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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 activity1

RIF dose n EBA0-2

300 mg 3 0.06600 mg 8 0 19

• In DAILY combination therapy with INH2

– Pts receiving <9 mg/kg RIF more likely to have positive sputum cultures at 8, 16 and 20 wks

– 19% of pts administered 600 mg received <9 mg/kg

600 mg 8 0.19

1200 mg 8 0.41p<0.05

1Jindani et al, ARRD 1980; 121:9392Long et al, ARRD 1979; 119:879

Factors associated with reduced RIF exposure

• Population pharmacokineticsMarked differences person-to-person and dose-

to-dose differences in bioavailability1,2

• Patient-specific conditionsLarge body mass3,4 Hx of GI surgery3

Diabetes mellitus3,4 Poor nutritional status3

HIV infection2,3 Childhood5

1Antimicrob Agents Chemother (2008);52:2138 4Clin Infect Dis (2006);43:848 2Antimicrob Agents Chemother (2008);52:2138 5Clin Pharmacokinetics (1978);3:1083Drugs (2002);62:2169

Inferiority of intermittent regimens

Systematic review of published clinical trials with short-course regimens

Frequency of Initial Freq. of Continuation Odds of Relapse vs. q yPhase Therapy

qPhase Therapy

pDaily Therapy

Daily Daily 1.0Daily 3x/wk 1.6 (0.6 - 4.1)Daily 2x/wk 2.8 (1.3 - 6.1)3x/wk 3x/wk 2.8 (1.4 - 5.7)

Chang et al, AJRCCM (2006); 174:1153

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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

*

AUC0-24

Med (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

R10HZR15HZR20HZR40HZ

U p

er L

ung

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%)b

awith 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 In

crea

sing

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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