Neurotoxicity Associated with Prescription Drugs many slides from Melissa Tassinari, Ph.D., Pfizer

1
Neurotoxicity Associated with Prescription
Drugs(many slides from Melissa Tassinari, Ph.D.,
Pfizer)

• Non clinical studies in animals attempt to
  predict human toxicity
• Assess potential cellular and functional damage
• Identify target organs and potential biomarkers
• Establish a no effect level in dose/exposure
• Look at potential for reversibility
• Provide relevance for any findings

2
Reproductive And Developmental Toxicology

• Premating to Conception (gamete development,
  mating behavior, fertilization)
• Conception to Implantation (maternal function,
  early embyogenesis, implantation)
• Post-implantation to Hard Palate Closure
  (maternal function, embryogenesis, organ
  development)
• Hard Palate Closure to End of Gestation (maternal
  function, fetal organ development and growth)
• Parturition to Weaning (maternal function,
  neonatal survival, postnatal growth and
  development)
• Post-weaning to Sexual Maturity (growth and
  development, sexual maturation)

3
Reproductive Study Fertility, Implantation, and
Early Embryonic Development

• Parameters monitored in Rats
• Mating ability (sperm presence in vaginal smear)
• Fertility (ability to impregnate/become pregnant)
• Gamete maturation (males)
• Pre-implantation survival
• Post-implantation survival
• Implantation success

4
General Design Reproductive Study For Fertility
5
Developmental Toxicology Study Embryo-fetal
Toxicity (Teratogenicity)

• Parameters monitored in Rats and Rabbits
• Fetotoxicity
• embryo/fetal death, fetal weight decrements
• Delayed Development
• delays in skeletal ossification
• Structural abnormalities
• skeletal and visceral

6
General Design Developmental Toxicology Study

• STAGE Implantation to closure of hard palate
  (organogenesis)
• TREATMENT Days 6-17 of gestation for rats 7-19
  of gestation for rabbits
• ANALYSIS Deliver the fetuses (Cesarean section)
  just prior to natural parturition (day 21 in
  rats, 29 in rabbits). Assess live/dead,
  visceral and skeletal abnormalities, skeletal
  ossification, fetal weights and sex
  distribution.

7
General Design Peri- Postnatal Study
8
Reproductive Study Peri - Postnatal Development
and Maternal Function

• Parameters monitored in Rats
• Parturition success/ maternal behavior
• Postnatal survival and neonatal development
• Functional developmental deficits
• Fertility (ability of F1 offspring to impregnate
  and become pregnant)

9
Clinical Studies

• PHASE I HUMAN PHARMACOLOGY,
• Safety and toleration in normal adults
• PHASE II THERAPEUTIC EXPLORATORY Proof of
  efficacy, continued safety in people with the
  condition
• PHASE III THERAPEUTIC CONFIRMATORY Can it work
  in extended patient populations?

10
Safety Studies For Inclusion Of
ChildrenPediatric Rule

• Clinical safety experience from adult studies
• Comparative clinical pharmacokinetics in adults
  and children
• Full genetic toxicity battery
• Reproductive Studies
• Repeated-dose juvenile animal toxicity studies on
  a case-by-case basis
• Carcinogenicity study prior to long-term
  pediatric studies on a case-by-case basis

11
Why do a Juvenile Animal Study? Human Adult
Pediatric Differences Growth Development

• Differences in growth rate
• Age, gender related
• Differences in functional capacity
• Altered kidney excretion rate than adult
• Pharmacokinetics (ADME)
• Higher metabolic rate than adult
• Smaller body size and larger surface areabody
  weight
• Higher water concentration in lean body tissue
• Enhanced lipophillic drug distribution to CNS
• a result of increased brain/body mass and high
  lipid
• Unique exposure routes (placenta, breast milk)

12
Why do a Juvenile Animal Study? Pediatric
Toxicities Not Predicted from Human Adult Studies
Taken from T. Zoetis, FDA presentation 11/99
13
And then- Post-Marketing Surveillance by Drug
Co. FDA - Research by scientists
Example of Research on the Developmental
Toxicity/ Neurobehavioral Teratology of
Anticonvulsant Medications Neurobehavioral
Teratology field of study that deals with the
effects of prenatal exposure to adverse agents on
brain development and behavior
14

• Risk-Benefit Concerns are Present for
  Prescription Drugs
• Example Anticonvulsant Drugs Used to Treat
  Seizure Disorders
• Pregnant women with seizure disorders need these
  meds to lead a seizure-free life (seizures can be
  life-threatening can do brain damage to Mom may
  directly or indirectly harm fetus as well)
• But meds themselves increase risks for adverse
  outcomes of pregnancy - harmful to fetal
  development and long term functioning toxic
  side effects
• Goal to identify the safest meds by
  rank-ordering extent of harm

15
ANTICONVULSANT DRUGS

• OLD NEW
• CARBAMAZEPINE (TEGRETOL, 1974) FELBATOL
  (FELBAMATE, 1993)
• CLONAZEPAM (KLONOPIN, 1975) GABITRIL (TIAGABINE,
  1997)
• PARAMETHADIONE (PARADIONE, 1949) KEPPRA
  (LEVETIRACETAM)
• PHENOBARBITAL (1912) LAMOTRIGINE (LAMICTAL,
  1998)
• PHENYTOIN (DILANTIN, 1938) SABRIL (VIGABATRIN)
• PRIMIDONE (MYSOLINE, 1954) TOPAMAX (TOPIRAMATE,
  1998)
• TRIMETHADIONE (TRIDIIONE, 1946) TRILEPTAL
  (OXCARBAZEPINE)
• VALPROIC ACID (DEPAKOTE, 1978) ZONEGRAN
  (ZONISAMIDE)

16
MGH Anticonvulsant Study 1997 -
ongoing Phenobarbital, Carbamazepine, or
Hydantoin Aims 1) to determine the effects of
gestational monotherapy on the childs cognitive
and socio-emotional characteristics 2) to
quantitatively examine the effects upon midface
and digit hypoplasia 3) to examine the
relationships between structural and functional
effects
17
Neuroteratology of Phenobarbital Jane Adams and
Patricia Janulewicz University of Massachusetts
Boston Lewis B. Holmes Massachusetts General
Hospital
18

• Early Human Studies of the Teratogenicity of
  Anticonvulsant Medications
• examined the effects of polytherapy (mostly
  hydantoins and barbiturates)
• focused on malformations and growth impairments
• reported non-systematic observations of
  developmental delay and intellectual impairments
• did not control for important demographic
  variables

19

• Phenobarbital Monotherapy
• major malformations (cleft lip/palate heart
  defects)
• microcephaly
• growth reduction
• midface hypoplasia
• digit hypoplasia
• Major malformations in 5-8
• Major plus minor in 20-30
• (Holmes et al, 2001 2004)

20
(No Transcript)
21
DIGIT HYPOPLASIA

• DEFINITION INCREASED FREQUENCY OF
  ARCHES
• STIFF INTERPHALANGEAL JOINTS
• TAPERED FINGERS
• RADIOGRAPHS CONED EPIPHYSES
• PSEUDOEPIPHYSES
• HYPOPLASIA OF DISTAL PHALANGES
• SHORTENED METACARPAL
• HANDS gtgt FEET
• Ref. Lu MCK et al Teratology 61277-283, 2000
• Bokhari et al Teratology 6619-23,
  2002.

22
(No Transcript)
23
(No Transcript)
24

• Criteria for Inclusion
• maternal seizure history
• monotherapy throughout pregnancy
• willingness of both parents to participate
• normal intelligence in both parents
• singleton birth
• English as first language of child

25

• Criteria for Exclusion
• Mothers
• occurrence of tonic-clonic seizures during pg.
  
• maternal exposure to other teratogenic drugs or
  illnesses
• Children
• neurologically-relevant birth complications
• neurologically-relevant illnesses or injuries
• orofacial malformation
• auditory or visual impairment

26

• Matching of Exposed and Control Cases
• age
• sex
• socioeconomic status
• parental education

27

• Physical Evaluations of Children
• dysmorphological exam
• quantitative cephalic measures via radiographs
• quantitative measures of hands via radiographs
• Functional Assessments of Parents
• performance of both parents on the Ravens
  Progressive Matrices test, a
  non-verbal measure of intelligence
• maternal performance on the WAIS-R

28
DIGITIZED CEPHALOMETRIC LANDMARKS
29
(No Transcript)
30
(No Transcript)
31

• Neurobehavioral Evaluations of the Children
• maternal administration of the Behavioral
  Assessment Scale for Children and the Child
  Behavior Checklist
• examiner-blinded administration of a
  comprehensive neuropsychological battery of tests
  to the child (the WISC-III selections from the
  K-ABC, the Stanford-Binet IV, the CELF, Wechsler
  Memory Scale for Children)
• Goal to determine the childs general mental
  ability as well as abilities across processing
  areas

32
General Mental Ability on WISC-III Phenobarbital



33
Multivariate ANOVAs were performed using SPSS
11.1
34
Is there a relationship between minor
malformations and cognitive performance?
35
From Holmes, Coull, Dorfman, and Rosenberger, J.
Pediatrics, 2005.