Determining the correct dose
Everybody deserves to be treated differently
The dose you receive as a patient is determined and limited by two main factors. The established dose range and the size of your body. In cases where flat dosing is applied the size of your body is also redundant. The dose range is established during clinical trials and determines the maximum dose tolerable and the minimum level needed for an effective treatment. If the minimum effective level is close to the maximum tolerable dose the drug is considered to have a narrow therapeutic window. In most cases the dose given is calculated individually to provide a certain number of milligrams either per kilo or per square meter of body area.
Establishing dose range
Due to the fact that a certain amount of cell death is needed in many oncologic treatments, a certain amount of toxic side effects are hard to avoid. Based on an assumption that the general level toxicity and the level of efficiency are linked, doses in oncology are often established during clinical trials by means of the so called 3+3 modified Fibonacci study design. This method establishes the maximum tolerable dose as the dose where at least one of six patients experiences severe toxicity. Assuming an exposure-response relationship, the patients experiencing this kind of toxic response also have a high exposure. Assuming a conservative variability in pharmacokinetics between patients and a therapeutic window where minimally effective exposure lies at two-thirds of the max dose, only half of all patients fall within the therapeutic window. One of every six patients are being overdosed and will discontinue therapy before deriving the benefit. Yet the largest proportion of patients that fall outside the therapeutic window- more than one third of all patients- is under-dosed, experiences subtherapeutic exposure, and are also unlikely to derive benefit. And this is with a conservative count. In cases where the pharmacokinetic variability is bigger or the therapeutic window more narrow, the proportion of patients being under-dosed is even larger. Despite the fact that under dosing will lead to suboptimal treatments, the maximum dose can not be increased as this would lead to severe and potentially lethal side effects in other patients. To avoid unnecessary toxicity, doses are adjusted to the individual before the start of a treatment but no further measurements are routinely made.
Methods for individualized dose measurement
In general, individual dosing of cytostatic drugs is based on the patient’s body surface area (BSA) and measured in milligrams per square meter, or weight (mg/kg), although little evidence actually validates these approaches. The major concern is that BSA and body weight based dosing does not take into account individual variations in metabolism and rate of clearance.
A more effective and safer approach is therapeutic dose monitoring (TDM), which involves determining the blood level of the cytostatic agent in an individual and adjustment of the dose on the basis of this value. However, TDM is rarely employed, since the traditional analytical procedures currently available require multiple blood samples to obtain a valid value. Moreover, metabolites which exhibits a short half-life in patients occurs at low concentrations and is difficult to isolate from blood and exceedingly difficult to quantify.