Clinical Trials in Geriatric Population

8/3/2019 Clinical Trials in Geriatric Population

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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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Distribution

Decreased lean body mass

Decreased total body water

Plasma albumin decreases Increased fat is present

Decreased cardiac output


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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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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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Clinical Trials in Geriatric Population

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