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Clinical Trials in
Geriatric Population
Rahul, Gurudutt, Vishal
PGD ACR Batch V,
ICRI, Blore
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Scope of ICH E7 Guideline: Directed principally towards new
entities having significant use inelderly, because
i) Disease in question is characteristic
aging disease like Alzheimers, orii) Population to be treated includes
geriatric patients.
Applies to new formulations or newcombinations which alters the patientresponse(w.r.t.
safety/tolerability/efficacy).
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The geriatric population is arbitrarily defined as
patients aged 65yrs or older. It is important,
however, to seek patients in the older age range,
75 and above, to the extent possible.
It is important not to exclude unnecessarily
patients with concomitant illnesses; it is only by
observing such patients that drug-disease
interactions can be detected.
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Factors Relating to Elderly Patients
That May Bias Data:
Age
Physical state
Concurrent disease
Concomitant medicines
State of renal & hepatic function
Function of other organ & physiological
systems.
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Physiological Changes and Disease
Associated with the Elderly
There are physiological changes in the elderly
that affect how they react to certain medicines.
For e.g. their total muscle mass decreases which
affects the distribution of some medicine.
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Physiological & Physical Changes in
Elderly
Decreased lean body mass. Increased body fat.
Menopause in women.
Decreased flexibility of the lens- manifested as
decreased ability to accommodate near vision. Increased opacity of lens- cataract formation.
Arteriosclerosis accompanied by increase insystolic blood pressure.
Decreased pulmonary function. Decreased renal function (e.g. glomerular
filtration rate).
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Physiological & Physical Changes
in Elderly
Decreased hepatic blood flow
Decreased immunological function
Decreased cardiac output & cardiac index
Decreased gastrointestinal motility
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Impaired Homeostasis
This could be related to medicine induced casesof hypothermia, orthostatic hypotension andconfusion.
Decreases in homeostatic capabilities of various
organs (e.g. kidney, liver) to function normallylead to a decreased overall homeostatic capacity.
Receptor sensitivity and number of receptorshave been reported to change in the elderly.
The elderly are more sensitive to somemedicines (e.g. warfarin) and less sensitive toothers (e.g. propranolol).
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Pharmacokinetics in the Elderly
Most medicines- no age related change in rate orextent of absorption. With few medicines there
may be decreased absorption in older patients.
The volume of distribution of lipophilicmedicines (e.g. diazepam) often increases with
age because of a relative increase of body fat.
Medicines that undergo oxidation may have
reduced hepatic clearance.
Renal excretion of medicines decreases with
age.
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Factors that Affect pk in Elderly
Absorption
Diminished acid secretion by stomach
Reduced gastric motility and increased gastric
emptying time Decreased intestinal surface area
Decreased active transport system for
monosaccharides
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Factors that Affect pk in Elderly
Distribution
Decreased lean body mass
Decreased total body water
Plasma albumin decreases Increased fat is present
Decreased cardiac output
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Factors that Affect pk in Elderly
Metabolism
Decreased liver size
Decreased hepatic blood flow
Decreased number of functional liver cells Decreased first pass effect
Decreased enzyme activity. They may become
resistant to induction.
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Factors that Affect pk in Elderly
Renal elimination
Glomerular filtration rate decreases (creatinine
clearance falls). Normal range is 100-
130mL/min/1.73m2
(body surface area). Afterthe age of 40yrs, rate decreases by about 0.4-
1.2mL/min per year.
Decreased renal blood flow
Renal mass decreases
Renal tubular excretory/secretory function
decreases
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Formal Pharmacokinetic Studies
Formal PK studies can be done either in healthygeriatric subjects or in patient volunteers with
the disease to be treated by the drug.
The initial PK study can be a pilot trial oflimited size conducted under steady-state
conditions to look for sizable differences
between older and younger subjects or patients.
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Pharmacokinetic Studies in Renally
or Hepatically Impaired Patients Renal impairment is an aging-associated finding
that can also occur in younger patients.
Therefore, drugs excreted (parent drug or activemetabolites) significantly through renal
mechanisms should be studied to define theeffects of altered renal function on theirpharmacokinetics.
Similarly, drugs subject to significant hepatic
metabolism and/or excretion, or that have activemetabolites, may pose special problems in theelderly.
Pharmacokinetic studies should be carried out inhepatically- impaired elderly patient volunteers.
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Pharmacodynamic /Dose Response
Studies The number of age-related
pharmacodynamic differences (i.e., increased
or decreased therapeutic response, or side
effects, at a given plasma concentration ofdrug) discovered to date is too small to
necessitate dose response or other
pharmacodynamic studies in geriatric
patients as a routine requirement. Separatestudies are, however, recommended in the
following situations:
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1. Sedative/hypnotic agents and other
psychoactive drugs or drugs with important
CNS effects, such as sedating antihistamines.
2. Where subgroup comparisons (geriatric versus
younger) in the Phase 2/3 clinical trials
database indicate potentially medically
significant age-associated differences in the
drug's effectiveness or adverse reaction profile,
not explainable by PK differences.
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Drug-Drug Interaction Studies
Geriatric patients are more likely to be usingconcomitant medications than younger patients.
Digoxin and oral anticoagulant interaction studies,
because so many drugs alter serum concentrations of
these drugs, they are widely prescribed in the elderly,and they have narrow therapeutic ranges
For drugs that undergo extensive hepatic metabolism,
determination of the effects of hepatic-enzyme inducers
(e.g., phenobarbital) and inhibitors (e.g., cimetidine) Interaction studies with other drugs that are likely to be
used with the test drug (unless important interactions
have been ruled out by a Pharmacokinetic Screen).
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SCHEDULE Y w.r.t. Geriatric Patients
Geriatric patients should be included in PhaseIII clinical trials (and in Phase II trials, at theSponsor's option) in meaningful numbers, if-
(a) The disease intended to be treated is
characteristically a disease of aging; or (b) The population to be treated is known to
include substantial numbers of geriatric patients;or
(c) When the new drug is likely to alter thegeriatric patient's response (with regard to safetyor efficacy) compared with that of the non-geriatric patient.
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Clinical Case StudyMontelukast in Patients With Seasonal Allergic
RhinitisSponsor: Merck.
Purpose: This study will evaluate the ability of
Montelukast to improve the signs and symptoms
of seasonal allergic rhinitis compared with
loratadine and placebo.
Study Design: Ramdomised, Controlled, llel,
Double blind, Multicentric.Enrollment: 1577
Started: Mar 2000 Completed: Aug 2000
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Eligibility: Age : 15-85yrs
Genders: Both
Healthy Volunteers: No
Criteria:
Inclusion
Patients with documented history of seasonal allergicrhinitis.
Non-smoker for 1yr.
Exclusion
Patient is hospitalized.
Patient has had any major surgery within 4 weeks ofstudy start.
Patient is a current or past abuser of alcohol or illicitdrugs.
Patient has been treated in an emergency room forasthma in the past month.
Patient had an upper respiratory infection with in 3
weeks prior to study start.
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Trial: 4 arms
Placebo - Once daily, at bedtime - 2 weeks
Montelukast - 10mg
Loratadine - 10mg
Montelukast/Loratadine - 10mg-10mg combinationtablet given orally. Discontinued during study due tobusiness decision by sponsor.
Result: Mean Change From Baseline in Daytime NasalSymptoms Score Over 2 Weeks
Patients - asked to rate - 4 nasal symptoms
Congestion, Rhinorrhea, Itching, and Sneezing
Rated on a 4 point scale
0(best), 3(worst)
*The mean change in day time nasal symptom score wasseen to be higher in Montelukast 10mg patients whencompared to Loratadine 10mg patients.
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Mean Change From Baseline in Daytime Eye
Symptoms Score Over 2 Weeks
Patients - asked to rate - 4 day time eye symptoms
Tearing, Itching, Red, and Puffy eyes
* The mean change in day time eye symptom score
was seen to be higher in Montelukast 10mg
patients when compared to Loratadine 10mgpatients.
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