Individualization

INDIVIDUALIZATION

Because of reasonable homogeneity in humans, the dosage regimens are calculated on population basis. However, same dose of a drug may produce large differences in pharmacological response in different individuals. This is called as intersubject variability. In other words, it means that the dose required to produce a certain response varies from individual to individual. Rational drug therapy requires individualization of dosage regimen to fit a particular patient's needs. This requires knowledge of pharmacokinetics of drugs. The application of pharmacokinetic principles in the dosage regimen design for the safe and effective management of illness in individual patient is called as clinical pharmacokinetics.

The two sources of variability in drug responses are:

1. Pharmacokinetic variability which is due to differences in drug concentration at the site of action (as reflected from plasma drug concentration) because of interindividual differences in drug absorption, distribution, metabolism and excretion.

2. Pharmacodynamic variability which is attributed to differences in effect produced by a given drug concentration.

The major cause for variations is pharmacokinetic variability. Differences in the plasma levels of a given drug in the same subject when given on different occasions is called as intrasubject variability. It is rarely encountered in comparison to interindividual variations. The differences in variability differ for different drugs. Some drugs show greater variability than the others. The major causes of intersubject pharmacokinetic variability are genetics, disease, age, body-weight and drug-drug interactions. Less important causes are pharmaceutical formulation, route of administration, environmental factors and patient noncompliance.

The main objective of individualization is aimed at optimising the dosage regimen. An inadequate therapeutic response calls for a higher dosage whereas drug related toxicity calls for a reduction in dosage. Thus, in order to aid individualization, a drug must be made available in dosage forms of different dose strengths. The number of dose strengths in which a drug should be made available depends upon 2 major factors—

1. The therapeutic index of the drug, and

2. The degree of inter-subject variability.

Smaller the therapeutic index and greater the variability, more the number of dose strengths required.

Based on the assumption that all patients require the same plasma drug concentration range for therapeutic effectiveness, the steps involved in the individualization of dosage regimen are:

1. Estimation of pharmacokinetic parameters in individual patient and determining their deviation from the population values to evaluate the extent of variability. Greater the accountability of variations, better the chances of attaining the desired therapeutic objective.

2. Attributing the variability to some measurable characteristic such as hepatic or renal disease, age, weight, etc.

3. Designing the new dosage regimen from the collected data.

The design of new dosage regimen involves:

1. Adjustment of dosage, or

2. Adjustment of dosing interval, or

3. Adjustment of both dosage and dosing interval.

Dosing of Drugs in Obese Patients

The apparent volume of distribution of a drug is greatly affected by changes in body weight since the latter is directly related to the volume of various body fluids. The ideal body weight (IBW) for men and women can be calculated from following formulae:

IBW (men) = 50 Kg ± 1 Kg/2.5 cm above or below 150 cm in height        (12.17)

IBW (women) = 45 Kg ± 1 Kg/2.5 cm above or below 150 cm in height           (12.18)

Any person whose body weight is more than 25% above the IBW is considered obese. In such patients, the lean-to-adipose tissue ratio is small because of greater proportion of body fat which alters the V_d of drugs. The ECF of adipose tissue is small in comparison to lean tissue in obese patients.

Following generalizations can be made regarding drug distribution and dose adjustment in obese patients:

1. For drugs such as digoxin that do not significantly distribute in the excess body space, V_d do not change and hence dose to be administered should be calculated on IBW basis.

2. For polar drugs such as antibiotics (gentamicin) which distribute in excess body space of obese patients to an extent less than that in lean tissues, the dose should be lesser on per Kg total body weight basis but more than that on IBW basis.

3. In case of drugs such as caffeine, theophylline, lidocaine and lorazepam which distribute to the same extent in both lean and adipose tissues, the V_d is larger in obese patients but same on per Kg total body weight basis; hence, dose should be administered on total body weight basis.

4. For drugs such a phenytoin, diazepam and thiopental which are lipid soluble and distribute more in adipose tissues, the V_d is larger per Kg body weight in obese patients and hence they require larger doses, more than that on total body weight basis.

Changes in dose based on alteration of V_d is also attributed to modification of clearance and half-life of the drug.

Dosing of Drugs in Neonates, Infants and Children

The usual dosage regimen calculated on population basis refers to that for adults. Neonates, infants and children require different dosages than adults because of differences in body surface area, TBW and ECF on per Kg body weight basis. The dose for such patients are calculated on the basis of their body surface area and not on body weight basis because the body surface area correlates better with dosage requirement, cardiac output, renal blood flow and glomerular filtration in children. A simple formula in comparison to DuBois and DuBois for computing surface area (SA) in square meters is Mosteller’s equation:

Infants and children require larger mg/Kg doses than adults because:

1. Their body surface area per Kg body weight is larger, and hence

2. Larger volume of distribution (particularly TBW and ECF).

The child’s maintenance dose can be calculated from adult dose by using the following equation:

where 1.73 is surface area in m² of an average 70 Kg adult. Since the surface area of a child is in proportion to the body weight according to equation 12.21,

SA (in m²) = Body Weight (in Kg)^0.7            (12.21)

The following relationship can also be written for child’s dose:

As the TBW in neonates is 30% more than that in adults,

1. The V_d for most water-soluble drugs is larger in infants, and

2. The V_d for most lipid-soluble drugs is smaller.

Accordingly, the dose should be adjusted.

Dosing of Drugs in Elderly

Drug dose should be reduced in elderly patients because of a general decline in body function with age. The lean body mass decreases and body fat increases by almost 100% in elderly persons as compared to adults. Because of smaller volume of body water, higher peak alcohol levels are observed in elderly subjects than in young adults. V_d of a water-soluble drug may decrease and that of a lipid-soluble drug like diazepam increases with age. Age related changes in hepatic and renal function greatly alters the clearance of drugs. Because of progressive decrease in renal function, the dosage regimen of drugs that are predominantly excreted unchanged in urine should be reduced in elderly patients.

A general equation that allows calculation of maintenance dose for a patient of any age (except neonates and infants) when maintenance of same C_ss,av is desired is:

Dosing of Drugs in Hepatic Disease

Disease is a major source of variations in drug response. Both pharmacokinetics and pharmacodynamics of many drugs are altered by diseases other than the one which is being treated.

The influence of hepatic disorder on drug availability and disposition is unpredictable because of the multiple effects that liver disease produces—effects on drug metabolising enzymes, on drug binding and on hepatic blood flow. Hence, a correlation between altered drug pharmacokinetics and hepatic function is often difficult. For example, unlike excretion, there are numerous pathways by which a drug may be metabolised and each is affected to a different extent in hepatic disease. Generally speaking, drug dosage should be reduced in patients with hepatic dysfunction since clearance is reduced and availability is increased in such a situation.

Dosing of Drugs in Renal Disease

In patients with renal failure, the half-life of a drug is increased and its clearance drastically decreased if it is predominantly eliminated by way of excretion. Hence, dosage adjustment should take into account the renal function of the patient and the fraction of unchanged drug excreted in urine. One such method was discussed in chapter 6 on Excretion of Drugs.

There are two additional methods for dose adjustment in renal insufficiency if the V_d change is assumed to be negligible. These methods are based on maintaining the same average steady-state concentration during renal dysfunction as that achieved with the usual multiple dosage regimen and normal renal function. The adjustments are based on equations 12.6 and 12.7.

1. Dose adjustment based on total body clearance: Rewriting equation 12.6, the parameters to be adjusted in renal insufficiency are shown below:

If Cl_T', X_o' and τ' represent the values for the renal failure patient, then the equation for dose adjustment is given as:

Rearranging in terms of dose and dose interval to be adjusted, the equation is:

From above equation, the regimen may be adjusted by reduction in dosage or increase in dosing interval or a combination of both.

2. Dose adjustment based on elimination rate constant or half-life: Rewriting equation 12.7, the parameters to be adjusted in renal insufficiency are:

If t½', Xo' and τ' represent the values for the renal failure patient, then:

Rearranging the above equation in terms of dose and dose interval to be adjusted, we get:

Because of prolongation of half-life of a drug due to reduction in renal function, the time taken to achieve the desired plateau takes longer, the more severe the dysfunction. Hence, such patients sometimes need loading dose.