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Pharmacokinetic Drug-Drug Interactions of Protein Therapeutics Science and Development Strategies Frank-Peter Theil Genentech Inc. Early Development PKPD Sciences New Jersey ACS, Oct 14, 2009

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Pharmacokinetic Drug-Drug Interactions ofProtein Therapeutics

Science and Development Strategies

Frank-Peter Theil

Genentech Inc.Early Development PKPD Sciences

New Jersey ACS, Oct 14, 2009

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Cytokines during inflammation, infection, cancer

Influenza outbreak – Seattle 1980

. . . During an outbreak of influenza in Seattle in 1980, 11 asthmatic children developed a sudden

decrease in theophylline clearance and were admitted to hospital with methylxanthine toxcities ranging

from headaches to seizures . . .

None of the children had experienced problems with theophylline dosage prior to infection. It was

postulated that endogenous IFN, known to be released in response to viral infections, played a central

role in the drug response . . .

Immunotoxicology and immunopharmacology, by Jack H. Dean

Influenza infection – PK & safety of theophylline

CL ⇓, T1/2 ⇑ by about 60 %, plasma concentration ⇑, á safety issues

Suppression of CYP1A2

INFα and INFγ transiently increased á down modulation of CYP450

Other cytokines are known to affect CYP expression – IL-6, TNF, TGF, IL-1, others

Cytokine activities can be a relevant part of the disease status and progression

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Influenza vaccination – cytokines – CYP450

J Clin Pharmacol 2003, 43: 1377-1381

Although INFα and INFγ increased transiently, the impact on CYP450 was statistically not significant.So get your flu-shot!

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CYP450 & cytokines – preclinical arthritis model I

Basic Clin Pharmacol Toxicol. 2009;105(1):24-9

Arthritis model in rats reduced genetic and protein expression of CYPs

Anti-TNFα (infliximab) reverses the CYP down modulation in the arthritis model

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CYP450 & cytokines – preclinical arthritis model II

Basic Clin Pharmacol Toxicol. 2009;105(1):24-9

R/S-Verapamil PK (model substrate, 2 mg/kg, day 8 post infliximab) PK:No significant impact of arthritis & infliximab. Inflammation – causes higher protein binding

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Protein Therapeutics: Cytokines & anti-Cytokines

Therapeutic Cytokines

Drug Producer Cell IndicationIL-2 Lymphocytes malignant melanoma, renal cell cancerINF-α Monocytes Hep B & C, antitumor activityINF-β Fibroblasts Multiple sclerosisEPO renal capillary cells maturation of erythrocytesGM-CSF T lymphocytes, monocytes neutropenia

Therapeutic anti-Cytokines

Drug Drug Type Target IndicationAnakinra Receptor antagonist IL-1 receptor RADaclizumab MAb CD25, IL-2 receptor Acute organ rejectionTocilizumab MAb IL-6 receptor RAAdalimumab MAb TNFα RACertolizumab-pegol MAb fragment TNFα Crohn’s Dis.Etanercept Fc fusion protein TNFα RAInfliximab MAb TNFα RA, Crohn’s Dis.

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SMD: Market Withdrawals because of PK based DDIs

The “other” problemPK based DDIs alter the PK and consequently the safety profile of drugsMarket withdrawals because of safety issues, not because of PK changes

SMD DDI Mechanism Enzyme Safety Problem Year withdrawnterfenadine Inhibition victim CYP3A4 QTc prolongation 1998mibefradil Inhibitor CYP3A4 / P-gp QTc prolongation 1998astemizole Inhibition victim CYP3A4 QTc prolongation 1999cisapride Inhibition victim CYP3A4 Toxicity 2000cerivastatin Inhibition victim CYP2C8, OATP-C Toxicity 2001nefazodone Inhibitor CYP3A4 QTc prolongation 2003

Modified from Wienkers L. and T. Heath, Nature Rev Drug Disc 2005, 4, 825-833

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Protein (Peptide) Therapeutics

Compared to small molecule drugs still a relatively new class of compoundsStill somewhat limited knowledge on their drug dispositionIncluding drug-drug interaction potential

Antibodies, Antibody derivatives (e.g. Antibody Drug Conjugates)

Cytokines (e.g. interferon-α ,IL11)

Enzymes (e.g. streptokinase)

Growth factors (e.g. human growth factor)

Hormones (e.g. insulin)

Interferons (e.g. peg-interferon)

Receptors (e.g. TNF receptor fusion protein – etenercept, Enbrel®)

Others

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Drug-Drug Interactions: PK and PD based

Pharmacokinetic Interactions Pharmacodynamic Interactions

March 20, 2008 DDI Strategy Proposal Slide 9

AbsorptionDistributionMetabolismExcretion

Pharmacokinetic & Pharmacodynamic Interactions

Victim Drug

Plasma Concentrations

Receptor

PD (Efficacy)

Metabolic Clearance

Perpetrator

Receptor

Toxic Effect(Safety)

AbsorptionDistributionMetabolismExcretion

Victim Drug

Plasma Concentrations

Receptor

PD (Efficacy)&/or Safety

Metabolic Clearance

Perpetrator

SynergisticAdditive

Antagonistic

Receptor Interaction Changes

May or may not be affected

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Drug-Drug Interactions of Protein TherapeuticsPK- and PD-based Drug-Drug interactions

- PD-based interactions are always major focus of research and development programs

PK-based DDIs: Potential combinations of victim and perpetrator drugs

Protein (e.g. IgG1, cytokines) +

Protein (e.g. IgG1, cytokines)Small Molecule Drug +

Protein (e.g. IgG1, cytokines) +

Protein (e.g. IgG1, cytokines)

Small Molecule Drug

Victim Perpetrator Drug-D

rug Interaction

What is the risk potential for safety and efficacy?

Higher risk if victim drug has got Narrow Therapeutic Index (e.g. SMD)

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Biologicals: Cover highly unmet medical need Areas

Global Biotechnology Market 2006-2008

Biotechnology Protein Market size $ billion2006 2007 2008

Cancer, Arthritis, Infection Monoclonal Antibodies 20 27 33Infections Vaccines 15 19 25Anemia Erythropoietin 12 11.8 9.5Autoimmune Inflammatory TNF Blockers 10.6 13.5 18Diabetes Insulin 9 11 12.5MS & Hepatitis C Interferon 6.7 7.6 8Growth, fertility Hormones 6.5 7.4 8

World Top Ten Biologic Drugs in 2008

Generic Name Brands Companies Indications Sales $ billion2006 2007 2008

Etanercept Enbrel® Amgen, Wyeth Takeda RA, JRA, Ps, PsA, AS 4.4 5.2 7.66Infliximab Remicade® J&J, Schering, Mitsubishi RA, UC, CD, Ps, PsA, AS 4.2 5.04 6.2Rituximab Rituxan® Genentech, Roche NHL, RA 4.7 5.01 5.48Bevacizumab Avastin® Genentech, Roche Colon, Lung Cancer 2.4 3.93 4.82Trastuzumab Herceptin® Genentech, Roche Breast Cancer 3.14 4.4 4.72Adalimumab Humira® Abbott RA, Ps, JIA, PsA, AS, CD 2.04 3.06 4.5Enoxaparin Lovenox® Sanofi Aventis Anticoagulant DVT 3.06 3.65 3.99Insulin Lantus® Sanofi Aventis Diabetes 1.9 2.4 3.58Darbepoetin Aranesp® Amgen Anemia 4.1 4.2 3.1Human Papilloma Virus Gardasil® Merck Cervical Cancer 1.4 2.8Pneumococcal Vaccine Prevnar® Wyeth Pneumococcal Disease 1.9 2.4 2.7

http://knol.google.com/k/krishan-maggon/global-biotechnology-market-review

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Biologicals: Safety Review 2008

JAMA 2008, 1939

ORIGINAL CONTRIBUTION

Safety-Related Regulatory Actionsfor Biologicals Approved in the United Statesand the European UnionThijs J. Giezen, PharmDAukje K. Mantel-Teeuwisse, PhDSabine M. J. M. Straus, MD, PhDHuub Schellekens, PhDHubert G. M. Leufkens, PhDAntoine C. G. Egberts, PhD

BIOLOGICALS, DEFINED AS PROD-ucts of which the active sub-stance is produced by or ex-tracted from a biological

source, represent an important andgrowing part of the therapeutic arse-nal.1 In the United States, the first bio-logical, recombinant insulin, was ap-proved in October 1982.2 Since then,more than 250 biologicals, including re-combinant (blood) products, mono-clonal antibody−based products, andrecombinant vaccines have been ap-proved by regulatory authorities.3 Be-tween 2003 and 2006, biologicals rep-resented 24% and 22% of all newchemical entities approved by the USand EU regulatory authorities, respec-tively.4 Sales of biotech products in theUnited States showed an annual growthrate of 20% between 2001 and 2006compared with 6% to 8% in the phar-maceutical market.5

Knowledge of a new drug is incom-plete at the time of approval, espe-cially with reference to its safety pro-file, due to a variety of factors includingconstraints in the sample size and the

For editorial comment see p 1939.

Author Affiliations: Utrecht Institute for Pharmaceu-tical Sciences, Divisions of Pharmacoepidemiology andPharmacotherapy(DrsGiezen,Mantel-Teeuwisse,Leuf-kens, and Egberts) and Pharmaceutics (Dr Schelle-kens), and Department of Innovation Sciences (DrSchellekens), Utrecht University, and Department ofClinical Pharmacy, University Medical Center Utrecht

(Dr Egberts), Utrecht, the Netherlands; and Medi-cines Evaluation Board, the Hague, the Netherlands(Drs Giezen, Mantel-Teeuwisse, Straus, and Leufkens).Corresponding Author: Aukje K. Mantel-Teeuwisse,PhD, Utrecht Institute for Pharmaceutical Sciences,PO Box 80082, 3508 TB Utrecht, the Netherlands([email protected]).

Context Biologicals are a relatively new class of medicines that carry specific risks(eg, immunogenicity). However, limited information is available on the nature and tim-ing of safety problems with their use that were identified after approval.

Objective To determine the nature, frequency, and timing of safety-related regu-latory actions for biologicals following approval in the United States and/or the Euro-pean Union.

Design and Setting Follow-up of a group of biologicals approved in the UnitedStates and/or European Union between January 1995 and June 2007. Vaccines, al-lergenic products, and products for further manufacture and transfusion purposes wereexcluded.

Main Outcome Measures Nature, frequency, and timing of safety-related regu-latory actions defined as (1) dear healthcare professional letters (United States) anddirect healthcare professional communications (European Union), (2) black box warn-ings (United States), and (3) safety-related marketing withdrawals (United States andEuropean Union) issued between January 1995 and June 2008.

Results A total of 174 biologicals were approved (136 in the United States and 105in the European Union, of which 67 were approved in both regions). Eighty-two safety-related regulatory actions (46 dear healthcare professional letters, 17 direct health-care professional communications, 19 black box warnings, and no withdrawals) wereissued for 41 of the 174 different biologicals (23.6%). The probability of a first safety-related regulatory action, derived from Kaplan-Meier analyses, was 14% (95% con-fidence interval [CI], 9%-19%) 3 years after approval and 29% (95% CI, 20%-37%)10 years after approval. Biologicals first in class to obtain approval had a higher riskfor a first safety-related regulatory action compared with later approved products inthat class (12.0/1000 vs 2.9/1000 months, respectively; hazard ratio, 3.7 [95% CI,1.5-9.5]). Warnings mostly concerned the classes general disorders and administra-tion site conditions, infections and infestations, immune system disorders and neo-plasms benign, malignant, and unspecified.

Conclusions The nature of safety problems identified after approval for biologicalsis often related to the immunomodulatory effect (infections). Because the biologicalsfirst to be approved in a class were more likely to be subjected to regulatory action,close monitoring is recommended.JAMA. 2008;300(16):1887-1896 www.jama.com

©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, October 22/29, 2008—Vol 300, No. 16 1887

at Genentech on October 22, 2008 www.jama.comDownloaded from

Safety-related Regulatory Actions

Assessment for all protein therapeutics

approved 1995-2007 in Europe and US

(n=176)- Healthcare Professional Letters (US) & direct

Healthcare Professional Communications (EU)- Black box warnings (US, EU)- Market withdrawal

“. . . No biologicals were withdrawn dueto safety reasons . . . ” (Oct 2008)

The assessment did not provideevidence for regulatory actions onrelevant DDIs.

Specific risks identified (e.g.immunogenicity, infections)

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Drug-Drug Interactions: SMD and MAbs

The Problem Statement“Unexpected clinical drug interactions, for example, can lead to a higher risk of adverse eventsand substantially reduce the probability of treatment success.”Seitz and Zhou, J Clin Pharmacol 2007, 47, 1104

Small Molecule Drugs - PK-based Drug-Drug Interactions:

- Serious side effects and even market withdrawals- Primarily metabolism and/or transport processes involved

Protein Therapeutics - PK-based Drug-Drug Interactions:

- Often in the past not studied because clearance pathways are distinct from SMD- Only few PK-based DDIs with modest PK based DDIs identified

á limited therapeutic relevance

QuestionIs the low prevalence and limited therapeutic relevance of PK-based DDIs of proteintherapeutics due to limited incidence or limited clinical exploration?

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FDA / EMEA: Guidance

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FDA Guidance: Draft – September 2007

Current Draft ProposalClassical biotransformation studies are not a general requirement for the evaluation oftherapeutic biologics . . .

However, certain protein therapeutics such as cytokines or cytokine antagonists may modify themetabolism of drugs that are metabolized by the P450 enzymes through interaction with the regulationpathways of P450 enzymes. For example, Type I interferons are shown to inhibit CYP1A2 productionat the transcriptional and post-translational levels leading to decreased clearance of theophylline. Theincreased clinical use of therapeutic proteins may raise concerns regarding the potential for theirimpacts on drug metabolism. Generally, these interactions may not be adequately detected by invitro assessment.

In vivo drug-drug interaction studies may be indicated when a biologic product is designed to beadministered with other drug product(s) as a combination regimen, and when a biologic product is acytokine or cytokine antagonist due to its potential alteration of CYP-mediated metabolism of otherdrugs.

When a biologic product and an narrow therapeutic index drug products are administeredconcomitantly, drug-drug interaction studies are recommended. Consultation with FDA is appropriatebefore initiating metabolic drug-drug interaction studies involving biologics.

Jang-Ik Lee, NBC 2008 Roundtable on DDI of TPs

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EMEA Guidance: Guidance on PK of therapeutic Proteins

EMEA: 2007“The requirements for in vivo drug-drug interaction studies, with respect to e.g.cytochrome P450 (CYP) enzymes, are generally lower for therapeutic proteinsthan for conventional products."

“However, some therapeutic proteins (e.g. immunomodulators such ascytokines) have shown a potential for inhibiting or inducing CYP-enzymes andthus the need for in vitro or in vivo studies should be considered on acase-by-case basis"

“Interaction studies should be considered when the protein induces changes toelimination pathways (receptors) also involved in the elimination of other drugs orwhen suppression of the immunological system is likely"

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Example: Interferons

http://www.biojobblog.com/tags/protein/

Example: Pegylated Interferon α-2a (Pegasys®)

IFN, a cytokine, produced by cells of the immune system inresponse to challenges such as viruses, parasites and tumorcells.

Hepatitis C and B, hairy cell leukemia, malignant melanoma

DDI studies performed – known DDI concerns

Potential mechanisms:

Decrease in gene expression (Delaporte et al., 1997)Reactive oxygen intermediates (Ghezi et al., 1985)Enzymatic degradation (Gooderham et al, 1986)

Ref: Pegasys® Label

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Interferon-α: Impact on CYPs

Consistent decrease of CYP1A2. Moderate and variable impact on CYPs.

Interferon-α 2a/2b↓ 5-47% antipyrine CL Williams et al 1986↓ 31-81% theophylline CL Williams et al 1987↓ O-demthylase (31%) and O-deethylase (33%) activities in liver Okuno et al 1993No effect on AUC or oral CL of didanosine Piscitelli et al 1996No effect on CYP1A2 by caffeine index or CYP3A4 by 6β -OH cortisol/cortisol ratio Pageaux et al 1998↓ 63% cyclophosphamide CL Hassan et al 1999↓ 60% inhibition CYP1A2; no effect on CYP2E1; significant inhibition of CYP2D6 and 2C19 Islam et al 2002

Interferon-α 2a/2b + ribavirin↑ in CYP3A4 by 112-1677% in some subjects and ↓ by 47-67% in others Becquemont et al 2002↑ in CYP2D6 by 120-322% in some subjects and ↓ by 42-93% in others Becquemont et al 2002

Pegylated Interferon-α 2a/2b↑ 15% R,S and total methadone exposure (CYP3A4, 2D6, 1A2 & 2B6) Gupta et al 2007↑ 25% AUC theophylline (CYP1A2): no effect on CYP2C9, 2C19, 2D6 and 3A4 Pegasys® Package Insert↑ 10-15% in methadone plasma levels Sulkowski et al 2005↑ 24 & 17% methadone Cmax and AUC, respectively Berk et al 2007

B. Brennan et al, NBC AAPS 2008

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Pegylated Interferon-α-2a – Pegasys®

Drug-Drug Interaction Strategy

Cocktail approach

CYP1A2: theophylline, CYP2C9 (extensive metabolizers): tolbutamide, CYP2C19:mephenytoin, CYP2D6 (extensive metabolizers): debrisoquine, CYP3A4: dapsone

Dose of peg-INF-α-2a – 180 µg qw x4wk

Cocktail administered with 4th dose

Results 25 % increase in theophylline AUC, no effect on others

Dedicated DDI study with methadone

Pegasys® Label

No effect on the PK of representative drugs metabolized by 2C9,2C19, 2D6, or 3A4

Inhibition of CYP1A2 and a 25 % increase in theophylline AUC

“Methadone PK parameters were 10-15 % higher”

Methadone did not significantly alter the PK of Pegasys®

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Monoclonal Antibodies vs Small Molecule Drugs

March 20, 2008 DDI Strategy Proposal Slide 11

Clearance of SMD vs Biologics

mAb

Target mediated Clearance(e.g. target binding, internalization, proteolysis)

Nonspecific Clearance(e.g. proteolysis)

Monoclonal AntibodiesSmall Molecule Drugs

SMDBiliary Renal

Metabolism(e.g. CYP450)

Transporter(e.g. P-gp)

Large CL Capacity for major CLprocesses

iv, sc or im applications only; no oral

Distribution limited to plasma V, limitedintracellular distribution

Proteolysis, target mediated drugdisposition

March 20, 2008 DDI Strategy Proposal Slide 11

Clearance of SMD vs Biologics

mAb

Target mediated Clearance(e.g. target binding, internalization, proteolysis)

Nonspecific Clearance(e.g. proteolysis)

Monoclonal AntibodiesSmall Molecule Drugs

SMDBiliary Renal

Metabolism(e.g. CYP450)

Transporter(e.g. P-gp)

Typically smaller Capacity of CLprocesses than those for MAbs

Oral administration preferred

Typically all tissues accessible

Oxidation, conjugation, others

Excretion: Passive or active via transporter

Clearance mechanisms of SMD and MAbs are distinct, i.e. direct DDIs are not expected.Indirect response mechanisms (e.g. via cytokine effects) are possible.

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MAbs: Structure – Clearance Mechanisms

ref: http://131.111.9.218/ mrc7/pdb/index.html

Fab – Antigen binding fragment

Target mediated clearance

Target interaction, internalization, targetmodulation

Fc – Effector function

FcRn - neonatal Fc receptor – salvage systemprotecting MAbs from proteolysis in lysosomes

FcγR – Interaction with immune cellse.g. engaging NK cells, limited impact on CL

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Clearance of MAbs: Target Mediated Drug Disposition

13

Mechanistic PK/PD Model for Antibody with Large Component of Receptor-Mediated CL

Antibody in Periphery

Antibody in Serum

VcReceptor+

Kon

Koff

Antibody-ReceptorComplex

Ksyn

Kdeg

Kel

KmKcp

Kpc

Input function

CLtotal = CLnon-specific + CLtarget

C. Ng et al , Pharmaceutical Research 2005

Clearance = CLnon−specific +CLTarget

D. Mager. Biochem Pharmacol 2006, 72, 1-10.

0 10 20 30 40 50

Time [days]

Con

cent

ratio

n [ µ

g/m

L ]

0.1

0.51.0

5.010.0

50.0100.0

Relevant Target mediated clearance

Dose 1Dose 2Dose 3

0 10 20 30 40 50

Time [days]

Con

cent

ratio

n [ µ

g/m

L ]

0.1

0.51.0

5.010.0

50.0100.0

No relevant Target mediated clearance

Dose 1Dose 2Dose 3

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Clearance of MAbs: Victim - DDI Risk Assessment

February 21, 2008 DDI Strategy Proposal Slide 14

Limited DDI Potential for mAbs

mAbs: Lower CL limit 2-5 mL/day/kgSMD: No limit for clearance decrease

Potential Safety Risk

Potential Efficacy Risk

Saturation of FcRnTarget mediated CL

Low DDI risk

Dose / Concentration

0 10 20 30 40 50

Time [days]

Con

cent

ratio

n [ µ

g/m

L ]

0.1

0.5

1.0

5.0

10.0

50.0

100.0

Relevant Target mediated clearance

Dose 1Dose 2Dose 3

0 10 20 30 40 50

Time [days]

Con

cent

ratio

n [ µ

g/m

L ]

0.1

0.5

1.0

5.0

10.0

50.0

100.0

No relevant Target mediated clearance

Dose 1Dose 2Dose 3

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Clearance of MAbs: Examples

Linear PK in the therapeutic dose range with CL between 2-5 mL/day/kgá Elimination primarily via large capacity, non-specific eliminationá Probably limited DDI risk

Monoclonal Antibody Target Antigen Clearance @ Dose Reference[mL/day/kg] [mg/kg]

Adalimumab TNFα 3.5-4.5 0.25 M Weisman et al, 2003Bevacizumab VEGF-A 3 >1 J-F Lu et al, 2007Daclizumab CD25 3-4 1 Prescribing Information, 2005Efalizumab CD11a Nonlinear 1-2 A Joshi et al, 2006Omalizumab IgE 2.5 >0.5 N Hayashi et al, 2006Panitumumab EGFR 4.9 >2 Prescribing Information, 2006Pertuzumab Her2 3 2 C Ng et al, 2006Rituximab CD20 3-4 101 Prescribing Information, 2006Trastuzumab Her2 3.2 >4 R Bruno et al, 2005

1375 mg/m2

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Clearance of MAbs: Example of Dose RelationshipFor MAbs with typical IgG1 CL (2-5 mL/day/kg), limited contribution of targetmediated clearance á risk of relevant PK DDIs is small.

February 21, 2008 DDI Strategy Proposal Slide 15

DDI Potential = f (clinical Dose, CL mechanism)

Raptiva

Dose (mg/kg) 0 2 4 6 8 10 12

CL

(mL/

day/

kg)

1

10

100

Pertuzumab

Dose (mg/kg) 0 5 10 15 20

CL

(mL/

day/

kg)

0

2

4

6

8

10

12

14

16

18

20

Relevant target mediated clearancevia target antigen

Primarily nonspecific clearance(proteolysis)

Clinical Dose> 50% target related

Clinical Dose

• Change in target expression = Change in CL (DDI)

• e.g. efalizumab + cyclosporine/MMF2fold lower CL

• No change in target expressionexpected

• No DDI expected

PertuzumabEfalizumab

A Joshi et al, J Clin Pharmacol 2006,46, 10-20 Ch Ng et al, Pharm Res 2006, 23, 1275-1284

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Clearance of MAbs: Impact of parallel CL Processes

Parallel CL processes typically reduce the risk of PK drug-drug interactions.

March 20, 2008 DDI Strategy Proposal Slide 11

Clearance of SMD vs Biologics

mAb

Target mediated Clearance(e.g. target binding, internalization, proteolysis)

Nonspecific Clearance(e.g. proteolysis)

Monoclonal AntibodiesSmall Molecule Drugs

SMDBiliary Renal

Metabolism(e.g. CYP450)

Transporter(e.g. P-gp)

March 20, 2008 DDI Strategy Proposal Slide 11

Clearance of SMD vs Biologics

mAb

Target mediated Clearance(e.g. target binding, internalization, proteolysis)

Nonspecific Clearance(e.g. proteolysis)

Monoclonal AntibodiesSmall Molecule Drugs

SMDBiliary Renal

Metabolism(e.g. CYP450)

Transporter(e.g. P-gp)

Ito, Hallifax, Obach & Houston DMD 2005Impact of Parallel Metabolic Pathways

840 ITO ET AL.

Ito et al, DMD 2005: 33, 837

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MAbs: Victim Drug – Risk of PK-based DDIs

PK-based DDI: Clearance mechanisms – moderate to low risk for MAbs being a victim drugFew DDI examples suggest modest impact on CL - e.g. Adalimumab - Methotrexate; CL ⇓ ca 50 %

Drug Disposition Target mediated CL

FcγR mediated CL

FcRn mediated CL

Immunogenicity

Potentially small capacityImpact of target expression changes(e.g. Depletion of traget antigen / target cellby comedication)

Modulation of receptor expressione.g. Methotrexate down modulation of FcγRI

High capacity – low risk of saturation

Impact of Immunsuppressive Agentse.g. Methotrexate reduces ATA

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MAb as victim: Examples

Influence of SMD on MAbs

Limited PK DDI data available

Potential influence on antigen target expressioná Change of target mediated CLInfluence on immunogenicityInfluence on FcR affinitiesUnknown mechanisms

Drug Name Mechanism Example Clearance

Immunosuppressives Immunogenicity ⇓ methotrexate→ adalimumab 22-44% ⇓ 2

methotrexate→ infliximab? ?? 3

Immunosuppressives Target Expression ⇓ cyclosporine→ basiliximab? ⇓ 4

azathioprine→ basiliximab? ⇓ 3

Cytotoxic Drugs Target Expression ⇓ ?? ⇓ ??(Immunosuppressives)

2Abbott Lab., Prescribing Information 2007

3R Maini et al, Arthr& Rheumat 1998, 41, 1552

4J Kovarik et al, Clin Transplant 2001, 15, 123

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Infliximab – DDI Victim in Combination with Methotrexate1560 MAIN1 ET AL

P looo1

8 g 100 .- Y

3 mg/kg

0 22 0.1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 t t t t t

Weeks

Figure 3. Pharmacokinetics of cA2 in patients treated with cA2 at 1, 3, or 10 mdkg with (0) or without (0) methotrexate (MTX). Shown are median serum cA2 concentrations 1 hour postinfusion on day 0, immediately before and 1 hour after infusion at weeks 2,6, 10, and 14, and at weeks 1, 4, 8, 12, 16, 18, 20, 22, and 26.

ment of flares of RA and during the early phase of introduction of Dh4ARDs. However, our preliminary experience with repeated cA2 therapy used after clinical relapse in a small group of patients had also shown that it was immunogenic in up to 50% of patients (12). It therefore seemed possible that long-term use might be limited by allergic reactions and loss of efficacy as a result of the development of “blocking” antiidiotypic antibodies. In light of these potential problems, the results of the current randomized controlled trial are revealing and encouraging.

As judged by established response criteria, re- peated administration of cA2 over 14 weeks according to the regimen specified in the protocol, with or without

MTX, is rapidly efficacious, with marked suppression of swollen and tender joints, reduction in CRP levels, and achievement of Paulus response criteria in -60% of all patients compared with the placebo-treated group. The only exception was in the group receiving low-dose (1 mg/kg) cA2, in which the response was limited to the first infusion and lasted only a median of 2.6 weeks. The robust response data obtained in other groups left little doubt about efficacy despite the relatively small num- bers of patients in each group and some differences in disease activity at study entry. We had previously shown that the median duration of response to a single 1-mg/kg dose of cA2 alone lasted -3 weeks, and 3- and lO-mg/kg doses lasted 5 and 8 wecks, respectively (24). It was therefore not unexpected that during repeated treat- ment every 4 weeks, no increment in the number of patients exhibiting a clinical response, as assessed by the Paulus 20% criteria, during the period of 0-14 weeks in the 3- and 10-mgikg dosage groups was observed (Fig- ure 1B).

The design of this trial tested the hypothesis that cA2 as continuing monotherapy may be effective but limited by its immunogenicity, and that additive or synergistic action could be obtained by combining cA2 and MTX. The rationale was based on preclinical expe- rience in murine collagen-induced arthritis (25). Since data were available on the duration of response to cA2 alone, MTX alone, and the combination of cA2 plus MTX, it was possible to assess synergy by examining whether the response period with combination therapy exceeded the sum of the response periods with cA2 and MTX alone. Using these criteria, synergy was demon- strated in the duration of response when MTX was coadministered with 1 mg/kg of cA2. That the combina- tion therapy led to greater efficacy is supported by the finding that almost all patients receiving combination therapy at this dosage completed their treatment pro- gram, compared with only 53% receiving monotherapy with cA2 at 1 rngikg and 43% receiving MTX and placebo infusion (Table 3). At 3 m a g of cA2, coadmin- istration of MTX did not reveal a synergistic effect. However, synergistic trends were especially observed at 10 mg/kg of cA2 at the Paulus 20% level and at all doses at the Paulus 50% level, and a more enduring benefit was noted from week 14 through to week 26 in patients receiving cA2 at 3 and 10 mgikg plus MTX (Figure 1).

It has been suggested that “process” variables such as swollenitender joints and CRP should ideally be segregated from “outcome” measures such as physical disabilities (26). In this regard, a reduction of 60% in

Maini RN et al. - Infliximab in RA

Arthritis Rheum. 1998 Sep;41(9):1552-63

Infliximab 1, 3, and 10 mg/kg with andwithout methotrexate 7.5 mg/kg iv

26-week placebo-controlled studyconducted in RA (n=101)

Immunogenicity – @ 1 mg/kg,15 % with vs 53 % without MTX

Immunsuppression of ATA mechanisms –DDI???

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MAbs: Perpetrator Drug – Risk of PK-based DDIs

Risk of PK-based DDIs via target- / downstream effects e.g. on cytokine levelsFew DDI examples suggest modest impact on CL

pegylated interferon – Pegasys®(theophylline CL 25% ↓, CYP1A2 ↓)anti-IL6R MAb tocilizumab – Actemra®(simvastatin CL ca 50% ↑, CYP3A4 ↑)

Drug Disposition

Target modulation

Downstream Effects

Unknown Effects

Effect of Immunosuppressive agents

Modulation of target expressione.g. Change in cytokine expression, impact on CYP / Transporter expression

?????

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Potential PK DDI Mechanisms

Influence of MAbs on SMD

Limited PK DDI data available

No direct DDI expected, since SMD and MAbs do not share commonCL pathways

However, potential indirect effects on expression of metabolizingenzymes / transporter

Cytokine like effects (e.g. interferons)á CYP expression ⇓ ⇑á e.g. peginterferon α-2a – CYP1A2 ⇓ – theophylline CL ⇓Effects of anti-cytokine MAbs on cytokine levels(e.g. anti-IL6R MAb - tocilizumab, Actemra®)á CYP expression ⇑, CL of CYP3A4 ⇑Other unknown mechanisms?

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DDI of Protein Therapeutics on SMD

Literature data, often case reports and not enough controlled

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DDI of Protein Therapeutics on SMD – GNE experience

No evidence of impact of protein therapeutics on SMD

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Clearance Mechanisms – Conclusions

DDI – MAbs and SMD

MAbs and SMD do not share common CL pathwaysHowever, SMD can potential change the PK of MAbse.g. Influence of immunsuppressive agents on the PK of MAbsHowever, MAbs can potentially induce indirect downstream effectse.g. cytokine effects on CYP expressionHowever, some DDI mechanisms are not yet fully understood

MAbs are often cleared by large capacity processesá probably lower DDI risks

In contrast, SMD are typically cleared by smaller capacity Processesá potentially higher DDI risk

Focus: Impact of PK DDI on safety and efficacy given the TI of MAbsand SMD (e.g. narrow therapeutic index compounds)

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Protein Therapeutics: Risk based DDI assessment

DDI risk assessment

Science-based, risk-based approach as part of clinical pharmacology plans

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Acknowledgements

FDA – DDI working group / Clinical PharmacologyBiosafe – DDI working groupNational Biotech Conference 2008/2009 – DDI working group

@ Genentech / RocheDDI working groupsSandhya GirishLisa BellAmita JoshiPaul FielderEarly Development PKPD SciencesClinical PKPD Sciences

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