Investigation of the Impact of CYP3A5 and CYP2C19 Polymorphisms on Drug-Drug Interactions between Tacrolimus and Voriconazole Based on Physiologically-Based Pharmacokinetic Modeling

ABSTRACT Aims: This study aimed to develop a PBPK model for tacrolimus incorporating CYP3A5 and CYP2C19 polymorphisms to predict the DDIs between tacrolimus and voriconazole. Methods: Pharmacokinetic (PK) data in rats and healthy subjects receiving tacrolimus with and without voriconazole were used for model development and evaluation. Then, we used the final model to simultaneously investigate the effect of CYP3A5 and CYP2C19 polymorphisms on the PK data of tacrolimus when combined with voriconazole. Results: The final results showed that the predicted Cmax in CYP3A5 nonexpressers was 1.5-fold higher than expressers, and the predicted AUC0-∞ was 1.92 to 1.96-fold higher in nonexpressers. However, the Cmax and AUC0-∞ of tacrolimus both have no significant difference between different CYP2C19 metabolizers. Conclusions: A physiologically-based pharmacokinetic (PBPK) model for tacrolimus integrated with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole in patients with different CYP3A5 and CYP2C19 genotypes. Furthermore, this study highlights the feasibility of PBPK modeling to predict DDIs between these two drugs and the need to include CYP3A5 polymorphisms but not CYP2C19 polymorphisms.

Prevalence of CYP2C19 Polymorphisms in Clopidogrel Treated Turkish Patients: Preliminary Results, 2017

Background: Clopidogrel is one of the most frequently prescribed antiplatelet agents to reduce the risk of atherosclerotic symptoms. CYP2C19 enzyme is involved in clopidogrel metabolism, and several genetic variations of CYP2C19gene are able to affect the clinical response of clopidogrel. Despite the lack of a fully accepted guideline for CYP2C19 pharmacogenetic testing before clopidogrel treatment by relevant communities, we believe that determination of the variant frequencies is important to predict the efficiency and possible clopidogrel related risks before the initiation of treatment on the basis of populations. Our aim was to determine the distribution of gene polymorphisms affecting the enzyme activity in Turkish cardiac patients prescribed clopidogrel. Methods: 54 clopidogrel prescribed patients were included in the study. The presence of CYP2C19*2, *3, *4, *5, *6, *7, *8, *9, *10 and *17 polymorphisms were investigated using a microarray platform. Results : No variant allele was detected for *4, *5, *6, *7, *8, *9 and *10 polymorphisms. The genotype frequencies were detected as 38.89% for *1/*1, 16.67% for *1/*2, 11.11% for *2/*17, 1.85% for *1/*3, 1.85% for *2/*3, 27.78% for *1/*17 and 1.85% for *17/*17. According to genotype analysis, 1.85% of the patients were recorded as poor and 29.63% intermediate; whereas 27.78% as rapid and 1.85% ultra-rapid metabolizers. Conclusion: Although our study population does not consist of a high number of patients, since the high frequency of intermediate, rapid and ultra-rapid metabolizer patients were detected in relatively high frequencies, CYP2C19 polymorphisms should be taken into account for efficiency and possible clopidogrel related risks in Turkish cardiac patients.

Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis

Aims: To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. Methods: We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to March 18, 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity and neurotoxicity. Results: A total of 20 studies were included. Intermediate metabolizers (IMs) and Poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) (risk ratio (RR): 1.18, 95% confidence interval (CI): 1.03~1.34, I2=0%, p=0.02; RR: 1.28, 95%CI: 1.06~1.54, I2=0%, p=0.01). PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR: 2.18, 95%CI: 1.35~3.53, I2=0%, p=0.001; RR: 1.80, 95% CI: 1.23~2.64, I2=0%, p=0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR: 1.60, 95%CI: 0.94~2.74, I2=27%, p=0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. Conclusions: IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deservers clinical attention.

A meta-analysis of effects of CYP2C9 and CYP2C19 polymorphisms on phenytoin pharmacokinetic parameters

Aim: Phenytoin is metabolized through CYP2C9 and CYP2C19 . Polymorphisms of CYP2C9 and CYP2C19 may increase plasma concentration and side effects. Materials & methods: Systematic review and meta-analysis were performed to evaluate the effects of CYP2C9 and CYP2C19 polymorphism on pharmacokinetic parameters. PubMed, Science Direct, Cochrane library, and Thai databases were systematically searched. Results: Eight observational studies, comprising a total of 633 patients were included. Michaelis–Menten constant was significantly higher in the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups as compared with the control groups (CYP2C9EM/CYP2C19EM) at 2.16 and 1.55 mg/l (p < 0.00001, p < 0.0001). The maximum rate of action was significantly lower in the control groups as compared with the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups at 3.10 and 3.53 mg/kg/day (p = 0.00001, <0.0001). Conclusion: The dosage regimen for patients in the CYP2C9IM group to achieve phenytoin therapeutic levels was 2.1–3.4 mg/kg/day.