Question 4

College Answer

The majority of the information required for this question is covered within the general pharmacology section of the syllabus. The main points expected for a pass were: 

• Mention and discussion of pharmacokinetic factors such as drug absorption, volume of distribution, clearance, protein binding, dosing frequency and drug level sampling.
• Mention and discussion of pharmacodynamic factors such as drug sensitivity, and therapeutic range.
• Clinical relevance of a drug concentration (e.g. peak or trough level, total or free drug, etc).

Candidates often failed to frame their answer to the question that was asked. Candidates could have made a greater use of illustrations and examples of drugs to help answer the question. 

Among other relevant listed references, candidates should seek information from within the
text books - Basic and Clinical Pharmacology by B. G Katzung and Pharmacology by H. P Rang, J. M Ritter and M. M Dale.

Syllabus Pharmacokinetics 2i

Discussion

Judging from the college comments, they wanted a structure similar to the one suggested here:

• Pharmacokinetic factors:
  • Measurement assay: the measurement of the drug level may be 
  • Protein binding: the total plasma drug levels may not be reflective of the drug activity, as in the case of phenytoin and hypoalbuminaemia (i.e. with a low total level there is still enough free unbound drug around to have a significant therapeutic effect). Even if you manage to monitor free drug levels, the situation is made more complicated by the fact that the drugs bind variably depending on pH and competition for binding sites (which may not be well represented in the cooled and centrifuged blood sample)
  • Relationship of plasma concentration to effect site concentration:  if the drug penetrates variably and incompletely, it is difficult to relate the robust serum levels to effect site levels. One example of this is vancomycin being administered to treat ventriculitis, where high plasma levels are no guarantee of bactericidal CSF levels  (Moelering et al, 1981)
  • Factors which influence plasma concentration:  these include the volume of distribution, tissue binding, sites of metabolism, rate of clearance, and organ-independent biotransformation (which my carry on inside the blood sample tube and then inside the measurment apparatus, leaving one to measure the metabolic breakdown products instead of the parent drug).
  • Timing of the sampling in relation to the dosing:  most drug levels are trough levels, which makes it important to collect them before the next dose rather than at some arbitrary point in the dosing regimen (particularly for drugs with short half-lives). The trough is generally viewed as the least variable point in the dosing regimen because the drug concentration is changing the least over time - in contrast, after the peak the concentration would be changing (falling) rapidly.
  • Steady state concentration: most intermittently dosed drugs will achieve the steady state after 3-5 half-lives, and any drug levels collected before this point will need to be interpreted accordingly.
• Pharmacodynamic factors:
  • Relationship of the plasma concentration to clinical drug effect: in some cases, there is no such relationship, making it pointless to measure drug level (eg. in the case of levitiracetam).
  • Active metabolites:  the presence of chemically distinct daughter molecules which have their own therapeutic (or adverse) effect makes it difficult to relate measured drug levels to the clinical effect.
  • Individual variability in drug response: there may be groups in the population who have a satisfactory response to therapy at plasma levels which are below the expected "low" concentration threshold, and there may be those who experience toxicity below the "high" threshold.
• Clinical and pragmatic factors:
  • Simplicity of the assay:  there is often no point in measuring drug levels if the measurement requires such equipment and expertise as to take weeks.
  • Convenience of sample collection, eg. whether the blood sample needs to be handled in some carefully ritualised manner before being transferred to the laboratory (on ice, on dry ice, in liquid helium, etc)
  • Accuracy of the measurements:  the assay may be accurate, but it may be interfered with by other factors, rendering it uninterpretable
  • Cost and benefit of the assay, i.e. it may be inefficient to measure drug levels if they be expensive and will not alter the design of the dosing regimen and prevent the administration of the expensive drug, or if it cheaper and equally effective to titrate the drug to some sort of clinical effect.
  • Therapeutic range misalignment when the population in whom the therapeutic ranges were first defined may be completely mismatched to the scenario in which the drug is being monitored - i.e. it may be inappropriate to relate adult therapeutic ranges to the drug levels measured in the neonate
  • Relationship of the therapeutic range to the clinical situation, i.e. where the therapeutic range which is quoted does not represent the clinical scenario - for instance, the therapeutic plasma levels quoted for an antibiotic may be well above or well below the MIC for the organism being targeted

Moellering Jr, Robert C., Donald J. Krogstad, and David J. Greenblatt. "Pharmacokinetics of vancomycin in normal subjects and in patients with reduced renal function." Reviews of infectious diseases 3.Supplement (1981): S230-S235.

Ghiculescu, R. A. "Therapeutic drug monitoring: which drugs, why, when and how to do it." Aust Prescr 2008;31:42-41 Apr 2008

Vožeh, Samuel. "Cost-effectiveness of therapeutic drug monitoring." Clinical pharmacokinetics 13.3 (1987): 131-140.

Sjoqvist, F. "Interindividual differences in drug responses: an overview." Variability in drug therapy. Description, estimation, and control (1985): 1-11.

Clarke, William. "Overview of Therapeutic Drug Monitoring." Clinical Challenges in Therapeutic Drug Monitoring: Special Populations, Physiological Conditions and Pharmacogenomics(2016): 1.

Schumacher, Gerald E., and Judith T. Barr. "Therapeutic drug monitoring." Clinical pharmacokinetics 40.6 (2001): 405-409.