Pharmacokinetics and dosage of drugs

Pharmacokinetics is a means to improve the dosage of a drug. The aim is to reach the prescription of each drug at the dosage which ensures the best efficacy and the minimum of adverse effects.

The measurement of the plasma concentration of a drug, when it is possible, makes it possible to seek a relationship between plasma concentration and effects and facilitates dosage adjustment, by avoiding ineffective or toxic concentrations. The dosage adjustment according to the target concentration is relatively easy: when the concentration is insufficient, one increases the dose administered or the frequency of administrations, and conversely.

There remain many uncertainties about the desirable levels of drugs in plasma during the nyctohemeral, a steady concentration 24 hours a day can be sought, for others (glyceryl trinitrate), it is to be avoided and for others such as certain antibiotics, one seeks to obtain one or two peaks and troughs.

For the old drugs, it is experience which has determined the quantity of drug administered by intake and daily. For the recent drugs, the recommended dosages generally result from phase II studies. The dosage which appears most suitable is retained and then, used for phase III and IV trials. One finds in the literature few data comparing the effects of a drug according to the dose, because the pharmaceutical laboratories must show the efficacy of their product at a given dosage and that such comparisons are difficult to make and expensive.

Conditions of determination of the dosage

In adults, one can distinguish three dosage regimen: standard dosage, i.e. identical whatever the morphological differences, dosage according to weight and dosage according to body surface area.

In the elderly person, without metabolic disorder and renal impairment, one adopts the same conditions as in adults.

In children, the infant, the premature one, the dosage is established according to the body weight and sometimes according to the age, for example dosage for children from 2 to 5 years, from 6 to 12 years.

Standard dosage in adults

To prescribe the same quantity of a drug to an adult of 50 or 100 kg can appear surprising. However, if the drug has a particular affinity for a determined tissue, for example the brain which is well irrigated, a standard dosage can be better adapted than the dosage according to the body weight.

In addition, when the drug has a great tolerance, i.e. when its minimum effective concentration is very far from the toxic concentrations, the adjustment of its dosage requires less attention than in the contrary case and a standard dosage is sufficient.

Dosage according to the body weight

When a drug has a rather homogeneous distribution in the body and the effective concentrations are close to the toxic concentrations, the dosage according to body weight appears desirable.

Dosage according to body surface area

The establishment of the dosage of a drug according to the body surface area, m2, of the patient, frequently used in cancerology, is a practice without any experimental or theoretical justification. Indeed the drug is not administered and is not eliminated by the body area and all the concepts of pharmacokinetics are based on volumes, volume of distribution, clearance etc, and never on surface area.

Dosage according to body volume

The establishment of the dosage of a drug according to the body volume rather than area would be the most logical solution, because it reveals a direct relation between the dosage and the volume of distribution. However, as the average density of the human body is close to 1, the volume expressed in liters and the weight expressed in kilograms is approximately identical.

For the drugs having a particular affinity either for lipids or for water, it would be desirable to have, in addition to the body volume, an approximation of the distribution of the fat volume and thin volume. There is in the elderly a relative decrease of the thin volume compared to the fat volume.

Therapeutic drug monitoring

The request for determinations of drugs is limited by the fact that only a certain number of them are measured routinely and that the therapeutic window for most of the others is not well defined.

For the drugs determined routinely and which have a known therapeutic range, the determination can be asked:

  1. at the beginning of the treatment, when the steady state concentration is reached, i.e. after five half-lives, to make the first sampling.
  2. during the use of drugs such as the cyclosporine, lithium, etc with more or less frequent systematic controls.
  3. when the expected therapeutic results are not obtained.
  4. when adverse effects possibly related to the drug appear.
  5. when a disorder such as renal impairment is found in a patient.
  6. when a new drug likely to induce metabolic interactions is added to the treatment.

If the measured concentration appears unexpected according to the dosage, it should be ensured that blood sampling was made at the appropriated time and that the administration of the drug was made with the dosage indicated.

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