Applications of Pharmacokinetics

Session objectives

By the end of this session, students will be able to:

• Define and explain dosage regimen

• Discuss the individualization of drug therapy

Dose size

• The magnitude of both therapeutic and toxic responses depends upon dose size

• Dose size calculation also requires the knowledge of amount of drug absorbed after administration of each dose

• Greater the dose size, greater the fluctuation between C_ss,max and C_ss,min    during each dosing interval and greater the chances of toxicity

• For drugs administered chronically, dose size calculation is based on average steady state blood level and is computed as equation

Xss,av = 1.44FX₀t_1/2/ז

Dosing frequency

• The dose interval (inverse of dosing frequency) is calculated on the basis of half-life of the drug.

• If the interval is increased and the dose is unchanged C_max, C_min and C_av decreases but the ratio C_max /C_min increases.

• Opposite is observed when dosing interval is reduced or dosing frequency increased

• Also results in greater drug accumulation in the body à toxicity

• A proper balance between both dose size and dosing frequency is often desired to attain steady- state concentration

Individualization of Drug Dosage Regimens

Therapeutic Drug Monitoring: In administering potent drugs to patients, the physician must maintain the plasma drug level within a narrow range of therapeutic concentrations

The functions of a TDM service are listed below:

• Select drug

• Design dosage regimen

• Evaluate patient response

• Determine need for measuring serum drug concentrations

• Assay for drug concentration in biological fluids

• Perform pharmacokinetic evaluation of drug concentrations

• Readjust dosage regimen, if necessary

• Monitor serum drug concentrations

Drug Selection

• The choice of drug and drug therapy is usually made by the physician

• Pharmacokinetics   and   pharmacodynamics   are   part   of   the   overall considerations in the selection of a drug for inclusion into the drug formulary (DF)

• Drugs with similar therapeutic indications may differ in dose and Pharmacokinetics

Dosage Regimen Design

• The overall objective of dosage regimen design is to achieve a target drug concentration at the receptor site

• The usual pharmacokinetics of the drug—including its absorption, distribution, and elimination profile—are considered in the patient

• Pathophysiologic conditions, such as renal dysfunction, hepatic disease or congestive heart failure, may change the normal pharmacokinetic profile of the drug and the dose must be carefully adjusted

Drug Dosage Form (Drug Product):

• Affect drug bioavailability

• The rate of absorption

• The route of drug administration and the desired onset will affect the choice of drug dosage form

Patient Compliance:

• Cost of the medication

• Complicated instructions

• Multiple daily doses

• Difficulty in swallowing

• Adverse drug reactions

Evaluation of Patient's Response

• Practitioner should evaluate the patient's response clinically

• If the patient is not responding to drug therapy as expected, then the drug and dosage regimen should be reviewed

Measurement of Serum Drug Concentrations

• A major assumption made by the practitioner is that serum drug concentrations relate to the therapeutic and/or toxic effects of the drug

• A single blood sample gives insufficient information. Several blood samples are often needed to clarify the adequacy of the dosage regimen

• The pharmacokineticist should be aware of the usual therapeutic range of serum concentrations from the literature.

Dosage Adjustment

• The new dosage regimen should be calculated using the   pharmacokinetic parameters derived from the patient's serum drug concentrations

Steps involved in Individualization of Dosage Regimen

• Estimation of Pharmacokinetic parameters in individual patient & determining their deviation from the population values to evaluate the extent of Variability

• Attributing the variability to some measurable Characteristics such as Hepatic or Renal disease, Age, Weight etc.

• Designing the new dosage regimen from collected data

Dosing of Drug in Obese Patient

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

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

• Any person whose body weight is more than 25% above the IBW is considered as obese

Dosing of drug in Neonates, Infants & Children

Mosteller’s equation:

SA (in m²) = (height X weight)^1/2/60

• Child’s maintenance dose can be calculated from adult dose by using the following equation :

Child’s dose= SA of Child in m² X Adult Dose/1.73

SA (in m²) = Body weight (Kg)^0.7

 

Monitoring drug therapy

• Depending upon the drug and the disease to be treated, management of drug therapy in individual patient can be accomplished by:

• Monitoring therapeutic effect- therapeutic monitoring

• Monitoring pharmacologic actions- pharmacodynamic monitoring

• Monitoring plasma drug concentration - pharmacokinetic monitoring

Summary

• The search for new drugs can be divided functionally into two stages:   discovery and development

• Application of pharmacokinetics are Drug Development, Formulation Development Deciding Dosage Regimen, Designing Rational Dose, Frequency and Duration In Vitro –In Vivo correlation studies and Pharmacokinetics, Pharmacodynamics Relationship

• Therapeutic Drug Monitoring is administering potent drugs to patients, the physician must maintain the plasma drug level within a narrow range of therapeutic concentrations