In order to identify the correct dose of any therapeutic agent there are 2 pharmacological phases: 

  • Pharmacokinetic phase in which the dose, dosage form, frequency, and route of administration are related to the amount of time for which the drug is maintained in the body in specific levels.
  • Pharmacodynamic phase in which the concentration of drug at the site(s) of action is related to the magnitude of the effect(s) produced. 

We can have therapeutic failure if the concentration of the drug in the body is too low to trigger the desired effect or if it is too high and cause toxicity. The drug limits in between as known as therapeutic window.

Because it is difficult to measure the drug concentration directly in the body this is achieved with obtaining plasma and blood samples. 

However, as always, things are not a simple as they look. In oncology pharmacodynamic parameters could vary because the response to the drug depends on many factors such as age, gender, prior chemotherapy, prior radiation therapy, concomitant medications and others. In terms of cancer drugs the toxicity is important criteria to determine the dose. 

In pharmacokinetic often the drug affect is related to drug exposure. 

Is there variability in pharmacokinetic and pharmacodynamic?

It is often observed that the dose depends on the individual. Some dose which has acceptable toxicity for one patient may have unacceptable toxicity or even be life-threatening is another patient. 

  • Body size and body composition – Often the anticancer drugs have their dose calculated for each patient based on body surface area (BSA). However, this is not always adequate and there are attempts to replace BSA with hight and weight of the patient. BSA is still relevant for paediatric population. 
  • Age – It is know that the processes of absorption and disposition of the drugs depend on the age. The way the drugs are metabolised and excreted in paediatric population is different from adults.
  • Effect of Disease – In some cases malignancies could cause serious changes in the way the drugs are metabolised. 
  • Renal Impairment – If patients have renal impairment and the drug is excreted with the urine this could lead to drug accumulation and toxicity. In this case usually there is a dose adjustment that will take into consideration the patient’s condition.
  • Hepatic Impairment – Unlike renal impairment where there is some predictability when it comes to impaired liver functions it is more complicated and unpredictable. There are no clear guidance for dose management, however this could be determined by previous observations.  
  • Effects of Serum Proteins – For most of the anticancer drugs the binding of the serum proteins is independent of drug concentration. For some drugs, however, like paclitaxel, protein binding is highly dependable on dose and schedule. 
  • Sex Dependence – It is well-documented that male gender has maximum elimination capacity of various anticancer drugs and increased clearance in comparison to female gender.
  • Inherited Genetic Factors – There are inherited variations in drug metabolising enzymes, drug transporters and drug targets between patients. These differences are responsible for the variability of drug exposure or effects. 

The process of drug metabolism is complex and there are still many unknown of different mechanisms and factors affecting it.

Source: Principles and Practice of Oncology, edition 10, Rosenberg

Author: Olga Peycheva

Olga is a clinical research professional who has been working in clinical research since 2005. She has extensive experience in clinical research in Eastern and Western Europe. 

Originally published on 11 Nov 2020