INTRODUCTION In patient care, pharmacotherapy of the elderly is the most challenging aspect. It is a well-known phenomenon nowadays that the improvement in medical technologies has tremendously hiked the proportion of elderly people in the demographic of industrialized countries. However all with this change in the demographic trend there has also been an upsurge in the number of patients affected by multiple chronic disorders, it has been observed that half of Medicare beneficiaries receive 5 or more medications 1. Distribution, metabolism and renal elimination are the various aspects of pharmacokinetics that are altered with age, leading to clinically relevant consequences with regard to safety and efficacy. Although renal excretion may be measured or estimated by glomerular filtration rate, the other changes are tough to measure 2. Changes in physiological and functional capabilities, different retort to receptor stimulation and decrease in homeostatic mechanisms are all characterized by aging 3. Also with age there are more inter-individual variability seen in the physiological responses 4. Health Professional commonly face difficulties in drug therapy of the older patients, where a particular dose of a given drug portrays a different and many a times unexpected responses in the geriatric group as compared to the younger patients of the same gender and body weight. The reason behind this is the pharmacokinetic and/or pharmacodynamics changes caused due to ageing 5. Figure 1: Main Age-Related Changes in Pharmacokinetics. STATISTICS Exclusion of elderly patients from clinical trials is highly problematic, because older adults suffer the greatest health burden; they endure high rates of cancer, dementia, cardiovascular disease, arthritis, and Parkinson’s disease. 36% of total US personal health care investment is spent on them and 42% of all prescription drugs are consumed by them. Two thirds of cancer patients are older than 65 years but only about 25% of cancer trial participants are above this age group. Another statistic reveals that 60% of the nationwide disease load is being carried by the elderly but they represent only 32% in the phase II and III clinical trials 6. It has been projected that the occurrence of ADRs in a geriatric population is 50.1/1000 person years, with significant impact on health and quality of life. Since 1950, the proportion of older people, of the age 60 years or older has been rising increasingly, going from 8 % in 1950 to 11 % in 2007, and is predicted to reach 22 % in 2050 3. PHARMACOKINETIC VARIATIONS The change in the body composition of the geriatric patients affects the volume of distribution of drugs, depending on its hydro and lipophilicity. Due to the lean body mass of the patient, they require a smaller loading dose of aqueous soluble drugs (e.g. Digoxin). On the other hand, due to their expanded fat store, lipid soluble drugs like benzodiazepines distribute to the larger compartment, from which they are more slowly cleared. Moreover due to the decline in serum albumin levels with age, drugs that substantially bind to this protein will have a greater concentration of active, free drug in the serum. Taking an example of phenytoin, this drug’s dose will have to be lowered and adjusted to match with the low albumin levels of the patient. Many drug interactions occur due the freeing of drugs from the plasma albumins. Geriatric patients are more frequently susceptible to drug interactions because their microsomal hepatic enzymes are inhibited due to polypragmasia. A well-known drug interaction is the one between antihypertensives and general anesthetics, which leads to arterial hypotension. Along with polypharmacy another reason or cause for drug interaction could be due to the modified effect of drug 7. Reduction in liver mass and hepatic blood flow is commonly seen in older patients, these changes have an influence on hepatic clearance that in turn impacts variability in responses to drugs. The transport of the drugs to the microsomal enzymes within the hepatocytes is dependent on the hepatic blood flow, which is known to reduce with age 2. Modeling population PK/PD and simulation can be beneficial to assess drug PK/PD in geriatric patients. Constructing a population pharmacokinetics model is a multi-step technique. This modelling approach allows integration of data across trials (and so populations) with sparse individuals’ data. Random effects are allocated to a subsection of PK factors to capture degree of unexplained between-patient variability. Covariates are examined to explain between subject variability in terms of patient characteristics like BMI, race, gender, renal functions, hepatic functions. Covariate effects could be extrapolated to predict PK in subpopulations 6. Figure 2: The outline of population PK/PD modelling. Dosing recommendation need to consider all the following factors 6: • Often people of the same age do not have the same physiological similarity this is why renal clearance is a better predictor than age (example: dose adjustment for decreased creatinine clearance). • Combining multiple pharmacokinetic factors could help determine the correct dose: e.g. patients with creatinine clearance