Dosing Pattern and Drug Therapy Based On Pharmacokinetic

Dosing pattern or Drug dose frequency is called dosage regimen. Designing the correct dosage regimen is important for achieving the desired therapeutic efficacy and avoiding undesired effects. Because of significant homogeneity among humans, the dosage regimen is calculated on a population basis. Despite the same dose of drug, it produces variations in pharmacological response, which is generally attributed to intersubject variability. This intersubject variability leads to pharmacokinetic or pharmacodynamics variations for the same drug administered at the same frequency in different individuals.

Various factors like metabolizing enzymes, interactions (drug–drug, herb–drug, andfood–drug), multiple treatments, and dosage regimens affect the drug disposition. Enzymes regulate metabolism, interactions alter pharmacokinetic or pharmacodynamics parameters, genetic factors may produce individual variation, etc., hence resulting in drug disposition, and also transporters are involved in the disposition process. Proteins are the transporters in drug disposition.

Different Types of Doses

Effective dose: It is the amount of drug which will produce the specific intensity of effect i.e.; either to treat the disease or prevent the disease successfully.

Median effective dose (ED50): It is the amount of a drug that produces the desired therapeutic effect in 50% of experimental animals OR

  • It is the dose of a drug required to produce a specific intensity of effect in 50% of individuals.
  • It is a measure of the effectiveness of a drug.

Lethal dose: It is the amount of a drug that will kill a certain percentage of experimental animals to whom the drug is administered

Fatal dose: When the lethal dose reaches 100% or LD100 is known as a fatal dose

Median lethal dose (LD50): It is the amount of a drug that is fatal to 50% of the experimental animals

  • [i.e.; which kills 50% of the experimental animals]
  • It is the measure of the acute toxicity of drugs

Initial loading dose: In some conditions, certain drugs are given in large doses in the beginning to obtain an effective blood level rapidly, this is known as the initial loading dose.

Maintenance dose: After achieving a desired blood level by initial loading dose, a smaller quantity of drug is then required to maintain the blood level, this is known as a maintenance dose.

Loading Dose: Dose = Cp(Target) x Vd

Maintenance Dose = CL x CpSSav

  • CpSSav is the target average steady-state drug concentration
  • The units of CL are in L/hr or L/hr/kg
  • The maintenance dose will be in mg/hr so for total daily dose will need multiplied by 24.

Dosage Adjustment in Renal and Hepatic Disease

Adjustment of Dosage in Renal Impairment:

  • In patients with renal failure, the half-life of the drug is increased and its clearance drastically decreases 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.
  • There are two additional methods for dose adjustment in renal insufficiency if the Vd change is assumed to be negligible.

General Approach:

  • No change in the desired or target plasma concentration.
  • Diminished renal clearance but unchanged non-renal clearance.
  • Unaltered drug-protein binding & volume of distribution in the really impaired patient.
  • Unchanged drug absorption from the GIT.

Three Major Approaches are:

  • Dose adjustment based on Total body clearance.
  • Dose adjustment based on Elimination rate constant or half-life.
  • Dose adjustment in renal failure.

Dose adjustment based on Total body clearance:

The average drug conc. at steady-state CSS, av is a function of maintenance dose X0, the fraction of dose absorbed F, the dosing interval & זclearance Cl T of the drug.

Css, av = Fxo / ClT ז

Dose adjustment based on Elimination rate constant or Half-life:

The average drug conc. at steady-state CSS, av is a function of maintenance dose X0, the fraction of dose absorbed F, the dosing interval & ז volume of distribution vd & t1/2 of the drug.

Css, av =1.44 FXo t ½ Vd ז

  • Diseases are the major source of variation in drug response.
  • Both the pharmacokinetics and pharmacodynamics of many drugs are altered by diseases other than the ones that are being treated.

Disease state:

  • Renal dysfunction: It greatly impairs the elimination of drugs especially those that are primarily excreted by the kidney. Causes of renal failure are hypertension, and diabetes mellitus.
  • Uremia: It is characterized by impaired glomerular filtration and accumulation of fluid and protein metabolism. In both cases, the half-life of the drug is increased as a consequence of drug accumulation and toxicity increases.

Adjustment of Dosage in Hepatic Impairment:

  • The influence of Hepatic disorder on the drug bioavailability & disposition is unpredictable because of the multiple effects that the liver produces.
  • The altered response to drugs in liver disease could be due to the decreased metabolizing capacity of the hepatocytes, and impaired biliary elimination, due to biliary obstruction.
  • Impaired Hepatic blood flow leads to an increase in bioavailability caused by a reduction in first-pass metabolism (e.g Bioavailabilities of Morphine and Labetalol have been reported to double in patients with Cirrhosis)
  • Decreased protein binding and increased toxicity of drugs highly bound to plasma protein (e.g. Phenytoin, Warfarin) due to impaired albumin production, the altered volume of distribution of drugs due to increased extracellular fluid (e.g. Rifampicin accumulates in obstruction jaundice).
  • Edema in liver disease may be increased by drugs that cause fluid retention (e.g.Acetylsalicylic acid, Ibuprofen, Prednisolone, Dexamethasone).
  • Generally, drug doses should be reduced in patients with hepatic dysfunction since clearance is reduced & bioavailability is increased in such a situation.

Renal function determination:

The glomerular filtration rate can be determined by following two methods:

  1. Insulin clearance
  2. Creatinine clearance
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