**14.7. Pharmacogenomics and drug development**

**14.6. Phase IV clinical trials**

In vivo/in vitro therapeutic profile for test and control model

> Phase IV Clinical trials

> > Phase III Clinical trials

in Fig 13 below;

candidate extract

*Phase IV clinical trials* 

condition.

504 Drug Discovery

*Phase IIIclinical trials* 

This phase is concerned with post-marketing surveillance and the main goal is to as‐ sess adverse reactions, patterns of drug utilization, discovery of additional indications. The interrelationships between the various studies in drug development are illustrated

Phase II clinical trials include inert placebos as negative controls and older active drugs as positive controls alongside the investigative compound. These studies are done in special clinical centers such as University Hospitals. A broader range of toxicities may be detected at this phase.

The drug is evaluated in a much larger number of patients (thousands) to further establish safety and efficacy. Phase III trials are performed in settings similar to those anticipated for the ultimate use of the drug. After successful phase III trials, the next step is the application for review of the new drug to seek approval to use the drug for clinical management of the disease

This phase is concerned withpost-marketing surveillance and the main goal is to assess adverse reactions, patterns of drug utilization, discovery of additional indications.The interrelationships

Crude drug preparation

Biochemical profiling of crude drug product

> In vivo toxicity profiles for test and control model

> > Phase I Clinical trials

Phase II Clinical trials

between the various studies in drug development are illustrated in Fig 1.13 below;

**Figure 1.13**Illustration of the key steps in the development of a drug from a putative drug

**Figure 13.** Illustration of the key steps in the development of a drug from a putative drug candidate extract

The personalized medication which takes into account the genetic make-up of individu‐ als is known as pharmacogenomics. The pharmacogenomic differences that determine in‐ dividualized therapy include genetic polymorphisms of drug transporters, drug receptors, and drug metabolizing enzymes. For example, genetic variation in Cyt P450 en‐ zymes that are largely responsible for drug metabolism shows that different individuals respond differently to drug efficacy or toxicity. Genetic variants in the drug target, the disease pathway, genes or drug metabolizing enzymes could all be used as predictors of drug efficacy or toxicity. For example, drug monitoring using perpherazine, a Cyt P450 substrate, shows that there are three main categories of individuals; the efficient metabo‐ lizers obtained from the heterozygotes, the poor metabolizers from the homozygotes and the ultra-rapid metabolizers which carry two or more active genes in the same chromo‐ some, a phenomenon known as gene duplication.

The information obtained from pharmacogenetic studies can be used to design new drugs that take the persons' genetic profile into consideration. The most common type of genetic variation are single nucleotide polymorphisms, therefore, a high resolution of sin‐ gle nucleotide map may expedite the identification of genes for various diseases. The molecular profiles of patients identified in phase I and II clinical trials as likely non-res‐ ponders to the putative drug under investigation might present an opportunity to ini‐ tiate new discovery programs for other pharmaceutical compounds.

#### **14.8. Individualized drug therapy**

Clinical usage of drugs requires a basic understanding of the pharmacokinetic and pharma‐ codynamic drug processes and an appreciation that a relationship does exist between the pharmacological effect or toxic response to a drug and the concentration of the drug. The interpatient and intrapatient variation in disposition of a drug must be taken into account in choosing a drug regimen.

A drug dosage regimen therefore is a recipe for the administration of a drug so as to pro‐ duce a desired therapeutic effect with minimum toxic effects.

The regimen is described in terms of the following:


The factors that determine the relationship between the prescribed drug dosage and drug effect operate at three levels; prescription level, drug administration level and at the physio‐ logical level of patient (Figure 14).

Drugs that are excreted primarily unchanged by the kidneys tend to have low variation among patients with similar renal function than do drugs which are inactivated by metabolism. For the extensively metabolized drugs, those with high metabolic clearance and large first pass elimination have marked difference in bioavailability, whereas those with low biotransfor‐

Introduction to Biochemical Pharmacology and Drug Discovery

http://dx.doi.org/10.5772/52014

507

The simplest way of determining a drug dosage regimen is to base it on the published recommended dosage. These are derived from the pharmacokinetics studies of the drug and the general procedure in using the published recommendations is to start at the low‐ er end of the recommended dosage range and monitor the therapeutic effect. If the de‐ sired effect does not occur, the dosage can be increased gradually until one reaches the upper limit of the range. In certain conditions it may be necessary a sufficiently high dose for the drug to accumulate in the body to a satisfactory degree. This dose is known as the loading dose and is equal to the volume of distribution multiplied by the target concentration in the plasma. The reason for giving a loading dose is to circumvent the sometimes unacceptable time lag preceding the steady state levels. Once the correct load‐ ing dose is given, a steady-state concentration can be achieved rapidly and then main‐

Adjustment of dosage in individual patients is often as a result of the modification of pharmacokinetic parameters of which the three most important include; the bioavailabili‐ ty or the fraction of a drug that is absorbed into systemic circulation, its clearance and

For drugs with a high toxicity to therapeutic ratio, the loading dose can be given as a single dose and for drugs with a low toxicity: therapeutic ratio and a long half-life, the loading dose can be divided into several portions and given at intervals long enough to allow detection of adverse effects, but short enough to ensure that the loading dose is a true loading dose i.e. relatively little amounts of the drug is eliminated from the body during the period of loading.

The extent of availability of a drug after oral administration is expressed as a percentage of the dose. The fractional availability (F) varies from 0 to 1. The extent of availability is more

A true decrease in bioavailability could be due to several reasons including, a poorly ad‐ ministered dosage form that fails to disintegrate or dissolve in the GIT, interaction with other drugs in the GIT, metabolism of the drug in the GIT and/or first pass hepatic me‐

Hepatic disease may in particular cause high availability because the metabolic capacity decreases or development of vascular shunts in the liver. Significantly high availability requires dosage adjustment by a factor of two, while significantly low in availability requires

important parameter to measure rather than the rate of availability.

mation tend to have largest variation in elimination rates among individuals.

**14.9. Determination of drug dosage**

tained by giving a smaller maintenance dose.

the volume of distribution.

**14.10. Systemic drug availability**

tabolism or biliary excretion.

dosage adjustment by a factor of half.

**Figure 1.14:** The operational levels that determine the relationship between prescribed drug dosage and the drug effect. **Figure 14.** The operational levels that determine the relationship between prescribed drug dosage and the drug effect.

tend to have largest variation in elimination rates among individuals.

Drugs that are excreted primarily unchanged by the kidneys tend to have low variation among patients with similar renal function than do drugs which are inactivated by metabolism. For the extensively metabolized drugs, those with high metabolic clearance and large first pass elimination have marked difference in bioavailability, whereas those with low biotransformation

Drugs that are excreted primarily unchanged by the kidneys tend to have low variation among patients with similar renal function than do drugs which are inactivated by metabolism. For the extensively metabolized drugs, those with high metabolic clearance and large first pass elimination have marked difference in bioavailability, whereas those with low biotransfor‐ mation tend to have largest variation in elimination rates among individuals.

#### **14.9. Determination of drug dosage**

The simplest way of determining a drug dosage regimen is to base it on the published recommended dosage. These are derived from the pharmacokinetics studies of the drug and the general procedure in using the published recommendations is to start at the low‐ er end of the recommended dosage range and monitor the therapeutic effect. If the de‐ sired effect does not occur, the dosage can be increased gradually until one reaches the upper limit of the range. In certain conditions it may be necessary a sufficiently high dose for the drug to accumulate in the body to a satisfactory degree. This dose is known as the loading dose and is equal to the volume of distribution multiplied by the target concentration in the plasma. The reason for giving a loading dose is to circumvent the sometimes unacceptable time lag preceding the steady state levels. Once the correct load‐ ing dose is given, a steady-state concentration can be achieved rapidly and then main‐ tained by giving a smaller maintenance dose.

Adjustment of dosage in individual patients is often as a result of the modification of pharmacokinetic parameters of which the three most important include; the bioavailabili‐ ty or the fraction of a drug that is absorbed into systemic circulation, its clearance and the volume of distribution.

For drugs with a high toxicity to therapeutic ratio, the loading dose can be given as a single dose and for drugs with a low toxicity: therapeutic ratio and a long half-life, the loading dose can be divided into several portions and given at intervals long enough to allow detection of adverse effects, but short enough to ensure that the loading dose is a true loading dose i.e. relatively little amounts of the drug is eliminated from the body during the period of loading.

#### **14.10. Systemic drug availability**

**Figure 1.14:** The operational levels that determine the relationship between prescribed drug

Drugs that are excreted primarily unchanged by the kidneys tend to have low variation among patients with similar renal function than do drugs which are inactivated by metabolism. For the extensively metabolized drugs, those with high metabolic clearance and large first pass elimination have marked difference in bioavailability, whereas those with low biotransformation

tend to have largest variation in elimination rates among individuals.

**Intensity of effect** 

**Prescribed dose** 

506 Drug Discovery

**Administered dose** 

 Patience compliance Medication errors

 Rate and extent of absorption Distribution and

and body size

**Concentration at site of action** 

factors

drugs

 Drug - receptor interactions Signal transduction

**Figure 14.** The operational levels that determine the relationship between prescribed drug dosage and the drug effect.

 Physiological variables Pathological and Genetic

Interaction with other

Development of tolerance

composition of body fluids

dosage and the drug effect.

The extent of availability of a drug after oral administration is expressed as a percentage of the dose. The fractional availability (F) varies from 0 to 1. The extent of availability is more important parameter to measure rather than the rate of availability.

A true decrease in bioavailability could be due to several reasons including, a poorly ad‐ ministered dosage form that fails to disintegrate or dissolve in the GIT, interaction with other drugs in the GIT, metabolism of the drug in the GIT and/or first pass hepatic me‐ tabolism or biliary excretion.

Hepatic disease may in particular cause high availability because the metabolic capacity decreases or development of vascular shunts in the liver. Significantly high availability requires dosage adjustment by a factor of two, while significantly low in availability requires dosage adjustment by a factor of half.
