indicated dose (mg/kg)

    5

    6

    nt

    Initial CFU ct

    0

    1

    2

    3

    4

    (2/7) (3/7) (6/7)

    Frequency of administration

    Log(

    10) l

    ung

    CFU

    cou

    n

    510

    Ji et al, ARRD 1993; 148:1541

    Influenza-like syndrome associated with high-dose, intermittent RIF

    Study Dose (mg) Frequency Incidence (%)BMRC Hong Kong trials1

    1200 1/7 44900 1/7 36900 2/7 22450 5/7 0450 5/7 0

    Grosset & Leventis2

    1200-1800 1/7 35-371200-1800 2/7 16-22

    900 1/7 22-31900 2/7 8600 1/7 10600 2/7 1-4

    1Medicine (1999); 78:3612 Rev Infect Dis (1983); 5 Suppl 3:S440

    Rifapentine (RPT, P)

    • MIC90 = 0.06 μg/ml (vs. 0.25 for RIF)

    • Half-life = 14-18 h (vs. 2-4 for RIF)

    • Developed as a rifamycin for once-weekly regimens

    • Approved for this purpose in 1998

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    Clinical trials of once-weekly rifapentine-containing regimens

    Variable

    Hong Kong Chest Service

    Trial

    HMR Protocol 008 Trial

    USPHS TB Trials Consortium Study

    22

    Intensive phase regimen

    HRZS (3/7) HRZE (7/7) orHZE (7/7)+P (2/7)

    HRZ(E/S) (7/7, 3/7 or 2/7)( ) ( )

    Continuation phase regimen

    HR (3/7) orHP (1/7)

    HR (2/7) orHP (1/7)

    HR (2/7) orHP (1/7)

    Proportion (%) with relapse +/-treatment failure

    7/190 (3.7%)17/199 (8.5%)

    11/229 (5%)25/249 (10%)

    22/246 (8.9%)a

    40/278 (14.4%)a

    6/241 (2.5%)b

    6/210 (2.9%)bawith cavitation on CXR bwithout cavitation on CXR

    Adapted from Munsiff et al, Clin Infect Dis (2006); 43:1468

    Restrictions on use of rifapentine

    “(once-weekly HP) should be used only in HIV-negative pts without cavitation who have

    negative sputum smears at 2 mo.”

    “For pts with a positive culture at 2 mo., treatment should be extended an extra 3 mo.”

    Paraphrased from ATS/CDC/IDSA guidelines, Am J Respir Crit Care Med (2003); 167:603

    The potential for increasing rifapentine exposures

    • Some patients in HMR study accidentally received RPT 600 mg daily in initial phase

    O h i l d 600 d il f• Other patients tolerated 600 mg daily for over 1 week in a PK study1

    • Dose-dependent activity in mouse and in humans over a 600-1200 mg range that is well tolerated when given once weekly2-4

    2Daniel et al, AJRCCM 2000; 161:15724Bock et al, AJRCCM 2002; 165:1526

    1Keung et al, IJTLD 1999; 3:4373Sirgel et al, AJRCCM 2005;172:128

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    Twice-weekly, High-dose RPT in the Mouse Lung CFU counts after 2 Months Treatment

    3

    4

    2.56

    3.61

    2.88 3.06

    1 68

    2.37

    FU c

    ount

    RHZ (

    5/7)

    RHZ (

    2/7)

    RMZ (

    2/7)

    HZ (2

    /7)

    10PHZ

    (2/7)

    15PHZ

    (2/7)

    20PMZ

    (2/7)

    15PMZ

    (2/7)

    20P

    0

    1

    2

    0.842

    0.350

    1.68

    Lung

    log

    CF

    Rosenthal et al, AJRCCM 2006

    Twice-weekly, High-dose RPT in the Mouse Lung CFU counts after 2 Months Treatment

    3

    4

    2.56

    3.61

    2.88 3.06

    1 68

    2.37

    FU c

    ount

    RHZ (

    5/7)

    RHZ (

    2/7)

    RMZ (

    2/7)

    HZ (2

    /7)

    10PHZ

    (2/7)

    15PHZ

    (2/7)

    20PMZ

    (2/7)

    15PMZ

    (2/7)

    20P

    0

    1

    2

    0.842

    0.350

    1.68

    Lung

    log

    CF

    Rosenthal et al, AJRCCM 2006

    Time to Culture Negativity with More Frequent Administration of RPT

    5678

    2R10HZ + 4R10H (5/7)2P20MZ (2/7)2P15MZ (3/7)2P10MZ (5/7)co

    unt i

    ns

    Cx-: Culture negative, *: 1/5 mice culture positive with 1 CFU/Lung

    0 1 2 3 4 5 601234

    Cx-

    2P10MZ (5/7)

    *

    Duration of Treatment (mos.)

    Log 1

    0 C

    FU c

    lung

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    Relapse rates after more frequent dosing of PMZ regimens

    RegimenAfter 2

    mo.After 3

    mo.After 4

    mo.After 6

    mo.

    RHZ (5/7) Cx+ Cx+ 90% 0%

    P15MZ (3/7) 95% 0% _ _

    P10MZ (5/7) 35% 0% _ _

    (Cx+) All mice tested at treatment completion were culture positive

    Can the same benefit be accomplished with rifampin?p p

    Relapse after 8, 10 & 12 wks treatment

    Regimen(with HZ)

    Proportion (%) of mice relapsing after Rx for:8 wks 10 wks 12 wks

    R20 ND 100% (15/15) 67% (10/15)P5 ND 100% (15/15) 67% (10/15)R40 ND 27% (4/15) 0% (0/15)P10 100% (15/15) 33% (5/15) 0% (0/15)

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    Recapitulation of the short-course regimen in the mouse…as in humans?

    5

    6

    7

    8

    INH + SMINH + RIFINH + RIF + PZAn

    lung

    s

    0

    1

    2

    3

    4

    0 2 4 6 12 18

    INH + RPT + PZA

    months

    Log 1

    0cf

    u i

    Tubercle 1978: 59:287 & 1986;67:5

    AcknowledgementsMentors

    Jacques Grosset Bill Bishai

    TB Murine Trials ConsortiumIan Rosenthal Ming ZhangSandeep Tyagi Kathy WilliamsTianyu Zhang Si-Yang Li

    CollaboratorsDick Chaisson Susan DormanAndrew Vernon Charles Peloquin

    Funding Agencies:NIH/NIAID Potts Memorial Foundation

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    Objectives of TB Therapy• Kill actively multiplying bacteria

    – Improve symptoms & prevent death– Prevent transmission to others

    Prevent emergence of resistance– Prevent emergence of resistance

    • Sterilize disease sites– Cure the disease

    Bacterial Targets of TB Therapy

    • Rapidly multiplying bacteria (in cavities)

    • Slowly multiplying bacteria (in acidic y p y g (environment of macrophages or cavity wall)

    • Sporadically multiplying bacteria (location?)

    A

    Hypothetical Model of TB Chemotherapy3 anatomic/metabolic populations of bacilli in cavitary TB

    A: rapidly multiplying, INH>RIF>EMBB: slowly multiplying, acid pH, PZA>RIF>INHC: sporadically multiplying, RIF>INH

    M. Iseman, D. Mitchison

    B

    C

    # ba

    cilli

    # months of therapy1 2 3 4 5 6

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    Isoniazid (INH)

    DosagePO or IV/IM

    Metabolism Side Effects Drug-Drug Interactions

    5 mg/kg qd (300 mg qd)

    Liver Hepatitis Phenytoin(300 mg qd)

    15 mg/kg b.i.w. (900 mg)

    15 mg/kg t.i.w. (900 mg)

    Food, aluminum-containing antacids reduce absorption

    NeuropathyLupus

    (pyridoxine decreases risk of

    neuropathy*)

    Carbamazepine

    Disulfuram

    *use pyridoxine 25-50 mg for HIV, pregnancy, malnourished, EtOHism, diabetes, liver dz, cancer

    Rifampin (RIF)

    Dosage*PO or IV/IM

    Metabolism Side Effects Drug-Drug Interactions

    10 mg/kg Liver N/V Multiple:g g

    (600 mg q.d.)(600 mg b.i.w)(600 mg t.i.w)

    Food, antacids slow GI uptake

    Hepatitis“Flu-like” sx↓Platelets

    Orange staining of secretions

    pOCPs

    MethadoneHIV drugsCoumadin

    *RPT dose 600-900 mg q weekRBT dose 300 mg QD

    Pyrazinamide (PZA)

    DosagePO

    Metabolism Side Effects

    15-30 mg/kg qd Liver Hepatitis(2 gm)

    50-70 mg/kg b.i.w. (4 gm)

    50-70 mg/kg t.i.w (3 gm)

    Metabolites excreted by

    kidney

    Joint painGoutRash

    Nausea

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    Cmax

    AUC / MIC

    10

    8

    Cmax = 9 mcg / ml

    MIC = 3 mcg / ml

    Cmax / MIC = 3

    PD: Response Parameters

    MIC

    AUC / MIC6

    4

    2

    0

    T > MIC = 8 h

    AUC ( mcg * h / ml )

    Concentration-dependent killers• Activity correlated with Cmax/MIC• Examples: aminoglycosides, FQsTime-dependent killers• Activity correlated with T>MIC• Examples: β-lactams

    An example of dose fractionation

    A total dose of 300 mg/kg may be divided over 6 days as follows:– 300 mg/kg every 6 days

    150 mg/kg every 3 days g– 150 mg/kg every 3 days– 100 mg/kg every other day– 50 mg/kg every day– 25 mg/kg every 12 hours I

    ncre

    asin

    g C

    max

    /MIC

    Incr

    easi

    n gT

    >MIC

    Example of a dose fractionation study

    The parameter AUC/MIC correlates best with the bactericidal activity of RIF in the mouse model

    Jayaram et al, AAC 2003; 47:2118

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