Mouse Models for Antibacterial PK/PD · Garenoxacin . From ICPD . ... Note: PK-PD target was net...

Mouse Models for Antibacterial PK/PD

David Andes University of Wisconsin

Disclosures

• Research grants and/or consulting: Astellas, Merck, GSK, Scynexis, Cubist, Forrest, Rempex, Dipexium, Nexcida, Durata, Actelion, Zavante, Paratek, Meiji, Geom, Cidara, Melinta, Theravance, Iterum, Sentinella, Kalidex, Novozymes, Trius, Taxis

• Member ABIM

Outline

• What PK/PD questions can the models address?

• What study variables impact PK/PD answers?

• Can the model PK/PD results predict clinical efficacy?

Why do we conduct PK-PD infection models?

Host

Drug

Bug

Improving the Probability of Positive Outcome

What do we do?

MIC = minimum inhibitory concentration; AUC = area under the curve; T = time

Tie Drug Potency to Antimicrobial Exposure = Pharmacodynamics

MIC Time Above MIC

Peak:MIC AUC:MIC Ratio

Time

Seru

m D

rug

Con

cent

ratio

n

MIC

In vivo PK/PD Work Horse(s)

• Murine thigh and lung models – Mimics soft tissue/sepsis and pneumonia, respectively – Neutropenic – Organism burden primary endpoint – Supports growth of most bacteria – Multiple drug administration routes – Large group of comparator antibacterial agents – Outcomes correlated with treatment success in patients – Useful for trial dosing regimen selection and susceptibility

breakpoint development

Study Design

-2 hr

24 hr

Tnereaphy Antibiotic Therapy

Dose (mg/kg/24 h)0.1 1 10 100 1000 10000

Cha

nge

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og10

CFU

/Thi

ghov

er 2

4 H

ours

-4

-3

-2

-1

0

1

2

3

4

q 6h q 12h q 24 h

Infect

Bacterial Burden Assessment Pharmacodynamic Analysis

How do we determine how much and how often to administer an

antibiotic?

PK/PD Driver – Dose or Interval

Dose Level Dosing Frequency

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Andes and Craig. Antimicrob. Agents Chemother. 2006;50:1376-1383

Dose Fractionation Design

Dose (mg/kg/24 h)1 10 100

Chan

ge in

Log

10 C

FU/T

high

-3

-2

-1

0

1

2

3

4

5

q3q6q12q24

Andes and Craig. Antimicrob. Agents Chemother. 2006;50:1376-1383

Dose Fractionation Analysis

PK/PD Patterns Activity

Pattern Antibacterial Dosing Goal Concentration-dependent killing and prolonged persistent effects

Quinolones, Aminoglycosides, Ketolides, and Daptomycin

Maximize concentrations; Cmax/MIC or AUC/MIC

Time-dependent killing and minimal or no persistent effects

Beta-lactams Optimize duration of exposure; %T>MIC

Time-dependent killing and moderate to prolonged persistent effects

Macrolides, Azithromycin, Clindamycin, Tetracyclines, Glycylcyclines, Streptogramins, Glycopeptides, Oxazolidinones

Optimize amount of drug; AUC/MIC

Dose fractionation in the mouse models reliably defines the PK/PD

driver

How do we define the PK/PD target?

Dose Level





Nonlinear regression and Hill equation to estimate Emax (difference from untreated control), P50 (dose giving 50% of Emax) and slope (N) of the dose-response relationship

PK-PD Target Analysis

(Emax) DoseN DoseN + P50

N ∆CFU=

AUC/MIC0.1 1 10 100 1000 10000

Cha

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CFU

/Thi

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4 H

ours

-4

-3

-2

-1

0

1

2

3

4

Strain 1Strain 2Strain 3

Static Dose

1 Log Kill

Emax

PK/PD Target Design

Introduce additional isolates, preferably with MIC variation

PK/PD Target Variables

Strain Variability

MIC Variability

Resistance Mechanism Infection Site

Pharmacokinetics

Protein Binding

Right Dose PK/PD Target

Time Above MIC (%)

0 10 20 30 40 50 60

Cha

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CFU

/Thi

gh

-6

-5

-4

-3

-2

-1

0

1

2

3

4Strain 1 PsAStrain 2 PsA

Mouse Stasis %T>MIC

1 log Kill %T>MIC

Strain 1

1 15 21 2 15 21 3 16 22 4 16 20

Mean 16 21 SD 0.6 0.8

Strain 2

1 39 42 2 40 43 3 39 43 4 39 42

Mean 39 43 SD 0.5 0.6

Impact of Strain to Strain Variation on the PK/PD Target

Strain Variability

Time Above MIC (% over 24 h)

0 10 20 30 40 50 60

Cha

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CFU

/Thi

gh

-6

-5

-4

-3

-2

-1

0

1

2

3

4

14 PsA Strains

Emax 7.7ED50 37.1N 1.51R2 0.80

Organism Stasis % T > MIC

1 log kill %T>MIC

1 16 21 2 37 45 3 35 46 4 30 38 5 36 47 6 37 43 7 35 8 40 43 9 29

10 28 43 11 22 34 12 30 37 13 32 39 14 27 37

Mean 31 39 Median 31 41

SD 6 7 %CV 0.19 0.18

Impact of Strain to Strain Variation on the PK/PD Target

Strain Variability

Impact of MIC Variation on the PK/PD Target

MIC (mg/L)0.008 0.03 0.12 0.5 2 8

T>M

IC (%

)

0

10

20

30

40

50

- Cephalosporins - Penicillins - Carbapenems

MIC Variability

N=65, >1000 X MIC range

Impact of Resistance and ESBL Production

Time Above MIC (percent)

0 20 40 60 80 100

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er 2

4 H

ours

-3

-2

-1

0

1

2

3

0 20 40 60 80 100

-3

-2

-1

0

1

2

3ESBLs Non-ESBLs

Andes D, Craig WA. Clin Microbiol Infect 2005;11:10-17. 22 Resistance

Mechanism

N=20 organisms, 4 cephalosporins

MIC indexed to drug exposure predicts response

23

Impact of Resistance and ESBL Production

Resistance Mechanism Andes D, Craig WA. Clin Microbiol Infect 2005;11:10-17.

Impact of Protein Binding

Andes & Craig 40th and 41st ICAAC, 2000 and 2001

23% 30% 50%

67% 78%

25% 25%

Protein Binding

Impact of Infection Site

Lepak AAC 2012;56:5916 Louie AAC 2011;55:3453

Stasis 1 Log Kill

Tede

zolid

fAU

C/M

IC

0

20

40

60

80LungThigh

Mouse ELF:Blood Penetration > 10

Oxazolidinone and MRSA

Infection Site

Time (h)

0 2 4 6 8 10 12

Con

cent

ratio

n (m

g/L)

0.01

0.1

1

10

Plasma Total DrugPlasma Free DrugELF Total Drug

Pharmacokinetics



AUC/MIC

1 10 100 1000

Cha

nge

in L

og10

CFU

/Org

an

-4

-3

-2

-1

0

1

2

3Lung ELF AUC/MICThigh plasma fAUC/MIC

Infection Site Pharmacokinetics

&

ELF/Plasma Penetration: Mouse and Man

Drug Mouse ELF:Plasma Ratio

Man ELF:Plasma Ratio

Ceftibiprole 0.69 0.26

Meropenem 0.60 0.80

Levofloxacin 0.77 1.16

Tedezolid 10 2-4

Tigecycline 10-20 1.12

Vancomycin 0.50 0.50

Gentamicin 1.0 0.30-0.85

In vivo PK/PD Target Identification (>100 individual drugs)

Penicillins Aminoglycosides Cephalosporins Fluoroquinolones Carbapenems Metronidazole Aztreonem Ketolides Flucytosine Polyenes Echinocandins Plectasins Azithromycin Macrolides Streptogramins Oxazolidinones Vancomycin Clindamycin Tetracyclines Triazoles Glycylcyclines Beta peptides Glycopeptides Pleuromutalins

Mouse models can define the PK/PD target, but there are important variables

to consider

Let’s put this pre-clinical PK-PD in context with

clinical efficacy

Despite: • Different doses (mg/kg) • Faster half-life in small animals BUT: • Drug target is in the organism and NOT the host • Exposure relative to MIC is the determinant

Why Does This Work?

PK-PD INFECTION MODELS Do They Forecast Regulatory Approval?

PK-PD INFECTION MODELS Do They Forecast Success?

Preclinical data: Craig/Andes Clinical data: Bhavnani SM et al. Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline. Antimicrob Agents Chemother. 2012; 56:1065-1072 Rubino CM, et al.. Evaluation of tigecycline penetration into colon wall tissue and epithelial lining fluid using a population pharmacokinetic model and Monte Carlo simulation. Antimicrob Agents Chemother, 2007 November; 51(11), 4085-4089.



Preclinical data: Craig/Andes Clinical data: Bhavnani SM et al. Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline. Antimicrob Agents Chemother. 2012; 56:1065-1072 Rubino CM, et al.. Evaluation of tigecycline penetration into colon wall tissue and epithelial lining fluid using a population pharmacokinetic model and Monte Carlo simulation. Antimicrob Agents Chemother, 2007 November; 51(11), 4085-4089.

From ICPD



Preclinical data: Louie A, et al. Impact of meropenem in combination with tobramycin in a murine model of Pseudomonas aeruginosa pneumonia. Antimicrob Agents Chemother. 2013 June; 57(6), 2788-2792. Surveillance data: EUCAST (2016).MIC distributions and ECOFFs. Clinical data: Mattioli F, et al. Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients. European journal of clinical pharmacology, 2013;1-10. Lodise TP, et al. Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia. Antimicrob Agents Chemother. 2011 April; 55(4), 1606-1610.



Preclinical data: Louie A, et al. Impact of meropenem in combination with tobramycin in a murine model of Pseudomonas aeruginosa pneumonia. Antimicrob Agents Chemother. 2013 June; 57(6), 2788-2792. Surveillance data: EUCAST (2016).MIC distributions and ECOFFs. Clinical data: Mattioli F, et al. Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients. European journal of clinical pharmacology, 2013;1-10. Lodise TP, et al. Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia. Antimicrob Agents Chemother. 2011 April; 55(4), 1606-1610.

From ICPD


• Relationship between the regulatory approval and the probability of pre-clinical PK-PD target attainment o The study period was December 1996 through 2011

• Indications included community- and hospital-acquired pneumonia o For CAP, S. pneumoniae was the index pathogen o For HAP, the index pathogen was antibiotic spectrum dependent o 14 antibiotics that gained regulatory approval and 6 that failed to gain

approval

Moxifloxacin Televancin Teilithromycin Tigecycline Trovafloxacin

Cefditoren Ceftaroline Ceftobiprole Daptomycin

Gatifloxacin Gemifloxacin Levofloxacin Linezolid

Doripenem Ertapenem Faropenem Garenoxacin

From ICPD


The Answer: Yes! The probability of regulatory approval increases with the probability of PK-PD target attainment

Note: PK-PD target was net-bacterial stasis in neutropenic mice for CAP agents and 1-2 log10 unit reduction in bacterial burden for HAP agents

PK-PD INFECTION MODELS Do They Forecast Success? From ICPD

Quartile Target Attainment

Median

% NDA Approval

(n/N)

1 0.62 40% (2/5)

2 0.85 60% (3/5)

3 0.94 80% (4/5)

4 0.985 100% (5/5)

But, A Mouse is Not a Human

• Host susceptibility – Difference in lung

anatomy – Different pattern

recognition receptors – Lower pulmonary WBC

and no defensins RESULT – Variable susceptibility to

human lung pathogens

• Pharmacokinetics – Penetration into AM

and ELF sometimes, but not often same as humans

Murine infection models can be used to forecast effective regimens

in patients

THANK YOU

MIC Time Above MIC

Peak:MIC AUC:MIC Ratio

Time

Serum Drug Concentration

“It all started with a mouse.” - Walt Disney

Mouse Models for Antibacterial PK/PD · Garenoxacin . From ICPD . ... Note: PK-PD target was net...

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