Venetoclax was the first approved Bcl-2 inhibitor by FDA and showed rational efficacy and selectivity than traditional chemotherapy. Treatment failure due to insufficient drug exposure may hinder its efficacy. In this study, we enrolled 54 treatment naive unfit AML patients which underwent VEN combination chemotherapy, and found C6/D of VEN correlated with efficacy, especially in patients with good and moderate prognosis stratification, which correlated with previously reported results(16, 17). Triazoles were known to be strong inhibitors of CYP3A4/3A5 enzymes, and VEN was recommended to reduce the dosage of at least 1/3 in the drug label(11). However, the C0/D and C6/D still higher when combined with voriconazole or posaconazole. CYP3A5 rs776746 genotype were found to be correlated with C0/D and C6/D in VA-based regimen. Through LASSO-logistic regression and nomagram analysis, ELN prognostic stratification and neutrophil percentages were determined as the critical elements that may predict drug response. Consequently, our results confirmed that ELN stratification was applicable in these treatment native unfit AML patients. C6/D level may correlate with drug response especially in good and moderate stratification patients, co-administered with triazoles or carried by AA/AG CYP3A5 rs776746 should be paid more attention in order to attain sustainable efficacy with limited toxicity.
In a quantitative efficacy study of VEN, it was observed that Asian patients had a higher relative bioavailability compared to non-Asian patients, resulting in a mean elevated steady-state area under the concentration-time curve (AUC) of approximately 67%(25). Another study on VEN therapeutic drug monitoring revealed that patients with smaller body surface area tended to have higher VEN blood concentration(10). At our center, a total of 54 patients were enrolled in the treatment protocol. Of these, 45 patients completed the first course of treatment with VEN for 28 days, 2 patients for 21 days, and 7 patients for 14 days. Notably, among the 45 patients who underwent the 28-day course, 36 patients had their VEN dosage escalated to 400 mg. The average duration of the 400 mg dosage was 18.8 days with a standard deviation of 9.4 days, which is shorter than the standard treatment duration of 26 days. The VEN drug label recommended a dose reduction to 70 mg when combination with posaconazole, and 100 mg when combined with other strong CYP3A4 inhibitors(11). Similarly, in Japan, the recommended dose of VEN for maintenance therapy is 50 mg in combination with voriconazole and interestingly, the mean plasma concentration was 0.73µg/mL, similar to the steady-state plasma concentration of 400 mg VEN (0.808 ± 0.593µg/mL) reported in a Japanese Phase 1/2 study(26). Our study indicated that VEN concentration(C0 and C6) was significantly higher in the group of patients with triazoles co-administration despite VEN dose reduction(Supplementary Table 1, 3). Patients with voriconazole prone to gain much higher concentration than posaconazole. Consequently, it is suggested to monitor the VEN concentration carefully in clinic when co-administered with triazoles, voricoazole may need a sufficient dose reduction.
Besides, VEN mainly metabolized by cytochrome P450 enzymes (CYP3A4 and CYP3A5) and is also a substrate of ABCB1(24). It was known that this mode of metabolism would be significantly affected by drugs and food(27), especially when VEN is used together with potent or moderately potent CYP3A or P-gp inhibitors. Such inhibitors could alter the exposure of drugs, such as peak blood concentration (Cmax) and area under the concentration-time curve from 0 to infinity (AUC0 − INF) of VEN. Triazole antifungals, which are known as CYP3A enzyme inhibitors, were reported to increase the Cmax and AUC0 − 24 of VEN by 7.1-fold and 8.8-fold, respectively(23). Since VEN is an oral small molecule targeted drug, its blood concentration during oral administration exhibits high individual variability. To mitigate the influence of these factors, monitored blood concentration can help to adjust the optimal dosage of VEN. Study has found when VEN combined with voriconazole, the peak concentration of VEN can be increased to the same level as the higher VEN dosage group, suggesting a potential interaction between the two drugs(28) Our study further disclosed that, out of a total cohort of 54 patients, those co-administered with triazoles demonstrated a significant increase in the C0/D value by 8.18-fold and in the C6/D value by 3.88-fold for venetoclax (VEN), in comparison to patients not receiving triazoles.
It is well known that gene polymorphism plays a significant role in individual differences, with pharmacological and pharmacogenomic studies indicating that 20%-95% of variations in drug disposition and effects are attributed to genetic factors(21). Notably, CYP3A4/5 gene polymorphism can influence VEN metabolism, and one recently discovered single nucleotide polymorphism (SNP) site is CYP3A5 rs776746. Additionally, the most extensively studied SNP site to date is CYP3A5*3, which exhibits a mutation rate as high as 65% in the Chinese population. Our study results indicated that among patients undergoing chemotherapy with the VA-based regimen, those with the CYP3A5 rs776746 GG genotype exhibited significantly higher C0/D and C6/D values compared to patients with the AA + AG genotypes. This finding suggested that patients with the AA + AG genotypes may require a higher dose of VEN to achieve appropriate blood concentration levels. It is worth noting that VEN is primarily metabolized by the CYP3A4 enzyme, and coincidentally, voriconazole and posaconazole, strong inhibitors of the same enzyme, significantly increased the plasma concentration of VEN.
This study had some limitations. Firstly, though C6/D were found to be correlated with response rate, the concentration ranges still hard to establish mainly due to limited sampling; Secondly, CYP3A5 and ABCB1 genotypes may be a critical factor that influenced drug exposure, but only ELN stratification, neutrophils were ultimately found to be correlated with response rate through LASSO-logistic regression. Further, studies and larger samples should be made to extensively explore the relationship and construct a rationale regimen for patients with triazoles co-administration or carried varied CYP3A5/ABCB1 genotypes.