1 1

Alan Forrest1,3*

Jürgen B. Bulitta2,1

Olanrewaju Okusanya1,3 Elizabeth Lakota3,1

Long Half-life Drugs in Infectious Diseases:

Implications and Complications

1: State University of NY at Buffalo

Schools of Pharmacy & of Medicine

2: Monash University

Institute of Pharmaceutical Sciences

Melbourne Australia

3: Institute for Clinical Pharmacodynamics

Buffalo & Latham NY

* forrest@buffalo.edu

Authors’ Copyright © 2014. All rights reserved.

In Session: Drugs That Just Won’t Leave: From

Stars of the Party to Unwelcome Guests Annual Meeting of the AAPS, San Diego, California

Tuesday November 4, 2014

Paul Ehrlich (1854-1915): 1908 Nobel

Prize for Physiology/Medicine

• German physician and scientist

• Pioneer in hematology, immunology, oncology

and infectious diseases

• Invented the predecessor of Gram staining

• Autoimmunity, side-chain theory, antigen-

antibody interactions

• Named and defined the concept of chemotherapy

• Early work illuminated the existence of the blood-

brain barrier

• Therapia magna sterilisans, chemotherapia

specifica; arsphenamine (Salvarsan), the first

‘magic bullet’ (1910)

2

Outline

Heterogeneity of bacterial isolates

Mixture models for antibacterial PD

Definition and rationale for PD ‘front loading’

Azithromycin (AZT) sustained release formulation

Oritavancin (ORI) and Staph aureus pneumonia

ORI: complicated skin and skin structure infections

Dalbavancin and optimal sparse sampling strategies

Take-home messages

3

4

Concentrations

0 0.25 0.5 1 2 3 4 5 6 7 8 12 16 32

Lo

g1

0 (

CF

U/m

L)

1

2

3

4

5

6

7

8

9

10

11

12

Before Therapy

After Suboptimal Therapy

Heterogeneous Resistance: Subpopulation

Analysis in a Clinical Staph. aureus Isolate

Tsuji BT et al. Unpublished data.

Vancomycin concentration (mg/L)

(MIC, for the green curve, is 1.0, but

MIC of sub-populations are > 1 to 8)

‘Mixture Models’ for Antibacterial PD

8

• dCFU/dt = VGmax∙CFU/(CFUm + CFU) – Kd∙CFU

capacity-limited replication natural death

VGmax = Kd∙(CFUm + CFUmax)

Let Kg = VGmax/(CFUm + CFU)

• dCFU/dt = CFU∙(Kg – Kd)

• PD model with effect (E) on either Kd or Kg:

Kd∙(1 + Emax∙CH/(EC50H + CH)) = Kd∙E or

Kg∙(1 – Emax∙CH/(EC50H + CH)) = Kg∙E

• dCFU/dt = CFU∙(Kg – Kd∙E) or

• dCFU/dt = CFU∙(Kg∙E – Kd)

• One ODE per sub-population, which differ, at least, in EC50 and initial

inoculum (differences in VGmax have also been used for differing ‘fitness’)

• Numbers of populations are a problem in model discrimination, tested using

the corrected Akaike’s Information Criterion (cAIC)

Meagher AK, Forrest A, et al. 2004, AAC 48:2061-8.

The concept of PD front-loading (FL)

• At T=0 for a serious infection, total bacterial burden is

high (too much for the host defenses, alone) and the

percent of bacteria in resistant sub-populations, is low

• At the start of therapy (6-48 hours?), maximize rate and

extent of killing of drug-susceptible bacteria, leaving the

smallest possible residual (of more resistant bacteria) to

be killed by the capacity-limited immune system

• For ‘AUC-dependent’ drugs, with high maximum rate of

kill and with a good safety margin, FL with monotherapy

should be feasible

• For drugs with slower rates of kill, consider FL with

sustained-release, or multiple doses, or combinations

6

Pre-clinical Evaluation of Sustained Release Azithromycin (AZT), Given as a Single Dose

• PK model is linear, 3 cmpt, in humans1 and gerbils

• Regimens for gerbils were ‘humanized’ by giving small supplemental doses designed, in this study, to mimic time-course of human free drug AUC (fAUC)

1 Amsden GW et al. Clinical Drug Investigations 1997; 13(3):152-162

Vc

Vps

Gut VpfTLag,ka

CLt

CLdf

CLdsOral

Dose

Vc

Vps

Gut VpfTLag,ka

CLt

CLdf

CLdsOral

Dose

• Approved oral regimens were: 500 mg followed by 250 mg/day x 4

(5D) and 500 mg q. day x 3 (3D)

• Experimental regimen, using a sustained release formulation, was a

single dose of 1500 mg (SR); feasible due to long AZT T1/2?

• Animal infection model: Mongolian gerbils with acute otitis media

infections due to Haemophilus influenzae

• Adaptive study design; ‘humanization’ of AZT PK profiles

AZT Pharmacokinetic Parameters

Parameter

(units)

Humans Gerbils

Vc (L/kg) 6.67 3.45

Vpf (L/kg) 42.7 33.5

Vps (L/kg) 78.9 44.9

CLdf (L/h/kg) 4.55 19.3

CLds (L/h/kg) 0.59 6.96

CLt (L/h/kg) 1.77 5.38

T½ (h) 138 6.71

Azithromycin Regimens in Humans

5D: 500 + 250mg q. day x 4

3D: 500mg q. day x 3

SR: 1500mg SR x 1

‘Humanized’ Azithromycin Regimens

5 Day Human and Gerbil PK Profile

Time (hrs)

0 20 40 60 80

Co

nc (

g/m

L)

0.0

0.1

0.2

0.3

5D Gerbil Conc

5D Human Conc

3D Human and Gerbil Profile

Time (hrs)

0 20 40 60 80

Co

nc (

g/m

L)

0.0

0.1

0.2

0.3

3D Gerbil Conc

3D Human Conc

SR Human and Gerbil PK Profile

Time (hrs)

0 20 40 60 80

Con

c (

g/m

L)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

1D Gerbil Conc

1D Human Conc

Okusanya OO, et al Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

IMPACT OF EXPOSURE ‘SHAPE’: Same Exposure Administered Three Ways

Azithromycin (500 mg load, then 250 mg/day or 500 mg QD x 3 days or 1500 mg x 1 dose)

against H. influenzae in a Mongolian gerbil acute otitis media infection model

• In dose partitioning experiments, AZT PD was best associated with AUC/MIC

• The 3 regimens considered below all achieve the SAME AUC (Shape matters!)

• AZT regimens, in gerbils, were ‘humanized’

Simulations Results for Strain 1100

Log C

FU

Log C

FU

Log C

FU

Log C

FU

Time (h) Time (h)

Time (h) Time (h)

Co

nc

(m

g/L

) C

on

c (

mg

/L)

% o

f B

as

eli

ne K

d

% o

f B

as

eli

ne K

d

SR % of Baseline Kd SR Conc vs. Time Plot

3d Conc vs. Time Plot 3d % of Baseline Kd

AZT Summary and Conclusions

• Front-loading the AUC with the SR resulted in a more rapid and complete bacterial kill compared to the 3D and 5D

• PD was best modeled as enhancing Kd (Emax ~4.7-fold increase from baseline, which is small, for an AUC-dependent drug)

• Concentrations at near-Emax, during the first 24 h, resulted in greater kill, for both the sensitive and resistant sub-populations (reduced probability of emergence of resistance and treatment failure)

• 1500 mg AZT, as regular release, is not tolerable and would be less effective (‘wasted’ AUC at high concentrations)

• By the way, single-dose SR AZT works DESPITE its long terminal T1/2, NOT because of it!

- Results were similar in mice, with faster AZT clearance than gerbils, without humanization of AZT profiles

14

ORI and Staph aureus Pneumonia (SAP):

Translation from Mouse to Man

• PK (including ELF) and PD of SAP, in neutropenic mice,

and PK (including ELF), in human volunteers, were

studied

• SS AUC targets in murine ELF were characterized

– The ratios, of SS AUC in ELF to AUC in plasma, were similar in

mouse and in man (not a requirement for translation)

• The corresponding target SS AUC in plasma should be

achievable and tolerable, in humans

• 400 mg once daily, in man, predicted to provide the

desired SS drug concentration in ELF

• Traditional analysis would approve a pneumonia trial

• Predicted time course of PK/PD must also be

considered!

0 10 20 30 40 50 602

3

4

5

6

7

8

Growth Control

Oritavancin, 8 g/mL

Oritavancin, 4 g/mL

Oritavancin, 2 g/mL

Oritavancin, 0.5 g/mL

Vancomycin, 16 g/mL

Time (minutes)

Lo

g C

FU

/mL

S. aureus NRS127 (LIN-NS MRSA); McKay et al. 2008. 18th ECCMID. Poster P-544; and Data on file, The Medicines

Company

ORITAVANCIN IN VITRO TIME-KILL STUDY

AUC-Dependent Killing1

1 ORI PD was also modeled as increased Kd; Emax was much larger than AZT;

compared to AZT, ORI PD is better related to AUC, less sensitive to shape

AUC0-24 Exposure

Targets

STEP 1 RESULTS Non-Clinical Exposure-Response Relationship

for ORI Against S. aureus

Dose (mg/kg/24h) 40 20 10 5 2.5 1.25

Lo

g1

0 C

FU

/Th

igh

or

Lu

ng

afte

r

24

hrs

of T

he

rap

y

-2

-1

0

1

2

Lung

Thigh

Starting CFU

2.5 5.0 10 20 40 80 Free-Drug

AUC (mg/L h) 0-24

S. aureus Smith strain MICold = 1.0 mg/L

1. Dose-response relationship for ORI is based on data from Craig WA, Andes DR. ICAAC 2004, abstract A-1863.

2. Murine PK data are based on data from Bhavnani SM et al. ICAAC 2007, abstract A-51.

Endpoint Dose

(mg/

kg)

Free-

drug

plasma

AUC0-24

stasis 15.8 31.4

1-log kill 30.5 60.6

2-log kill ~ 80 159

Oritavancin and Staph. aureus Pneumonia:

From Mouse to Man

17 Bhavnani SM, et al. ICAAC 2008, Abstract A-51.

V3

Vc

V2

Dose Rate CLt

CL2

CL3

ELF

Kin

Kout

Data were best fit by a 3 -compartment model with a zero-order rate input and linear clearance; the ELF was modeled as a biophase compartment

Rubino CM et al. Oritavancin population pharmacokinetics in healthy subjects and patients with complicated

skin and skin structure infections or bacteremia.. Antimicrobials Agents and Chemotherapy 2009, in press.

ORITAVANCIN POPULATION PK MODEL

Predicted Concentration-Time Profile in Man

● 400 mg PO every 24 hour;

no loading dose given

● Terminal T1/2 seen only in

slow accumulation & washout

CONFOUNDING VARIABLE

Differing Inter-Compartmental Rate Constants

Bhavnani SM, et al. ICAAC 2008, Abstract A-51.

• Oritavancin pharmacokinetics were

studied in both murine and human serum

and epithelial lining fluid (ELF)

• Outcomes in mice at 24 hours are used to

forecast outcomes in humans

• In this simulation, mice & humans were

given identical serum profiles but species-

specific equilibration between serum and

ELF

• In humans, it takes (at least) 96 hours to

reach the ELF exposures associated with

efficacy, in mice at 24 hours

• These data suggest that very large initial

doses (for pneumonia) would be needed

in humans to match the early exposures in

animals

• Oritavancin pneumonia program targeting

S. aureus halted due to these data

20

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Day

0

1000

2000

3000

4000

Daily

AU

Cp

lasm

a

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Day

0

80

160

240

Daily

AU

Ce

lf

ORI for SAP, Front Loaded Regimen 800 mg Q12 X 2; Then 400 mg Q24 X 13 Doses

Plasma ELF

Note: many cases still take 3-7 days to achieve the target fAUC in ELF

Oritavancin: Complicated Skin and Skin

Structure Infections

• Oritavancin had been in late-stage clinical development for

nearly 10 years with multiple sponsors

o Primary indication sought was complicated skin and skin structure

infections

o Phase 3 dose regimen was 200 mg IV once daily for 3-5 days

• Late in the game, Sponsor and ICPD scientists asked two

questions:

o Could oritavancin be dosed in a manner that would result in

improved efficacy ?

o If so, how could we demonstrate it pre-clinically to support future

clinical development?

Bhavnani SM et al. Use of pharmacokinetics-pharmacodynamics to support oritavancin dose selection for patients with

complicated skin and skin-structure infection: clinical confirmation of proof of concept. ICAAC 2009, Poster A1-1288.

STEP 1 RESULTS

Comparison of Daily Free-Drug AUC Values

Rubino CM et al. Use of pharmacokinetic-pharmacodynamic principles for decisions for short-course oritavancin dosing

regimens for complicated skin and skin structure infections. 18th European Congress of Clinical Microbiology and

Infectious Diseases.

STEP 2 METHODS

Neutropenic Murine Infection Model

• Based upon population PK in mice and humans,

‘humanized’ ORI dosing regimens for mice were designed

to mimic 2 human oral regimens: 200 mg/day and a single

1200 mg dose

• Staphylococcus aureus was the challenge pathogen;

study duration was 3 days

• PK and PK-PD modeling was done using Monte Carlo

Parametric Expectation Maximization as implemented in

S-ADAPT 1.53

• Again, the one dose regimen (regular release, in this case)

was more active than the traditional regimen

ORITAVANCIN NOVEL DOSE REGIMENS

A Phase 2 Study

• Phase 2 study, international, multi-center, randomized,

double-blind, controlled study in patients with cSSSI

presumed or proven to be caused by gram-positive

pathogen(s)

• The study consisted of 3 treatment arms:

o 200 mg oritavancin IV daily for a minimum of 3 days up to a

maximum of 7 days,

o A single dose of 1200 mg oritavancin IV, or

o A single dose of 800 mg oritavancin IV, with a further dose of 400

mg IV on Day 5 at the discretion of the attending physician

Dunbar LM, et al. Efficacy of oritavancin at single or infrequent doses for the treatment of complicated skin and skin structure infections. 19th European Congress of Clinical Microbiology and Infectious Diseases. Helsinki, Finland, May, 2009.

ORITAVANCIN NOVEL DOSE REGIMENS

A Phase 2 Study

Dunbar LM, et al. Efficacy of oritavancin at single or infrequent doses for the treatment of complicated skin and skin structure infections. 19th European Congress of Clinical Microbiology and Infectious Diseases. Helsinki, Finland, May, 2009.

Dalbavancin (DAL) • Modeled with linear 3 compartment model

• T1/2: alpha phase = 2.5 hours, beta phase = 8.5 days,

terminal phase = 14 days

• Fraction bound: 93%

• Free-drug AUC0-120/MIC = primary PD index

• Approved regimen: 1000 mg followed by 500 mg on

day 8

• Trial planned to compare efficacy of the approved

dosing regimen to a single 1500 mg dose regimen

– Sparse sampling strategy needed

Lakota E et al.. Determination of optimal sparse pharmacokinetic sampling times for a Phase 3 dalbavancin trial. Poster

presented at 54th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC. September 5-9,

2014

Methods

• Using developed population PK model,

Monte Carlo Simulation of 2000 subjects

was performed

• Wide range of PK variability

– 20 randomly selected subjects PK profile

displayed on right

• To determine optimal sampling times,

stepwise linear regression with bi-

directional selection was performed

• AUC0-∞ was the dependent variable

• DAL concentrations at selected time

points from 0 to 1344 hours (8 weeks)

represented the independent variables

Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

Sampling Strategy for AUC0-∞

• Optimal sampling strategy to estimate AUC0-∞ is displayed

below

• All suggested samples occur at or after 120 hours,

indicating that most PK variability occurs after day 5

– The portion of total AUC which occurred after 120 hours ranged

from 21.3% to 92.2%, with a median of 65.9%

# of samples

Suggested time point of samples (h)

Precision

1 1008* 64.0%

2 144, 1008 73.4%

3 144, 1008, 1344** 79.9%

4 144, 192, 1008, 1344 84.6%

5 120, 144, 192, 1008, 1344 86.7% *1008 h = 6 weeks, **1334 h = 8 weeks

Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

Sampling Strategy for AUC0-120h

• AUC0-120h is the PK/PD index most closely related to DAL efficacy

• Linear stepwise regression performed again

– AUC0-120h as the dependent variable and concentrations at time

points ranging from 0 – 120 hours as the independent variables

• Optimal sampling strategy to estimate AUC0-120h is displayed

below

# of samples

Suggested time point of samples (h)

Precision AUC0-120

1 23 66.6%

2 18, 23 78.9%

3 18, 23, 36 84.6%

4 5, 18, 23, 36 86.8%

5 5, 18, 23, 36, 48 89.3%

Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

Sampling Strategy for Precision of PK

Parameters

• Optimal sampling theory using D-optimality

• Minimizes overall uncertainty in parameter estimates

• Sampling times(h): 1.8, 10, 124, 412, 894, 1344

PK Parameter Predicted CV%

CL 4.8

Vc 40

Vp1 13

Vp2 45

CLd1 34

CLd2 8.5

Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

Sampling Strategies are Complicated

• Even with overlapping objectives, optimal sampling

strategy is very dependent on goal of the study

Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

Take Home Messages

• Optimal regimens for all antibacterials require insightful

consideration of population PK, range of relevant MICs, site of

infection, and PD characteristics such as bacterial

heterogeneity, main PD driver and targets, rates of net kill,

probability of (new) random point mutations and PD of toxic

effects

• Drugs with very long terminal T1/2 present some interesting

challenges and opportunities but the long T1/2 is rarely

‘useful’ (rarely, if ever, favorable PK)

• Drugs with long T1/2 can accumulate throughout the course

(daily doses with no load) and/or persist long periods at low

concentrations (raising safety and resistance concerns)

32