Abstract
Background The aims of this pilot non-interventional observational study were to examine genetic polymorphisms of drug metabolizing enzymes (DMEs) and transporters (T) involved in voriconazole and/or cyclosporine disposition among patients undergoing allogeneic stem cell transplantation (SCT), and to assess the relationship between these polymorphisms and clinical and laboratory parameters related to cyclosporine kinetics and toxicity within the same patient population.
Methods Clinical data and DNA were collected from 40 subjects who underwent SCT and received cyclosporine based immunosuppression and prophylaxis for fungal infections with voriconazole. Samples were genotyped using DMET Plus arrays from Affymetrix. Only known candidate genes involved in the disposition (metabolism and transport) of cyclosporine and or voriconazole were analyzed. The average concentration/dose (C/D) ratio of cyclosporine ((ng/mL)/(mg/kg)) was calculated using available through levels and daily doses per participant's weight.
Results As expected, there was a definite interaction between voriconazole and cyclosporine whereby the C/D ratio of cyclosporine was lower when it was administered alone as compared to when it was administered with voriconazole, and this was statistically significant: median (range) C/D of cyclosporine ((ng/mL)/(mg/kg)) of 27.33 (90.12) vs. 116.75 (333.23) without and with voriconazole respectively; P<0.001. There was a statistically significant association between the 2677G>T>A (rs2032582) ABCB1 genetic polymorphism and the C/D ratio of cyclosporine combined with voriconazole (P=0.05) (Figure 1A). In parallel, ABCB1 allele carriers had statistically significantly higher creatinine values during therapy [median (range) creatinine (mg/dL) were of 0.74 (1.08) vs. 0.56 (0.64) for allele carriers vs. reference; P=0.003] (Figure 1B). Interestingly, there were trends of associations (though not statistically significant) between phenotypes of the other candidate genes and in the expected direction with C/D ratio of cyclosporine combined with voriconazole.
Conclusions This is one of the few pharmacogenetic studies in patients undergoing SCT, and the first to show that 2677G>T>A genetic polymorphism in the ABCB1 drug transporter plays a role in the interaction between voriconazole and cyclosporine and cyclosporine related nephrotoxicity in patients undergoing SCT. Moving forward is to increase sample size to potentially show significant associations with the additional candidate genes such as CYP2C9, CYP2C19 and CYP3A4/5.
