When and How to Use Therapeutic Drug Monitoring in IBD Patients

Bruce E. Sands, MD, MS

Chief of the Dr. Henry D. Janowitz Division of Gastroenterology

Dr. Burrill B. Crohn Professor of Medicine

Icahn School of Medicineat Mount SinaiNew York, NY

Disclosures

• AbbVie• Amgen• Celgene• Forest Research Institute• Janssen Biotech• Luitpold Pharmaceuticals• MedImmune• Millennium Pharmaceuticals• Pfizer• Prometheus Laboratories• Takeda

Overview

• To understand the relationship between pharmacokinetics (levels and distribution of drug) to pharmacodynamics (therapeutic and adverse effects)

• To determine the roles for therapeutic drug monitoring in treating IBD, as well as limitations of current knowledge

Duration of action

TherapeuticRange

Conc

entr

ation

Cmax

Onset time tmax Time

MTC

MEC

TOXICITY

LACK OF EFFICACY

AUC

Association of 6-thioguanine nucleotide levels and IBD activity: a meta-analysis

·Osterman MT. Gastroenterology 2006;130:1047-53.

Prospective Data Supporting Metabolite-Based Dose Optimization of Thiopurines are Inconclusive

Clinical Remission at 16 weeks(%)

0

20

40

60

80

100

40

16

Individualised Weight-Based

Clinical Remission at 16 weeks(%)

0

10

20

30

40

50

60

7060

25

Individualised Weight-Based

Dassopoulos T, et al. Aliment Pharmacol Ther 2014;39: 163-175

Inte

ntion

To

Trea

t

Per P

roto

col

p=0.11 p=0.12

•Multicenter RCT comparing AZA dosing - weight-based (2.5 mg/kg/day) versus individualized (stratified by TPMT, then optimized to target6TGN – 250-400 pmol/8 x 108RBC)•Powered for 226 subjects, 50 subjects randomized, 27 subjects completed

Higher 6-TGN Levels are Associated with Higher Infliximab Trough Levels in Patients on Combination Therapy

• Cross-sectional study of 72 patients on combination therapy• 6TGN levels (but not thiopurine dose or lymphocyte count) correlated with IFX

levels (rho:0.466, p<0.001) • 6TGN > 125 pmol/8 x 108 RBC predicted higher IFX levels – ROC: 0.82, p=0.002• 6TGN < 125 pmol/8 x 108 RBC predicted higher likelihood of ATIs – OR: 1.3, 95%

CI 2.3 – 72.5, p<0.01

Yarur A et al. DDW 2014, Abstract 788 Series1

0

50

100

150

200

250

193

117

ATI -ve ATI +ve

6TG

N le

vel –

pm

ol/8

x 1

08 RBC

P=0.02

Thiopurine Metabolites Help Clarify Reasons for Inefficacy or Intolerance to Thiopurines

•Metabolite measurements are indicated in patients not responding or experiencing adverse events to adequate weight-bases doses of thiopurines

Absent 6-TGN/Absent 6-MMP

Non-Adherence

Education

=Under-dosing

Increase dose

Low 6-TGN/Low 6-MMP

=

Adapted from Gearry RB et al J Gastroenterol Hepatol 2005; 20:1149-57

High 6-TGNHigh 6-MMP

Over-dosing

Decrease dose

=Low 6-TGN/High 6-MMP

ThiopurineResistance

Allopurinol

=Ther 6-TGN/Ther 6-MMP

Thiopurine Refractory

Another drug

=

Questions about therapeutic drug monitoring (TDM) with biologic therapy

· What is the relationship of exposure to response?

· Can we define a minimum effective concentration?

· Can we define a maximum therapeutic concentration above which there is – no additional benefit?– increased risk of toxicity?

· What is the relationship between drug concentration and anti-drug antibodies, and how should this affect treatment strategy?

· Is TDM cost-effective?

· In what clinical situations should TDM be used?– Induction?– Maintenance?– Loss of response?– Toxicity?– Retreatment after drug holiday?

Higher Serum Infliximab Concentration is Associated with a Higher Response Rate in CD

• Study design: prospective, cohort study

• N=125, 30% Rx for fistula • Median follow-up: 36 months• Efficacy

– Infliximab concentrations ≥12 μg/mL were associated with greater median duration of response

– Immunosuppressant use was associated with IFX concentrations ≥12 μg/mL

Baert F, et al. N Engl J Med. 2003;348:601.

Duration of Response Based onIFX Concentrations

≥12.0 μg/mL <12.0 μg/mL0

20

40

60

80

100

81.5

68.5

Du

rati

on

of

Re

sp

on

se

(d

ay

s)

P<0.01

·Pr

opor

tion

of P

atien

ts (%

)

IFX Concentration (mcg/ml) at Wk 30

Clinical Remission Without Corticosteroids by Trough IFX Concentration at Week 26: SONIC

Primary Endpoint

·*IFX and IFX+AZA patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis

0 >0-1 >1-3 >3-6 >60

102030405060708090

100

59 57

73 74 72

31/4336/4943/5913/2319/32

·Colombel JF, et al. N Engl J Med. 2010.

Higher Serum Infliximab Level is Associated with Longer Remission and Better Endoscopy Score in CD

• Study design: prospective cohort in moderate-severe CD

• N=105• Median follow-up: 88 weeks• Efficacy

– Infliximab concentrations were positively correlated with the interval of clinical remission and change in endoscopic score

Maser EA, et al. Clin Gastroenterol Hepatol. 2006;4:1248.

40

50

60

70

80

90

100

Rem

issi

on (%

)

Serum Infliximab (µg/ml)

R2= 0.61P<0.001

0 2 4 6 8 10 12

-100

50

0

50

100

Endo

scop

ic Im

prov

emen

t (%

)

Serum Infliximab (µg/ml)

R2= 0.46P<0.001

0 2 4 6 8 10 12

High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease

• Serum samples in 210 CD patients undergoing treatment with infliximab were collected

• Infliximab trough levels were correlated with endoscopic healing (complete, partial or none) Complete Partial None

0

1

2

3

4

5

6

7

5.77

3.89

0.950000000000001

Tro

ug

h l

ev

el

(mc

g/m

L)

· Van Moerkercke W. et al. DDW 2010. Abs #405

ACCENT I: Week 54 Sustained Clinical Outcome and Week 14 Serum Infliximab Level in CD

Sustained Clinical Outcome<3.5 μg/mL Week 14

Serum IFX Level≥3.5 μg/mL Week 14

Serum IFX Level P-value*

Subjects included in analysis 96 51

Subjects with sustained response 17 (17.7%) 20 (39.2%) 0.0042

Subjects without sustained response 79 (82.3%) 31 (60.8%)

*Chi-square test

Cornillie F, et al. Presented at the 19th Annual United European Gastroenterology Week (UEGW); October 25, 2011. Stockholm, Sweden. Abstract P0919.

Prospective cohort study of relationship between serum infliximab level and efficacy in luminal CD

Levesque BG, et al. Aliment Pharmacol Ther. 2014;39:1126-35.

Detectable Serum Trough Infliximab Associated with Higher Remission Rate and Endoscopic Improvement in UC

• Study design: cohort study• N=115 patients with moderate

to severe UC• Follow-up time: median 13.9

months• Efficacy

– Detectable serum IFX was associated with

• Higher remission rates (69% vs. 15%; P<0.001)

• Endoscopic improvement (76% vs. 28%; P<0.001)

Seow CH, et al. Gut. 2010;59:49-54.

Undetectable Detectable0

10

20

30

40

50

60

70

80

15

69

Re

mis

sio

n (

% o

f P

ati

en

ts)

P<0.001

Presence of Detectable Trough Infliximab Levels Reduces Colectomy Rates in Ulcerative Colitis

Seow CH, et al. Gut. 2010;59:49.

Undetectable Detectable0

20

40

60

80

100

55

7

Cole

ctom

y (%

of P

atien

ts) P < 0.001

Proportion of Patients Achieving Clinical Remission by Serum IFX Concentration: ACT 1 and 2

IFX Conc.(% patients)

1stQuartile

2nd Quartile

3rd Quartile

4thQuartile P-values

Week 826.3%

(<21.3μg/mL)37.9%

(≥21.3-<33μg/mL)43.9%

(≥33-<47.9μg/mL)43.1%

(>47.9μg/mL)P=0.0504

Week 3014.6%

(<0.11μg/mL)25.5%

(≥0.11-<2.4μg/mL)59.6%

(≥2.4-<6.8μg/mL)52.1%

(>6.8μg/mL)P<0.0001

Week 5421.1%

(<1.4μg/mL)55.0%

(≥1.4-<3.6μg/mL)79.0%

(≥3.6-<8.1μg/mL)60.0%

(>8.1μg/mL)P=0.0066

At wks 8, 30 and 54, the proportion of patients achieving clinical remission increased with increasing quartiles of IFX concentrations.

Reinisch W et al., Gastro Vol 142, Issue 5, suppl-1, May 2012, page S-114

* 6 discontinued IFX, 3 continued same dose 3, 3 proceeded to surgery, 5 patients could not be assessed

Clinical outcomes in patients with detectable HACA (n=35)*

* 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed

Clinical outcomes in patients with sub-therapeutic concentrations (n=69)*

Increasing dose of infliximab in the presence of ATI formation is inferior to changing anti-TNF

Com

plet

e / p

artia

l res

pons

e (%

)

P<0.004

Com

plet

e / p

artia

l res

pons

e (%

) P<0.016

Afif W, et al. Am J Gastroenterol 2010;105:1133-9.

Proposed algorithm for patients with loss of response to infliximab

Positive HACA

Change to another anti-TNF agent

Change to non–anti-TNF agent

persistent disease

Increase infliximab

dose or frequency

Change to non–

anti-TNF agent

Change to different anti-TNF

agent

Change to different anti-TNF

agent

Subtherapeutic IFX concentration

Therapeutic IFX concentration

Active disease on endoscopy/radiology?

Change to different anti-TNF

agent

Investigate alternate etiologies

yes no

Afif W et al. Am J Gastroenterol 2010;105:1133.

• 66 patients: 27% with detectable ATA 59 (89%) CD, 7 (11%) UC

• Mean ADA levels were higher in patients with Undetectable ATA Mucosal healing Concomitant use of immunosuppressants

• ADA level ≥ 5 µg/ml is associated with lower CRP and healed mucosa

• Variables associated with positive ATA (≥ 1.7 µg/ml) ADA < 5µg/ml: OR 8.6, 95%CI (2.3-31) Mucosal inflammation: OR 3.8, 95% CI (1.1-13) Steroid use: OR 3.7, 95% CI (1.1-13)

Serum Adalimumab (ADA) Levels and Anti-Adalimumab Antibodies (ATA) Correlate with Endoscopic Inflammation

and Inflammatory Markers

Yarur, AJ, et al. Presented at DDW; May 21, 2013. Abstract Tu1147.

Endoscopic Inflammation

ad

alim

um

ab

[g

/mL

]

0

10

20

30

40

p=0.016

adal

imu

mab

[ g

/mL]

0

10

20

30

40

p=0.002

Immunosuppresant Usead

alim

umab

[ g

/mL]

0

10

20

30

40

p=0.028

Cross-sectional study of ADA drug level as predictor of clinical response and CRP in CD

• ADA level of 5.85 μg/mL was optimal- Sensitivity 68%- Specificity 71%- Positive LR 2.3

• AAA were inversely related to ADA drug levels

Mazor Y, et al. Aliment Pharmcol Ther 2014;40:620-8.

Higher trough levels of adalimumab are associated with higher rates of mucosal healing

Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.

Trough adalimumab levels are higher in patients with mucosal healing

6.5 μg/mL

4.2 μg/mL

P<0.005

Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.

Adalimumab Trough Serum Levels < 0.33 µg/mL Predicts a Lower Rate of Sustained Complete Response in

Patients with Crohn’s Disease

Karmiris K, et al. Gastroenterology. 2009;137:1628.

Patie

nts

with

Sus

tain

edCl

inic

al R

espo

nse

(%)

0.0

0.2

0.4

0.6

0.8

1.0

0 210 240

LogRank: P=.01

Sustained Clinical Response (weeks)90 12030 15060 180

ADA TR>0.33 µg/mL, n=104

ADA TR<0.33 µg/mL, n=16

Proposed algorithm incorporating pharmacokinetics of adalimumab in IBD

AAA: antibodies against adalimumabADA: adalimumabTRA: trough levels of adalimumab

Low TRA: <4.9 μg/ml AAA present: >10 ng/ml

Roblin X, et al. Am J Gastroenterol 2014;109:1250-6.

• Single-center cohort of 125 steroid-refractory acute UC patients

• Standard infliximab induction/maintenance

• Fluid-phase assay for [IFX] and ATI

Trough Infliximab >2 µg/ml is Associated with Clinical Remission in Steroid-Refractory UC

Remission aOR [95%CI]

Colectomy aOR [95%CI]

Trough IFX > 2 µg/ml (vs. ≤ 2 µg/ml)

10 [3,35] 0.18 [0.07,0.44]

ATI (vs. no ATI) 0.64 [0.2,2.4] 1.0 [0.5,2.1]

IFX, infliximab Murthy S, et al. Presented at DDW; May 19, 2012. Abstract Sa2047.

Steroid-free Remission by IFX/ATI Status100

0

60

20

Pat

ien

ts i

n R

emis

sio

n (

%)

80

40

IFX+ATI-

70.0

16.6

28.5

13.0

IFX+ATI+

IFX-ATI-

IFX-ATI+

P=0.84

P=0.073

P<0.001

Steroid-free Remission by IFX Trough Status100

0

60

20

Pat

ien

ts i

nR

emis

sio

n (

%)

80

40

Serum IFX≤ 2µg/ml

17.5

69.4

Serum IFX> 2µg/ml

P<0.001

Colectomy by IFX Trough Status100

0

60

20Co

lect

om

y (%

)

80

40

Serum IFX≤ 2µg/ml

55.5

17.7

Serum IFX> 2µg/ml

P<0.001

Rapid IFX Clearance: Mechanism of Non-Response in UC

Kevans D, et al. Presented at DDW; May 19, 2012.

• Multicenter, propspective observational study in anti-TNF-naïve patients (N=19) with moderate-to-severe UC (Endoscopic Mayo 2/3)1

– IFX measured at 10 time points during first 6 weeks of induction therapy– Nonlinear mixed-effects modelling

• No difference in IFX concentration area under the curve (AUC) between endoscopic responders and endoscopic non-responders at week 8 (P=0.65 )

• Patients with CRP>50 µg/mL had lower IFX concentration (P=0.001)• 7/19 had positive ATI (homogeneous mobility shift assay)

– 6 of 8 endoscopic non-responders were ATI +– 2 of 8 endoscopic non-responders were ATI –

• Concomitant immunomodulator = 12/19 (P=NS)• IFX presumed to be lost in stool in severe IBD colitis2

Pharmacokinetics of Infliximab Induction Therapy in Patients With Moderate to Severe UC

1. Brandse JF, et al. Presented at DDW; May 5, 2014 A786. 2. Brandse JF, et al. Presented at DDW; May 18, 2013. A157.

Factors Affecting the Pharmacokinetics of Monoclonal Antibodies

Impact on Pharmacokinetics

Presence of ADAs • Decreases serum mAbs• Threefold-increased clearance• Worse clinical outcomes

Concomitant use of IS• Reduces formation• Increases serum mAbs• Decreases mAb clearance• Better clinical outcomes

High baseline TNF-α • May decrease mAbs by increasing clearance

Low albumin • Increases clearance• Worse clinical outcomes

High baseline CRP • Increases clearance

Body size • High BMI may increase clearance

Gender • Males have higher clearance

Ordas I et al. Clin Pharmacol Ther. 2012;91:635.

mAB, monoclonal antibody; ADA, antidrug antibody

Do early serial trough and antidrug antibody level measurements predict clinical outcome of infliximab and adalimumab treatment?

Vande Casteele N, et al. Gut 2012;61:321

• Retrospective cohort of patients in clinical remission, single physician practice– IFX dose optimization to trough concentrations 5–10ug/mL (n=48)– No IFX dose optimization (n=78)

• Evaluated probability of remaining on IFX, up to 5 years

Prospective Therapeutic Drug Monitoring to Optimize Infliximab Maintenance Therapy in IBD

Vaughn BP, et al. Presented at DDW; May 3, 2014 Abstract 209.

Dose optimization increases probability of remaining on IFX therapy up to 5 years

IFX TL withinoptimal interval

LB Group

CB Group

Randomized 1:1

IFX dosing based on clinical symptoms &

CRP

Maintenance phase (52 weeks)

IFX dosing based on IFX TL

(3-7 µg/mL)

Dosing based on IFX TL

(3-7 µg/mL)

Optimization phase (n weeks)

Prospective Controlled Trial of Trough Level Adapted Infliximab Treatment (TAXIT): Study outline

Screening Randomization Primary end point

Primary end point = rate of clinical (Harvey-Bradshaw or Partial Mayo score) and biological (C-reactive protein ≤5 mg/l) remission one year after randomization in each group

CB Group= Clinically Based Group; LB Group= Level Based Group

IFX maintenancetherapy –> Stableclinical response

Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1

TAXIT Results: Optimization PhaseDose escalation (N=76)

Dose escalation in Crohn’s disease patients with subtherapeutic levels results in a better disease control

CD (N=43)* UC (N=28)*0

20

40

60

80

100

Before optimization After optimization

P=0.02 P=1.0

65.1

88.4 88.9 88.5

Pat

ien

ts (

%)

CD UC0

5

10

15

Before optimization After optimization

P<0.001 P=0.16

Mea

n C

RP

Con

cent

ratio

n(m

g/lit

er)

*five patients (1 CD and 4 UC) were excluded from analysis because of withdrawal of consent during optimization phase.

CD: Harvey-Bradshaw ≤ 4 / UC: Partial Mayo ≤ 2

Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1

• Enrolled 52 IBD patients (34 CD and 18 UC) with secondary failure to IFX. Dose escalation to 10mg/kg in all.

• IFX trough, ATI, CRP, and calprotectin measured before dose optimization and at Week 8

• Endpoint – Mucosal healing at Week 8 • Conclusion: The change in infliximab

trough levels after dose intensification (delta IFX) predicts mucosal healing in IBD patients.

Therapeutic Drug Monitoring of Infliximab (IFX) Predicts Mucosal Healing Following Dose Intensification in IBD

<0.6 0.6-1.5

1.5-3.4

>3.40

10203040506070

Delta IFX and Mucosal Healing

Mucosal healing

Multivariate Predictors of Mucosal Healing

Factors LR 95% CI P value

Delta IFX >0.5 2.02 1.01-4.06 0.048

IFX<2μg/mL and ATI <200ng/mL (before) 5.28 0.82-34.3 0.08

UC 3.1 0.41-23.6 0.27

Sex F/M 0.58 0.13-3 0.52

Paul S, et al. Presented at DDW; May 19, 2013. Abstract 495.

TAXIT Results: Maintenance PhasePrimary end point

*Harvey-Bradshaw index score ≤4 (CD) or Partial MAYO score ≤2 (UC) and C-reactive protein level ≤5 mg/l. Primary end point could not be calculated for 3 Patients (1 CD from CB and 1 UC and 1 CD from LB group).

Clinical Remission*0

20

40

60

80

100

CB Group (N = 122) LB Group (N = 126)

P = 0.79

62.3 64.3

Pat

ien

ts (

%)

Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1

TAXIT Results: Maintenance PhaseSecondary end point (loss of response and need for an intervention)

17.3% of CB Group vs. 5.5% of LB Group

needed rescue therapy by the end of

the maintenance phase

N at risk127 126 122 122 119 116 65 1

120 118 116 109 105 100 57 1

0 8 16 24 32 40 48 56 640.0

0.2

0.4

0.6

0.8

1.0

CB GroupLB Group

LogRank P=0.0038Breslow P=0.0058

Maintenance Phase (Weeks)

Rel

apse

-fre

e su

rviv

al

Vande Casteele N, et al. United European Gastroenterology Journal 2013;1:A1

• Patients with secondary IFX failure randomized to: – IFX intensification group: IFX 5mg/kg

every 4 weeks OR– Algorithm group:

• Low IFX and 0 ATI: IFX q4• ATI positive and low IFX :adalimumab• High IFX +/- ATI: stop anti-TNF

• Endpoints– Costs related to treatment– Clinical response: reduction in CDAI≥70 or

≥50% reduction of active fistulas at 12 weeks• Conclusions: Treatment of IFX failure

using an algorithm significantly reduces average costs without compromising care

Algorithm-Based Approach Based on PK for Secondary Non-Responders to Infliximab More Cost-Effective

Intention to treat

Algorithm

n=33

IFX intensified

n=36P Difference

[95%CI]

Response– no. (%)

19(58)

19(53)

0.810 5%[-19 – 28]

Costs– $ mean (SD)

7,806(5,360)

11,867(2,661)

<0.001 -4,060 [-5,969;-

1,775]

Steenholdt C, et al. Gut 2014;63:919-27.

- Consecutive cohort of patients (n=128); 105 CD, 23 UC where IFX was restarted after a median drug holiday of 15 months (at least >6 months).

- Success at Week 14, 1 year, and end of follow-up (median 4 years); ATI and trough level (TL) assessed

- Restarting IFX successful in 84.5% (short term), 70% (at 1 year) and in 61% (end of follow-up)

- IFX discontinued in 12% due to infusion reaction. IMM at restart prevents infusion reactions.Multivariate analysis

• Conclusion: Restarting IFX after a drug holiday is safe, with success predicted by absence of early ATI formation, IMM at recommencement, and not having had previous infusion reactions

Trough Levels and Anti-drug Antibodies Predict Safety and Success of Restarting IFX After Long Drug Holiday

Response (%) Short-term Year 1

End of Follow-Up HR (95% CI)

ATI (at 2nd infusion) detectable N=31

71% 54.8% 38.7%0.14 (0.026-0.74)

P=0.021

IMM at restart N=84 91.6% 74.7% 66.6% 6 (1.3-2.7) P=0.019

Reason for discontinuation (remission &/or pregnancy)

90% 77.5% 66.6% 2.70 (1.09-6.67) P=0.033

TL (at 2nd infusion) > 2 μg/ml N=43

93% 74% 70% 2.94 (1.18-7.69) P=0.021

Baert FJ, et al. Clin Gastroenterol Hepatol. 2014;12:1474-1481.

Additional questions

• Should target trough levels differ at different phases of treatment?– Rate of early drug clearance seems important early in severe disease– Is a higher trough required in induction than in maintenance?– Would rate of early drug clearance be a clinically useful parameter?

• Should TDM be individualized, or do population means work?- Can accurate predictive models for individual PK be created?

• Is there a safety benefit to dose reduction for supratherapeutic levels?

• Questions of timing and frequency of TDM: maximizing the value

Conclusions

• TDM with biologics more complex than with thiopurines• Minimum effective concentration roughly defined

– IFX trough ~3 μg/mL– ADA trough ~5 μg/mL

• Role of TDM in assessing loss of response is best established• TDM appears to be cost effective when dose-reduction

incorporated into treatment algorithm, but will be highly dependent upon cost and frequency of assay

• Growing interest in early TDM to dose optimize in severe disease (especially UC)