Comparing Azole Plasma Trough Levels in Lung Transplant Recipients: Percentage of Therapeutic Levels and Intrapatient Variability

BACKGROUND This study compared therapeutic azole plasma trough levels (APL) of the azole antimycotics itraconazole (ITR), voriconazole (VOR), and posaconazole (POS) in lung transplant recipients and analyzed the influencing factors. In addition, intra-patient variability for each azole was determined. METHODS From July 2012 to July 2015, 806 APL of ITR, VOR, POS liquid (POS-Liq), and POS tablets (POS-Tab) were measured in 173 patients of the Munich Lung Transplantation (LTx) Program. Therapeutic APL were defined as follows: ITR, ≥700 ng/ml; VOR, 1000-5500 ng/ml; and POS, ≥700 ng/ml (prophylaxis) and ≥1000 ng/ml (therapy). RESULTS VOR and POS-Tab reached the highest number of therapeutic APL whereas POS-Liq showed the lowest percentage (therapy: ITR, 50%; VOR, 70%; POS-Liq, 38%; POS-Tab, 82%; prophylaxis: ITR, 62%; VOR, 85%; POS-Liq, 49%; POS-Tab, 76%). Risk factors for sub-therapeutic APL of all azoles were the azole dose (ITR, p < 0.001; VOR, p = 0.002; POS-Liq, p = 0.006) and age <60 years (ITR, p = 0.003; VOR, p = 0.002; POS-Liq, p = 0.039; POS-Tab, p < 0.001). Cystic fibrosis was a significant risk factor for sub-therapeutic APL for VOR and POS-Tab (VOR, p = 0.002; POS-Tab, p = 0.005). Double LTx was significantly associated with less therapeutic APL for VOR and POS-Liq (VOR, p = 0.030; POS-Liq, p < 0.001). Concomitant therapy with 80 mg pantoprazole led to significantly fewer therapeutic POS APL as compared to 40 mg (POS-Liq, p = 0.015; POS-Tab, p < 0.001). VOR displayed the greatest intra-patient variability (46%) whereas POS-Tab showed the lowest (32%). CONCLUSIONS Our study showed that VOR and POS-Tab achieve the highest percentage of therapeutic APL in LTx-patients; POS-Tab showed the lowest intra-patient variability. APL are significantly influenced by azole dose, age, cystic fibrosis, type of LTx, and co-medication with proton-pump inhibitors. Considering the high number of sub-therapeutic APL, therapeutic drug monitoring should be integrated in the post-LTx management.