Pharmacogenetic Testing or Therapeutic Drug Monitoring: A Quantitative Framework.

Area of Science:

• Pharmacokinetics and Pharmacogenomics
• Clinical Pharmacology
• Drug Metabolism and Disposition

Background:

• Inter-individual variability (IIV) in drug exposure necessitates personalized dosing strategies.
• Pharmacogenetic profiling and therapeutic drug monitoring (TDM) are key approaches to manage this variability.
• The optimal strategy for estimating drug exposure varies by drug and source of variability.

Purpose of the Study:

• To quantitatively assess when pharmacogenetic profiling outperforms TDM in estimating drug exposure.
• To investigate the influence of IIV, inter-occasion variability (IOV), and residual unexplained variability (RUV) on the performance of each approach.
• To provide data supporting clinical decision-making for drug dose individualization.

Main Methods:

• Selected pharmacokinetic models from literature for drugs with both pharmacogenetic and TDM considerations.
• Simulated drug exposures (trough concentration or AUC) under varying levels of IIV, IOV, and RUV.
• Compared the predictive performance of pharmacogenetic profiling versus TDM across six drug cases.

Main Results:

• The superiority of pharmacogenetic profiling over TDM varied significantly by drug: 5-fluorouracil (100%), vincristine (49.6%), risperidone (48.1%), efavirenz (49.2%), tamoxifen (12.7%), and tacrolimus (11.0%).
• TDM was superior when unexplained IIV was high and RUV/IOV were low.
• Pharmacogenetic profiling was preferred when unexplained IIV was low and IOV/RUV were high.

Conclusions:

• For drugs with low RUV and IOV (e.g., tamoxifen, tacrolimus), TDM provided the best exposure estimation.
• For drugs with low unexplained IIV and high RUV (e.g., efavirenz, 5-FU), pharmacogenetic profiling was more accurate for most patients.
• Factors like genotype prevalence, genetic influence on PK, and TDM's ability to estimate AUC impact the choice of strategy.