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Aim: Molecular alterations in drug targets may result in differential drug activity. Therefore, the authors aimed to characterize how molecular alterations in drug targets were assessed during drug development. Materials & methods: The authors analyzed nonclinical and clinical study reports submitted to the US FDA for novel drugs approved in 2020 to determine if in vitro studies, animal models or clinical studies assessed molecular alterations in the drug target. Results & conclusion: Assessment of the impact of molecular alterations in drug targets on drug activity varies considerably depending on the type of assessment and therapeutic area. Premarket assessment of drug target molecular alterations is common in the oncology setting, less frequent in the genetic disease setting and rare for other diseases.

Purpose: Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between genetic polymorphisms of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment.Methods: Genetic data was collected from an institutional genetic data repository. Genetic polymorphisms in CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1 were included in the analysis. Treatment and toxicity data were retrospectively collected from the patient’s medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate metabolizer (PM/IM) vs. other) have higher risk of severe toxicity or cyclophosphamide treatment modification due to toxicity. Results: In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. other (Odds ratio=0.97, 95% Confidence Interval: 0.62-1.50, p=0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (Odds Ratio=0.31, 95% Confidence Interval: 0.09-0.78, p=0.028). None of the other tested phenotypes or genotypes were associated with the primary or secondary endpoints in unadjusted analysis (all p>0.05).Conclusion: Patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients. Validation of this associations is necessary to justify development of personalized cyclophosphamide dosing strategies to optimize therapeutic outcomes in patients with cancer.

Cyclophosphamide is a commonly used cancer agent that is metabolically activated by polymorphic enzymes. This study aims to investigate the association between predicted activity of candidate pharmacogenes with severe toxicity during cyclophosphamide treatment.Genome-wide genetic data was collected from an institutional genetic data repository for CYP2B6, CYP3A4, CYP2C9, CYP2C19, GSTA1, GSTP1, ALDH1A1, ALDH3A1, ABCC1, ABCB1, and ERCC1. Treatment and toxicity data were retrospectively collected from the patient's medical record. The a priori selected primary hypothesis was that patients who have CYP2B6 reduced metabolizer activity (poor or intermediate (PM/IM) vs. normal (NM) metabolizer) have lower risk of severe toxicity or cyclophosphamide treatment modification due to toxicity.In the primary analysis of 510 cyclophosphamide-treated patients with available genetic data, there was no difference in the odds of severe toxicity or treatment modification due to toxicity in CYP2B6 PM/IM vs. NM (odds ratio = 0.97, 95% Confidence Interval: 0.62-1.50, p = 0.88). In an exploratory, statistically uncorrected secondary analysis, carriers of the ALDH1A1 rs8187996 variant had a lower risk of the primary toxicity endpoint compared with wild-type homozygous patients (odds ratio = 0.31, 95% Confidence Interval: 0.09-0.78, p = 0.028). None of the other tested phenotypes or genotypes was associated with the primary or secondary endpoints in unadjusted analysis (all p 0.05).The finding that patients who carry ALDH1A1 rs8187996 may have a lower risk of cyclophosphamide toxicity than wild-type patients contradicts a prior finding for this variant and should be viewed with skepticism. We found weak evidence that any of these candidate pharmacogenetic predictors of cyclophosphamide toxicity may be useful to personalize cyclophosphamide dosing to optimize therapeutic outcomes in patients with cancer.

Graphene has attracted intense attention to the use in extreme applications. However, its small thickness facilitates wrinkle formation, and it is not clear how such structural change affects its area-specific capacitance. Herein, we combine molecular dynamics and continuum mechanics-based simulations to study the changes in surface area induced by wrinkles. We find that the high specific surface area of graphene can only be affected up to 2% regardless of loading conditions, geometry, and defects.