Role(s) of EBA Studies – Substitute for Dose Ranging

JL Johnson, MDCase Western Reserve Univ

Mitchison. Thorax 1950;5:144Mitchison. Thorax 1950;5:144

Quantitative Culture in Response to TB Treatment

Nairobi EBA Study• 27 regimens of single drugs or

combinations• Sputum cfu on day -2, -1, 2, 4, 6, 8, 10,

12, 14 days• Day 0-2 mean decrease in cfu 0.422

logs• Day 2-14 mean decrease in cfu 0.129

logsJindani. ARRD 1980;121:939

Fall in CFU during Chemotherapy cfu 0-2 cfu 2-14

Nil -0.02 -0.02H 300 0.72 0.11R 10 per kg 0.19 0.10S 1g 0.09 0.13E 25 per kg 0.25 0.16Z 2g 0.04 0.11

Bacillary Killing During Early Treatment

• Phase 1 (Day 0-2) Rapid, exponential killing of rapidly dividing organisms. Rate determined by action of drug on log phase bacilli

• Phase 2 (Day 2 and beyond) – killing of slowly dividing bacilli; sterilizing action of drugs; rate determined by bacterial metabolism & rapidity of action of drug(s)

Response to TB Treatment

EBA• EBA = EBA 0-2 – penetration into

lesions & bactericidal action against rapidly dividing bacilli

• Extended EBA = EBA 2-7 – rough estimate of possible sterilizing activity

EBA for Current Drugs S. African MRC EBA Studies

DRUG EBA 0-2 EBA 2-5

INH 0.60 0.06OFL 0.39 0.17EMB 0.25RMP 0.20 0.30CIP 0.21STM 0.13RBT 0.08AMIK 0.05PZA 0.003

EBA in Different StudiesDrug Study EBA INH Jindani ’80 0.72

Chambers ’98 0.60Gosling ’03 0.77Dietze ’05 0.67

RMP Chan ’92 0.29RMP SA MRC 0.20RBT Chan ’92 0.05RBT SA MRC 0.08

CIPRO Kennedy ’93 0.20CIPRO SA MRC 0.21OFLO Chambers ’98 0.32MXF Gosling ’03 0.53

Sources of Variation between Patients

in the Same EBA Study• EBA unrelated to age, sex, weight, HIV

status• EBA correlated w/ radiographic severity

of disease, cavitary disease in 2 studies

Source of Variability in EBA Studies

• In 8 studies from S Africa, overall variability was 0.03 log10 cfu/ml/day– due to laboratory processing 0.0011– due to pt characteristics & sputum collection

0.0212• EBA is reproducible; greatest source of

variation is interpatient variation due to disease characteristics & sputum sampling

Risk of Acquired Drug Resistancein EBA Studies

• Not examined carefully in all studies, but appears to be low

• Only 1 pt in studies to date (over 880 patients)

Need for Untreated Nil Group

• Weighted mean EBA 0-2 for nil in 9 studies was 0.00036

• Can test drug arms vs. zero. Should measure pretreatment cfu for 2 days for pts

Sirgel. J Antimicrob Chemother 2001;47:177.

Need for INH Comparator Group

• Mean EBA 0-2 for INH 300 was 0.575 (95% CI 0.515-0.636)

• INH 300 arm useful as positive comparator & to assess whether assay is working

Sirgel. J Antimicrob Chemother 2001;47:177.

Contemporary EBA Study Design1. Newly Dx, sputum smear + TB; 10-12

pts per arm2. No recent Rx w/ drugs w/ known anti-

TB activity3. Pts w/ severe TB (miliary, meningeal)

excluded4. Treatment w/ monotherapy for up to 7

days acceptable to IRBs, then all treated w/ std chemotherapy

Contemporary EBA Study Design5. Able to produce adequate amounts of

sputum6. Daily overnight sputum collections w/

2 pretreatment collections7. INH 300 comparator group useful8. PK sampling9. Pre- and post-Rx drug susceptibility

Types of Trials

EBA

60 patients

6-9 months

2 Mo culture conversion

350 patients 18 months

Formal clinical trial comparing relapse rates

1200 patients 5 years

Use in Dose Ranging

Example of possible use of EBA (0-2) to identify doses to be further

evaluated

-0.2-0.1

00.10.20.30.40.50.6

0 9 18.5 37.5 75 150 300 600

INH dose

EBA

(0 -

2)

Donald. AJRCCM 1997;156:895

EBA 0-2 of INH, Rifampicin and Streptomycin

Sirgel. AJRCCM 2005;172:128.

EBA - RMP & Rifapentine

Sirgel. AJRCCM 2005;172:128

Use in Comparing Different Drugs

in a Class

EBA Day 0 to 295% CI for Mean

Drug nMean EBA SD

Lower Bound

Upper Bound

INHLevoGatiMoxi

10101010

0.670.450.350.33

0.170.350.270.39

0.550.200.150.05

0.800.710.540.62

EBA Day 2 to 795% CI for Mean

Drug nSlopeB2-7 SD

Lower Bound

Upper Bound

INHLevoGatiMoxi

910109

0.140.240.270.24

0.160.120.100.11

0.020.150.200.11

0.270.330.340.37

Use in Evaluating Combinations

EBA of Drug Combinations

00.10.20.30.40.50.60.70.80.9

1

H HR SHZ SHRZ

Am Rev Respir Dis 1980;121:939

What Might Be Learned from Combination EBA Studies?

• Drug-drug interactions• Synergy vs antagonism vs indifference• Increased toxicity

Two Drug Combination EBA1-7 8-14 >

HRZE HRZE HRZE

XH XH HRZEXR XR HRZEXZ XZ HRZEXE XS HRZE

EBA Method - Advantages•Reproducible; small # of pts required•Can detect significant differences between

drugs during the initial days of administration

•Drugs can be compared with one another•Different doses can be evaluated to define

dose for phase 2b & 3 trials•PK can be compared to bactericidal activity•Short term toxicity in humans with TB can

be evaluated

EBA - Disadvantages

• May not tell us much about sterilization by a drug or regimen as later measurements.

• Not useful for some drugs. Rifampin & PZA have little & no EBA but are best current sterilizing drugs.

• Less valuable for comparing regimens particularly in combination w/ INH

• Little experience w/ EBA of drugs that accumulate or are given infrequently

EBA Study of New Drug• Evaluate highest tolerable dose based

on initial toxicology data• If EBA 0-2 less than 0.2, further EBA

studies unlikely to be helpful• If EBA 0-2 significant, conduct dose

ranging studies to define therapeutic margin

• Do PK sampling of all subjects