IPEC America’s New PPT Template · build-up of lactose. There is then the risk of abdominal...

4/25/2013

1

EXCIPIENTS USED IN

PEDIATRIC DRUG PRODUCTS:

Are Juvenile Toxicology Studies Needed?

Elise M. Lewis, PhDCharles River Laboratories, Preclinical Services, Pennsylvania

29 April 2013 • Baltimore, MD

EXCIPIENTS USED IN PEDIATRIC

DRUG PRODUCTS

• Objectives:

– Define Pharmaceutical Excipients

• Types and Use

• Selection of Excipients for Pediatric Formulations

– “Good Intentions Gone Bad”

– When Should Juvenile Animal Studies Be Conducted?

– Points to Consider When Designing a Nonclinical Juvenile Animal

Study

EXCIPIENTSPediatric Drug Products

4/25/2013

2

EXCIPIENTS

• New Excipients (FDA, 2005)

– “Any inactive ingredients that are

intentionally added to therapeutic

and diagnostic products, but that: (1)

we believe are not intended to exert

therapeutic effects at the intended

dosage, although they may act to

improve product delivery (e.g.,

enhance absorption or control

release of the drug substance); and

(2) are not fully qualified by existing

safety data with respect to the

currently proposed level of

exposure, duration of exposure, or

route of administration.”

EXCIPIENTS

EX

AM

PL

ES • Fillers

• Extenders

• Diluents

• Wetting Agents

• Solvents

• Emulsifiers

• Preservatives

• Flavors

• Absorption Enhancers

• Sustained-Release Matrices

• Coloring Agents

Why Use Excipients?

Deliver the dosage form to the patient

Improve solubility

Ensure physical,

chemical and microbial stability

Improve palatability and patient compliance

Control release

Improve manufactur-

ability

EXCIPIENTS IN FORMULATIONS

• Points To Consider (EMA, 2013 - draft)

1. The choice of a suitable excipient in a

pediatric formulation is one of the key

elements of the pharmaceutical

development

2. The basic considerations regarding use

of excipients are similar for medicines

developed for all age groups

3. Inclusion of any excipient in a pediatric

formulation requires additional safety

considerations

4. Use of novel excipients must be weighed

against the use of other excipients with

an established safety profile, other dosage

forms or routes of administration

Sele

cti

on

of A

pp

rop

riate

E

xcip

ien

ts • Function of the excipient and potential alternatives

• Safety profile for children in the target age group on the basis of single/daily exposure

• Short term vs. long term use

• Severity of the clinical condition

• Acceptability/palatability

• Allergies/sensitization

4/25/2013

3

LESSONS LEARNED

“Everyone will extract different lessons from

these tales.” (Robertson, 2003)

EXCIPIENT-RELATED TOXICITY

• Not all excipients are inert substances; somehave been shown to be potential toxicants.

• The Federal Food, Drug, and Cosmetic Act of1938 (the Act) was enacted after the tragedyof the Elixir of Sulfanilamide in 1937 inwhich an untested excipient was responsiblefor the death of many children who consumedthe pharmaceutical.

• The Act required manufacturers to performsafety testing of pharmaceuticals and submitnew drug applications (NDAs) demonstratingsafety before marketing.

• Since that time, the agency has become awarethat certain other excipients used incommerce can cause serious toxicities inconsumers of prescription and over-the-counter (OTC) drug products in the US andother countries.

Source: FDA, 2005


Benzyl Alcohol – “Gasping Syndrome”

• In 1981, Gershanik et al. reported cases of

“gasping syndrome”

– Pre-term infants exhibited: severe metabolic acidosis,

hepatic/renal failure, signs of neurological

deterioration and gasping respiration

– Unmetabolized benzyl alcohol (benzoic acid) was in

the urine

– Conjugation of benzoic acid to hippuric acid is

deficient in premature infants

• Observed in infants of low BW who had

central venous catheters (umbilical artery/vein)

that were flushed frequently using

bacteriostatic normal saline containing 0.9%

benzyl alcohol

• FDA recommended the exclusion of benzyl

alcohol from flush solutions and diluents used

in newborns

Benzyl

alcohol

Hippuric Acid

Benzaldehyde Benzoic Acid

Alcohol

Dehydrogenase

Alcohol

Dehydrogenase

Glycine

Prior to FDA recommendation to cease use in small

infants, ~70% of hospitals were using benzyl

alcohol solutions in the care of sick newborn infants.

4/25/2013

4


E-Ferol (Vitamin E Toxicity)

• Classified as “one of the most deadly pharmaceutical errors in American history”

• E-Ferol = Vitamin E plus Polysorbate 80

• Used to treat infants with retrolental fibroplasia (RLF)

• Since very small infants were not fed orally in the 1st week of life, and since IM injections were considered traumatic, an IV form of vitamin E was introduced in 1983

• The new product was widely accepted by neonatologists who were encouraged about the potential to prevent or ameliorate RLF

• Premature babies exposed to E-Ferol began to exhibit hepatomegaly, thrombocytopenia, cholestatic jaundice, ascites and azotemia

• There were 40 infant deaths associated with E-Ferol; cause of illness was not established

• Suspected elevated levels of polysorbate

• This product was not approved by the FDA Source: Robertson, 2003


Propylene Glycol Toxicity

• Propylene glycol (PG) used widely as a

solvent, extractant and preservative in

various pharmaceutical formulations;

generally regarded as nontoxic

• Metabolized by the alcohol and aldehyde

dehydrogenase enzyme pathway

– not fully functional until 12 to 30 months of age

• Large volumes associated with CNS issues

in neonates and children

– Other adverse events: ototoxicity, cardiovascular

effects, seizures, hyperosmolality and lactic acidosis.

• Intravenous parenterals containing PG

must be infused slowly

• PG also has a laxative action at high oral

doses through high osmotic pressure effects

FA

CT

OID

S • In 1859, PG was first described by C. Wurtz

• In 1932, Seidenfeld and Hanzlik found PG to be less toxic than ethylene glycol; accepted as a pharmaceutical solvent

• In 1983, serum hyperosmolality (>300 mosm/l) reported in infants• Source was a parenteral multivitamin

preparation (MVI-12) containing PG; not recommended for use in patients <11 years of age

• Change in multivitamin preparation led to a 10-fold increase in PG dose

• 49 infants received excess PG; each weighed under 1500 g


Ethanol Toxicity

• Widely used as a co-solvent to aid

solubility

• In US, maximum permitted

quantities in OTC products:

– <0.5% for children under 6 yrs

– <5% for children 6 to 12 yrs

– <10% for children over 12 yrs

• Acute (overdose) or chronic (long-

term use) toxicity is possible

• May cause adverse symptoms of

intoxication, lethargy, stupor, coma,

respiratory depression and

cardiovascular collapse

Source: Mills, 2010

In young children, ethanol causes hypoglycemia and

hypoglycemic seizures.

Hypoglycemia occurs secondary to ethanol's

inhibition of gluconeogenesis and

secondary to the relatively smaller glycogen stores in

the livers of young children.

In toddlers who have not eaten for several hours, even small quantities of

ethanol can cause hypoglycemia.

4/25/2013

5


Peanut Oil Toxicity

• Peanut oil is used as a food additive

and as a solvent in intramuscular

injections

• It has been suggested that the use of

peanut oil in childhood (infant

formula and topical preparations) can

lead to later episodes of

hypersensitivity, and therefore,

should be discontinued

Source: Mills, 2010


Lactose Toxicity (Immature Metabolism)

• Lactose occurs widely in dairy

products and is used in infant feed

formula.

• In pharmaceutical preparations, it is

widely used as a diluent in tablets

and capsules, in lyophilized powders,

as a sweetener in liquid formulations

and as a carrier in dry powder

inhalation products.

• Lactose intolerance occurs when there is a deficiency in the intestinal enzyme lactase, leading to GIT build-up of lactose. There is then the risk of abdominal bloating and cramps.

• Lactase is normally present at high levels at birth, declining rapidly in early childhood (4 to 8 yrs). Hypolactasia (malabsorption of lactose) can thus occur at an early age and, furthermore, this varies among different ethic groups.

• Significant lactose intolerance can also occur in adults but this is rare.

WHEN SHOULD STUDIES IN JUVENILE

ANIMALS BE CONSIDERED?

Nonclinical Studies

4/25/2013

6

European Medicines Agency Guideline on

Pharmaceutical Development of Medicines for

Pediatric Use

The following information sources

(listed in hierarchy) should be

consulted in order to assess the

safety profile of each excipient in a

paediatric formulation resulting in

an overall conclusion as to whether

or not additional data are needed.

Are there Commission /CHMP/ICH guidelines

available related to this excipient?

Is there a CHMP opinion available relating to this

excipient?

Is this excipient approved in current paediatric

medicines?

Is the excipient included in the EU food legislation?

Is there information available from European

Food Safety Scientific Opinions ( EFSA)?

Are there any other sources of information

(incl. toxicological, pre-clinical or clinical data)

available supporting the use of this excipient?

Points for consideration in the evaluation of the safety profile of excipients in

pediatric formulations for a specific target age group. Source: EMA, 2013 - draft

Are there Commission

/CHMP/ICH guidelines available

related to this excipient?

Guidelines up-to-date?

Guidelines relevant to target age

group(s)?

Guidelines relevant to the route of administration?

Guidelines relevant to the maximum

daily exposure and treatment duration?

Guidelines supporting the use of this excipient?



Pediatric Use

Answer: Yes or No/Not Clear

Source: EMA, 2013 - draft

Is this excipientapproved in

current paediatricmedicines?

Excipient approved within the Union for children in the target age group?

Approved products to be administered

via the same or comparable route

of administration?

Excipient in the approved products results in a higher

or comparable daily exposure?

Approved products to be administered during comparable or longer treatment

duration?

Approved products intended for a less

serious or comparable indication?

Any new information not yet

considered?



Pediatric Use

Answer: Yes or No/Not Clear

Source: EMA, 2013 - draft

4/25/2013

7



Pediatric Use

Are there any other sources of information (incl. toxicological, pre-clinical or clinical data) available supporting the use of this excipient?

Is the information supporting the use of this excipient in children?

If No/Not Clear, then additional data is needed (e.g., juvenile animal studies, PK data, clinical studies), alternatively reformulate

Children Are Not Just Small Adults

The ability to predict from the

existing nonclincial and clinical

data as to whether studies in

juvenile animals are necessary

increases with age. Therefore, the

likelihood of conducting a

nonclinical study in older juvenile

animals decreases. In addition, the

duration of treatment and the type

of therapy are also factors that

determine whether a nonclinical

study in juvenile animals is

warranted.

Modified from: Lewis et al., 2012

Class History of Effects on Developing Systems

Age ≤ 2 years

Target Organs are Late Developing

Age ≤ 4 years

Exposure in Young Animals Differs From Young Adult

Metabolism/Activation is Age Dependent

Chronic Therapy

Age ≤ 11 years

SubchronicTherapy

Acute Therapy

Age 12 years

REGULATORY STATUS

• United States: Food and Drug Administration (FDA)

– Guidance Document: Nonclinical Safety Evaluation of Pediatric Drug

Products (2006)

• Europe: European Medicines Agency (EMA)

– Guideline on the need for Nonclinical Testing in Juvenile Animals on

Human Pharmaceuticals for Pediatric Indications (2008)

– Pediatric Investigation Plans (PIP)

• Japan: Ministry of Health, Labour and Welfare (MOHW)

– Japanese Pharmaceutical Manufacturers Association has a guidance

– Japanese guidance is not much different that that of US

4/25/2013

8

POINTS TO CONSIDER

1. Need for testing?

2. One or two species?

3. Is the drug for pediatric use only (chronic studies starting at juvenile ages)?

4. Design juvenile toxicology studies as part of the full drug development program and

allow time for any follow-up/ investigative studies

5. Parameters (biomarkers) to be evaluated in clinical trial

6. Assessment of organ development not in short-term clinical trial(s)

7. Discuss plans with regulatory agencies (EMA for PIPs)

8. Harmonize plans with multi-agency comments

WHEN TO DOSEAge Definitions

Age Groups HumanRat

(Postnatal Days)

Dog(Postnatal Days)

Premature less than term 1 to 4 1 to 4/10

Neonate birth to 1 month 4 to 7/14 5/11 to 21

Infant 1 month to 2 years 7/14 to 21 22 to 42

Children 2 to 12 years 21 to 28F/35M 43 to

140F/170M

Juvenile 12 to 16 years 28F/35M to

49F/70M

150F/180M to

250F/260M

M: male

F: female

POTENTIAL SPECIES

Rodent

• Rat

• Mouse

Alternative rodent models

• Hamster

• Guinea pig

• Transgenic mice

Nonrodent

• Dog

• Nonhuman primate

• Rabbit

Alternative nonrodent models

• Sheep

• Mini-pig

4/25/2013

9

ROUTES OF ADMINISTRATION

DOSE ROUTE(Earliest Day Postpartum)

SPECIES

Rat Mouse Rabbit Dog NHP

Oral gavage 1 7 7 4 >2 weeks

Intravenous (bolus) 4 to 15 7 ? 7 to 14 >2 weeks

Intravenous (infusion) 28 ? ? 49 to 56 >2 weeks

Inhalation 7 to 10 21 ?(10) 10 ?

Parenteral (IM/SC) 1 1 4 1 >2 weeks

Dermal 10 21 35 42 >2 weeks

? = Unknown Gradually improving

IM = intramuscular

SC = subcutaneous

EVALUATIONS

• Routine toxicology evaluations

• Evaluations of the development of organ systems of concern– Cardiovascular– Central Nervous System– Gastrointestinal– Pulmonary– Immune– Renal– Reproductive– Skeletal (growth)

• Reversibility (post-dosing development)

– Consider endpoints to be assessed

ROUTINE EVALUATIONSFDA/EMA

EARLIEST DAY (Post-Partum)

Parameters

SPECIES

Rat Mouse Rabbit Dog Cyno Mini-Pig

In-Life (clinical signs,

body weight)1 1 5 1 1 1

Food consumption 22 22 35 42 180 28

Clinical Pathology 1 1 5 1 1 1

Ophthalmology 21 21 21 21 21 7

Toxicokinetic sampling 1 1 5 1 1 1

Organ wt, macroscopic &

microscopic observations1 1 5 1 1 1

4/25/2013

10

ORGAN SYSTEMS OF CONCERNFDA/EMA

• Food and Drug Administration (FDA) Guidance for Industry: Nonclinical Safety Evaluation of Pediatric Drug Products. February 2006.

• Committee for Human Medicinal Products (CHMP): Guideline on the Need for Non-Clinical Testing in Juvenile Animals on Human

Pharmaceuticals for Paediatric Indications. January 24, 2008.

• Pulmonary

• Gastrointestinal

• Cardiovascular

• Immune system

• Renal• Behavior/cognition

• Reproduction

• Skeleton (growth)

Development up to

adulthood

Development up to one year

Development up to two years

Development up to five to 12

years

• Parameters

– Body weight

– Physical development

– Skeleton

• Physical Development– Rats, mice and dogs (minipigs, rabbits)

– Tooth eruption, eye opening

– Vaginal opening

– Preputial separation, testes descent

– Anogenital distance (rodents)

GROWTH & PHYSICAL DEVELOPMENT

• Physical measurements– Crown-rump length, tibia measurements (rat)

– Height, length (dog)

– Bone length (femur, tibia)

• In vivo radiographs

• Ex-vivo direct

• rat, dog, nonhuman primate

SKELETON: TIER I ASSESSMENTS Growth

Lumbar Spine (L1-L6)

14 21 28 35

Days of Age

Ra

dio

gra

ph

ic L

en

gh

t (m

m)

0

5

10

15

20

25

30

35

Right Femur

14 21 28 35

Days of Age

0

5

10

15

20

25

30

Right Tibia

14 21 28 35

Days of Age

0

5

10

15

20

25

30

35

Radiographic

Measurements

Male Rat Pups

4/25/2013

11

• Bone strength

– Bone mineral content (BMC)

– Bone mineral density (BMD)

– Architecture (histomorphometry)

• Bone densitometry (BMC and BMD)

– Dual-energy X-ray (DEXA)

absorptiometry

– Peripheral quantitative computed

tomography (pQCT)

• Biochemical markers of bone turnover

– Osteocalcin, Procollagen type I N-

terminal propeptide, C-telopeptide, N-

telopeptide

SKELETON: TIER II ASSESSMENTSGrowth

REPRODUCTION

• Sexual maturation

– Vaginal opening, preputial separation

and testes descent

– rats, mice and dogs

• Estrous cycles

– Rats and mice

• Functional

– Mating, gestation, parturition and

lactation

– rats, mice, rabbits, dogs and mini-pigs

• Hormone Assays

– LH, FSH, estradiol, progesterone,

prolactin and testosterone

– rats, mice and rabbits and dogs

• Male Reproductive Assessments

– Sperm count

– Motility

– Morphology

– Testicular staging

– rats, mice, rabbits and dogs

IMMUNOLOGY/RENAL

Immunology

• Toxicology Screen (Tier I)

– Hematology

– Immunohistopathology

• Immunology Screen (Tier II)

– Phenotyping

– Natural Killer cell activity

– T-cell dependent anti-body response

(TDAR) to Keyhole Limpet

Hemocyanin (KLH)

• Species

– rats, mice, cynomologus (dogs)

Renal Function

• Pre-weaning: urinalysis

• Post-weaning: urinalysis, function tests

• Clinical pathology parameters

• Histopathology parameters

4/25/2013

12

PULMONARY/CARDIOVASCULAR

Lung Function Testing

• Dogs and rats

• Respiratory minute volume

• Tidal volume

• Respiratory rate

Cardiovascular Function

• Dogs and rats

• Blood pressure, direct – telemetry

• Blood pressure, indirect - paw (tail)

cuff

• ECG

NEUROTOXICOLOGYRodents

FDA/EMA Requirements for CNS Function

Reflex ontogeny/

Sensorimotor

function

• Reflex tests (e.g.,

auditory startle

ontogeny)

• Functional observational

battery components

Locomotor

activity

• Motor activity test

• FOB components

Reactivity

• Auditory startle

habituation

• FOB components

Learning and

memory

• Water maze

• Passive avoidance

Rats

Test First Day Postpartum

Functional observational battery 4

Negative geotaxis from 8 until developed

Motor activity 13

Startle habituation 22

Learning and memory -

• Passive avoidance 22

• Water maze 22

Sensory development -

• Auricular startle ontogenyfrom 12 until

developed

• Visual placing/pupillary

response21

Macroscopic Observations

Electron microscopy(e.g., liver)

Morphometry(e.g., lung)

Bone Pathology, Mechanics

Neuropathology (CNS and PNS)

TERMINAL PROCEDURES

NEUROPATHOLOGY

• Whole-body perfusion with gluteraldehyde

• CNS: Paraffin embedding, special stains

• CNS/PNS: Plastic embedding, semi-thin sectioning,

toluidine blue staining

4/25/2013

13

TAKE HOME MESSAGES

1. The choice of a suitable excipient in a pediatric formulation is one of the keyelements of the pharmaceutical development.

2. When selecting an appropriate excipient for pediatric medicines it is important toconsider the overall function of the excipient, the safety profile based on acute orrepeat exposure, and allergies and sensitization as well as theacceptability/palatability of the formulation, short-term vs. long term use, and theclinical condition.

3. Good intentions in pediatric formulations have been demonstrated to go bad.

4. Toxicological studies may be necessary if the use of an existing excipient in apediatric medicine cannot be justified on the basis of available information sources.

5. Each study must be designed on a case-by-case basis to meet the needs of thepediatric development program.

REFERENCES

• Food and Drug Administration. Guidance for Industry: Nonclinical Studies for the Safety Evaluation of

Pharmaceutical Excipients. May 2005.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079

250.pdf

• Robertson, A.F. (2003). Reflections on Errors in Neonatology III. The “Experienced” Years, 1970 to

2000. Journal of Perinatology, 23: 240-249.

• European Medicines Agency (2013). Draft Guideline on Pharmaceutical Development of Medicines for

Pediatric Use

• Mills, S (2010). Pharmaceutical excipients – an overview including consideration for paediatric dosing.

Training Workshop entitled “Pharmaceutical development with focus on paediatric formulations”.

Beijing. http://apps.who.int/prequal/trainingresources/pq_pres/workshop_China2010/english/22/002-

Excipients.pdf

• Lewis, E.M., De Schaepdrijver, L.M. and Coogan, T.P. (2012). Introduction. In: Pediatric Non-Clinical Drug

Testing Principles, Requirements, and Practice. Edited by: AM Hoberman and EM Lewis. John Wiley &

Sons, Hoboken, NJ, p. 1-27.

CONTACT INFORMATION

Elise M. Lewis, PhD

Director, Reproductive and Neurobehavioral Toxicology

Charles River Laboratories, Preclinical Services Pennsylvania

[email protected]

Tel: 267.532.3741

Alan M. Hoberman, PhD, DABT, Fellow ATS

Executive Director, Global Developmental, Reproductive and

Juvenile Toxicology

Charles River Laboratories, Preclinical Services Pennsylvania

[email protected]

Tel: 267.532.3705

IPEC America’s New PPT Template · build-up of lactose. There is then the risk of abdominal...

Documents

Transcript of IPEC America’s New PPT Template · build-up of lactose. There is then the risk of abdominal...