be enrolled in clinical trials to learn more about the pharmacometabolomics and

assessment of safety, efficacy, and optimal dose schedules of new drugs.

15.9

Miscellaneous Factors Involved in ADME, PK, and PD

Alterations in Elderly

Elderly population is particularly susceptible to ADRs because of comorbidity,

polypharmacy, and age-associated changes in ADME and PK/PD properties of

drugs. A thoughtful strategy should be used to avoid drug-drug and drug-herbal/

food interactions and compliance problems. Physicians should design a simple drug

regimen with one or two treatments per day and decide whether a multidrug therapy

is necessary or the exposure can be avoided. The first issue regarding orally

administered drugs is gut metabolism prior to absorption that impacts on the

bioavailability of drugs. Most often, the role of gut metabolism by the CYP

450 coenzymes and transporters like P-gp is ignored by the physicians. Heart failure

and achlorhydria have been mentioned earlier as two reasons requiring drug dose

adjustments in treating elderly patients. In addition to oral drug administration, it is

worth mentioning about the topically applied medications. The epidermal and

subdermal layers of skin get atrophied in elderly because of reduced tissue blood

perfusion; hence, the rate and extent of transdermal drug absorption are expected to

be reduced in the skin of old age patients (Kaestli et al. 2008). Some barrier for

absorption is, however, observed in the subcutaneous and muscular tissue. It is

therefore recommended that subcutaneous and intramuscular injections should be

avoided in frail patients because of the erratic absorption and high risk of sterile

infiltrates (Trautinger 2001).

Decrease of muscle mass and relative increase in fat tissue may also alter Vd of

drugs. Therefore, this concern should be taken into consideration in light of the

lipophilicity of drug molecules. Presently, body impedance analysis (BIA) is an

economic and reliable method to assess the ratio of fat mass vs. fat free mass, and

thus failure in dosage can be avoided (Sampson 2013). Use of body mass index

(BMI) or body composition parameters for daily drug dose calculations may be

illusive due to the accidental presence of ascites or other fluid retentions. However,

PK and PD alterations of lipophilic agents have been demonstrated in obese patients.

For example, in obese patients (BMI > 30 kg/m²), dose adjustments are required for

several classes of drugs, such as general anesthetics, opioids, analgesics,

anticoagulants,

antidiabetics,

oral

contraceptives,

neuromuscular

blockers,

β-blockers, antibacterials, anticancer drugs, psychotropics, and anticonvulsants

(Telessy and Buttar 2017). Usually, the whole body water content falls by

10–15% in 80-year-old person. Therefore, the Vd of hydrophilic drugs is expected

to decrease in elderly; hence, administration of equivalent doses given to younger

individuals will result in higher plasma concentrations among elderly. This has been

observed in the case of aspirin, d-tubocurarine, edrophonium, famotidine, and

lithium therapy. Use of diuretics reduce the extracellular spaces and further accentu-

ate risk for drug intoxication (Turnheim 1998).

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