Development and Justification of Qualification Threshold

Ron WolffIPAC-RS RepresentativeFellow, Life SciencesNektar Therapeutics

Outline

• Decision criteria• Process for setting qualification threshold (QT)

– Comparison to non-carcinogenic reference thresholds in a similar manner to SCT

• Consideration of irritation, hypersensitivity, age• Relation of QT to

– Ambient particulate matter– Examples from marketed products

Decision Criteria

• A leachable with a tolerable daily intake (TDI) at or below the qualification threshold – would have a dose so low as to present negligible

safety concerns from noncarcinogenic toxic effects– would be considered qualified, so no toxicological

assessment would be required– would require a toxicology risk assessment with a

structural alert or known class effect for carcinogenicity/genotoxicity, irritation, or hypersensitivity

Reference Exposure Levels (RELs)

• Definition– Daily exposure concentration considered to present negligible

risk to human health from non-carcinogenic effects– Usually a no-observed-adverse-effect-level (NOAEL) from

animal toxicology studies with the use of an appropriate safety factor (usually 100)

• Sources– US EPA– Agency for Toxic Substances Disease Registry (ATSDR)– California Environmental Protection Agency (CAL EPA)

Inhalation Reference Levels in Various Databases

0%

20%

40%

60%

80%

100%

0.0001 0.01 1 100 10000 1000000

US EPA Inhalation RfD (µg/day)

Systemic Tox (N=62)

Respiratory Tox (N=38)

0%

20%

40%

60%

80%

100%

0.0001 0.01 1 100 10000 1000000

California REL (µg/day)

Systemic Tox (N=44)

Respiratory Tox (N=32)

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60%

80%

100%

0.0001 0.01 1 100 10000 1000000

ATSDR Minimal Risk Level (µg/day)

Systemic Tox (N=41)Respiratory Tox (N=18)

0%

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40%

60%

80%

100%

0.0001 0.01 1 100 10000 1000000

Combined Reference Value (µg/day)

Systemic Tox (N=98)

Respiratory Tox (N=57)

Summary of Inhalation Reference Toxicity Values (µg/day)

Respiratory Toxicity Systemic Toxicity

median 10th %tile median 10th %tile

CAL EPA RELs 60 1.2 5000 4.0

ATSDR MRLs 189 1.1 5426 5.4

US EPA RfDs 90 0.5 1400 4.2

Combined 120 1.5 1940 5.0

Most Compounds with Reference Levels < 5 g/day Are Metals, Carcinogens or Identified Irritants

Compounds with Respiratory Toxicity Compounds with Systemic Toxicity

CompoundRef Value

(µg/day)

Source CompoundRef Value

(µg/day)Source

chromium vi (chromic acid mists) 0.086 REL RfD MRL chlorinated dioxins 0.0008 REL

beryllium and compounds 0.237 RfD REL cadmium 0.4 REL

hexamethylene diisocyanate 0.525 RfD MRL arsenic 0.6 REL

acrolein 0.583 REL RfD MRL arsine 1.0 RfD

chloroacetophenone, 2- 0.600 RfD manganese 1.5 REL RfD MRL

toluene diisocyanate mixture 1.4 RfD REL mercury 1.9 REL RfD MRL

glutaraldehyde 1.6 REL chlordane 2.4 REL MRL

nickel & compounds 2.0 REL MRL dicyclopentadiene 4.0 RfD

cobalt 2.0 MRL nitroaniline, 2- 4.0 RfD

titanium tetrachloride 2.0 MRL disulfoton 4.0 MRL

nickel oxide 2.0 REL 1,2-dibromoethane 4.0 RfD

antimony trioxide 4.0 RfD1,2-dibromo-3-

chloropropane4.0 RfD

chlorine 4.0 RfD REL hydrazine 4.0 REL

chlorine dioxide 4.0 RfD

hexachlorocyclopentadiene 4.0 RfD

Note: For compounds with more than 1 source, Ref Value is geometric mean from all available sources. Ref Value = reference value.

Irritation

• Evaluated from the point of view that asthmatics are the most sensitive population

• Used the RD50 database developed on inhaled irritants in mice as a starting point– Validated, well-accepted, extensive database of commodity chemicals– RD50 is the concentration that produces marked effects in mice by

reducing respiratory frequency by 50%

• Confluence of data suggest that 0.001 X RD50 is a safe concentration for most asthmatics– Corresponds to a concentration that produces no discernible effects on

lung tissue, and thus also unlikely to elicit any bronchoconstrictor response, since the two are correlated

– RD50 based safe dose = 0.001 X RD50 breathed for 10 minutes

Sensitivity of Asthmatics Compared to Normal Population

• Cockcroft (Ann Allergy, 1985) studied 253 normals and 181 symptomatic asthmatics challenged with aerosolized histamine– 25% of normals responded at a concentration of 16 mg/L

[effectively, an RD50 concentration]– 25% of asthmatics responded at 0.2 mg/L– No observable responses in asthmatics at 0.015 mg/L

Illustrates that 1/1000 of RD50 values is likely to pose negligible risk for most asthmatics

RD50 Based Safe Dose in Asthmatics is Less than Occupational Short Term

Exposure Limits (STELs)

0%

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100%

0.01 0.1 1 10 100 1000 10000 100000

Inhaled Dose (ug)

Cu

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RD50 Based Non-Irritant Dose

15-min STEL

RD50 Based Safe Doses are Similar to California RELs Designed to Protect the General Population

(Including Sensitive Sub-Populations)

0%

20%

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100%

0.1 1 10 100 1000 10000 100000

Inhaled Dose (ug)

Cum

ulat

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Per

cent

CA Acute REL Based

RD50 Based

Hypersensitivity

• Data on isocyanates used to provide perspective• RD50 of toluene diisocyanate is 0.4 ppm• Permissible Exposure Level (PEL) is 0.02 ppm

– Level designated to prevent induction of sensitization

• Lowest concentration eliciting responses in sensitized subjects– 0.001 ppm

These data and other similar examples suggest that 0.001 X RD50 is also protective of hypersensitivity reactions

Acute Irritation and Sensitization Have Similar Dose-Response to Chronic

Respiratory Toxicity

0%

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100%

0.001 0.01 0.1 1 10 100 1000 10000 100000 1000000

Inhalation Dose (µg/day)

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Estimated Safe Human Exposures for Various Toxicity Endpoints

Carcinogenicity, 10-6 Risk Specific Dose for CPDB Mutagens (N=276)

Acute Irritation, Human Equivalent RD50/1000 (N=244)

Respiratory Toxicity, Chronic Inhalation Reference Dose (N=57)

Systemic Toxicity, Chronic Inhalation Reference Dose (N=98)

Carcinogenicity Acute Respiratory

Irritation

Chronic Respiratory Toxicity

Chronic Systemic Toxicity

Most Compounds with RD50 Based Reference Exposure Levels < 5 g/day Can be Identified with

Structural Alerts

• Isocyanates

• Aldehydes

• Pesticides

• Nitriles

• Styrenes

Comparison of 5 g/day QT with Ambient Particulate Exposures

• Ambient reference concentration - 18 g/m3

– Data from Portage, Wisconsin

• Cleanest environment in the “Six cities study”

• Best air quality and least cardio-respiratory disease

• Designated as the “control” city against which others were compared

– Well below the National Air Quality Standards for PM10 (respirable fraction)

• 50 g/m3 annual average

• 150 g/m3 twenty-four hr average

QT of 5 µg/day Compared to Inhaled Particulate in the Cleanest of the “Six Cities”

AgeBodyMass(kg)

VentilationInhaled Environmental

Particulates *5 µg/day Limit as %

of Inhaled Environmental

Particulates(m³/day) (m³/kg/day) (µg/day) (µg/kg/day)

1 year 11.5 † 5.1 † 0.4 93 8.0 5.4%

5 years 20.0 † 8.7 † 0.4 157 7.8 3.2%

10 years 33.7 † 15.3 † 0.5 275 8.2 1.8%

15 years 55.0 † 17.7 † 0.3 319 5.8 1.6%

Adult 58.0 † 17.8 † 0.3 320 5.5 1.6%70.0 ‡ 20.0 ‡ 0.3 360 5.1 1.4%

* Based on PM10 inhalable particle concentration of 18 g/m³ in reference city Portage WI, USA, (Dockery et al, 1993).† Estimates based on measurements for different ages of ventilation rate at various activity levels and percentage of daily time spent at those activity levels (Roy, 1992) ‡ Standard estimates used by US EPA for risk assessment

Perspective for Exposures to Children

• 5 g/day QT

– Represents a minor additional load compared to daily environmental exposure for any age group, including children

• Comparisons of toxicokinetics in adults and children are within the toxicokinetic safety factor of 3.16 greater than 90% of the time

• Comparison of deposition of particles and gases in adults vs children are within the toxicokinetic safety factor of 3.16

Therefore, the standard intraspecies safety factor of 10 (toxicokinetic factor of 3.16 x toxicodynamic factor of 3.16) appears to be adequate to account for possible differences between adults and children, however additional research in this area is warranted

Comparison of 5 µg/day QT with ICH ThresholdsProduct

Type

ActiveIngredient

Maximum Dose *

(µg/day)

ICH Qualification Threshold

Drug Substance Drug Product

basis (µg/day) basis (µg/day)

FORADIL DPI formoterol fumarate 20 0.15% 0.03 1% 0.2

SEREVENT MDI-DPI salmeterol xinafoate 100 0.15% 0.15 1% 1.0

FLONASE NAS fluticasone propionate 200 0.15% 0.30 1% 2.0

ATROVENT MDI ipratropium bromide 216 0.15% 0.32 1% 2.2

ATROVENT NAS ipratropium bromide 252 0.15% 0.38 1% 2.5

BECONASE AQ NAS beclomethasone dipropionate 336 0.15% 0.50 1% 3.4

QVAR MDI beclomethasone dipropionate 512 0.15% 0.77 1% 5.1

ASTELIN NAS azelastine hydrochloride 1,096 0.15% 1.6 1% 11.0

VANCERIL 84 MDI beclomethasone dipropionate 1,260 0.15% 1.9 1% 12.6

PULMICORT DPI budesonide 1,280 0.15% 1.9 1% 12.8

PROVENTIL HFA MDI albuterol sulfate 1,296 0.15% 1.9 1% 13.0

AZMACORT MDI triamcinolone acetonide 1,600 0.15% 2.4 1% 16.0

FLOVENT MDI-DPI fluticasone propionate 2,000 0.15% 3.0 1% 20.0

AEROBID MDI flunisolide 2,000 0.15% 3.0 1% 20.0

MAXAIR MDI pirbuterol acetate 2,400 0.15% 3.6 1% 24.0

INTAL MDI cromolyn sodium 6,400 0.15% 9.6 ≤50 µg 50.0

TILADE MDI nedocromil sodium 14,000 0.15% 21 0.50% 70.0

RELENZA DPI zanamivir 20,000 0.15% 30 0.50% 100

IMITREX NAS sumatriptan 40,000 0.15% 60 0.50% 200

NICOTROL NS NAS nicotine 40,000 0.15% 60 0.50% 200

Median 1,448 1.9 12.9

* Based on dose delivered from mouthpiece or actuator when reported. "Every 4 hours" is assumed to allow up to 6 times daily. Abbreviations: DPI = dry powder inhaler; MDI = metered dose inhaler; NAS = nasal spray

OINDP L&E Threshold Perspective

• Recommended thresholds based on dose inhaled by patients

– Rather than a percentage (%) as in ICH Guidelines

• 5 g/day QT

– Recommendations intermediate between API and drug product ranges

– Relevance maximized based on considerations of

• Total daily intake

• Structural alerts

• Conservative risk assessment

Summary

• A Qualification Threshold (QT) of 5 µg/day meets the criterion of a dose that is sufficiently low as to present negligible safety concerns for noncarcinogenic toxic effects.

• Consideration of possible irritancy and hypersensitivity suggest that 5 µg/day will adequately protect sensitive sub-populations

• The risk assessment must include structural alert information to provide case-by-case assessments for metals, isocyanates, aldehydes, nitriles, and styrenes whose levels are below the QT