Clinical pharmacokinetics · 2024
Pharmacogenetic Testing or Therapeutic Drug Monitoring: A Quantitative Framework.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Centanni Maddalena, Reijnhout Niels, Thijs Abel, Karlsson Mats O, Friberg Lena E
Аннотация
BACKGROUND: Pharmacogenetic profiling and therapeutic drug monitoring (TDM) have both been proposed to manage inter-individual variability (IIV) in drug exposure. However, determining the most effective approach for estimating exposure for a particular drug remains a challenge. This study aimed to quantitatively assess the circumstances in which pharmacogenetic profiling may outperform TDM in estimating drug exposure, under three sources of variability (IIV, inter-occasion variability [IOV], and residual unexplained variability [RUV]).
METHODS: Pharmacokinetic models were selected from the literature corresponding to drugs for which pharmacogenetic profiling and TDM are both clinically considered approaches for dose individualization. The models were used to simulate relevant drug exposures (trough concentration or area under the curve [AUC]) under varying degrees of IIV, IOV, and RUV.
RESULTS: Six drug cases were selected from the literature. Model-based simulations demonstrated that the percentage of patients for whom pharmacogenetic exposure prediction is superior to TDM differs for each drug case: tacrolimus (11.0%), tamoxifen (12.7%), efavirenz (49.2%), vincristine (49.6%), risperidone (48.1%), and 5-fluorouracil (5-FU) (100%). Generally, in the presence of higher unexplained IIV in combination with lower RUV and IOV, exposure was best estimated by TDM, whereas, under lower unexplained IIV in combination with higher IOV or RUV, pharmacogenetic profiling was preferred.
CONCLUSIONS: For the drugs with relatively low RUV and IOV (e.g., tamoxifen and tacrolimus), TDM estimated true exposure the best. Conversely, for drugs with similar or lower unexplained IIV (e.g., efavirenz or 5-FU, respectively) combined with relatively high RUV, pharmacogenetic profiling provided the most accurate estimate for most patients. However, genotype prevalence and the relative influence of genotypes on the PK, as well as the ability of TDM to accurately estimate AUC with a limited number of samples, had an impact. The results could be used to support clinical decision making when considering other factors, such as the probability for severe side effects.
METHODS: Pharmacokinetic models were selected from the literature corresponding to drugs for which pharmacogenetic profiling and TDM are both clinically considered approaches for dose individualization. The models were used to simulate relevant drug exposures (trough concentration or area under the curve [AUC]) under varying degrees of IIV, IOV, and RUV.
RESULTS: Six drug cases were selected from the literature. Model-based simulations demonstrated that the percentage of patients for whom pharmacogenetic exposure prediction is superior to TDM differs for each drug case: tacrolimus (11.0%), tamoxifen (12.7%), efavirenz (49.2%), vincristine (49.6%), risperidone (48.1%), and 5-fluorouracil (5-FU) (100%). Generally, in the presence of higher unexplained IIV in combination with lower RUV and IOV, exposure was best estimated by TDM, whereas, under lower unexplained IIV in combination with higher IOV or RUV, pharmacogenetic profiling was preferred.
CONCLUSIONS: For the drugs with relatively low RUV and IOV (e.g., tamoxifen and tacrolimus), TDM estimated true exposure the best. Conversely, for drugs with similar or lower unexplained IIV (e.g., efavirenz or 5-FU, respectively) combined with relatively high RUV, pharmacogenetic profiling provided the most accurate estimate for most patients. However, genotype prevalence and the relative influence of genotypes on the PK, as well as the ability of TDM to accurately estimate AUC with a limited number of samples, had an impact. The results could be used to support clinical decision making when considering other factors, such as the probability for severe side effects.