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

Abstract

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, intrapatient variability for each azole was determined.Methods:From July 2012 to July 2015, 806 APL of ITR, VOR, posaconazole liquid (POS-Liq), and posaconazole tablets (POS-Tab) were measured in 173 patients of the Munich Lung Transplantation 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%, and POS-Tab 82%; prophylaxis: ITR 62%, VOR 85%, POS-Liq 49%, and POS-Tab 76%). Risk factors for subtherapeutic APL of all azoles were the azole dose (ITR, P < 0.001; VOR, P = 0.002; POS-Liq, P = 0.006) and age over 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 subtherapeutic APL for VOR and POS-Tab (VOR, P = 0.002; POS-Tab, P = 0.005). Double lung transplantation (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 intrapatient 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 patients with LTx; POS-Tab showed the lowest intrapatient variability. APL are significantly influenced by azole dose, age, cystic fibrosis, type of LTx, and comedication with proton-pump inhibitors. Considering the high number of subtherapeutic APL, therapeutic drug monitoring should be integrated in the post-LTx management.

Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis

“…For all groups, more than 60% of the trough levels were in the therapeutic range, which is consistent with the findings of Stelzer et al (4). In the CFLT group, a third of the concentrations were less than 0.7 mg/liter.…”

“…The main indication for this drug is for hematological prophylaxis, but it may also be used for curative purposes and can potentially be of use in the field of lung transplants (LT), including in patients with cystic fibrosis (CF) (1,2). The rates of fungal colonization ranged from 20% to 50% in LT patients (3), a population particularly at risk for the development of fungal infections because of immunosuppressive therapy (4). This population is also at risk of fungal bronchitis, leading to abnormal healing and stenosis.…”

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations

“…Several studies reported CVs for the POS-tab C min , but comparing CV values is problematic since calculation methods of CV differ. Here, we used the method described by Bland (21) to calculate within-subject CV, whereas a different approach was used in other studies, i.e., the ratio between standard error and the mean POS C min in each patient (18,22). Finally, as explained above, we adjusted the POS C min for the POS dose in our cohort, which was not done in the other studies (18,22).…”

Inflammation is a potential risk factor of voriconazole overdose in hematological patients

“…Despite TDM, VRC C min are frequently out-of-the therapeutic range in clinical practice. Indeed, subtherapeutic VRC C min have been found in 20-33% of patients [6,7] and supratherapeutic VRC C min in 7-23% of cases [5][6][7][8], depending on the therapeutic threshold and study population. Although subtherapeutic VRC C min are often explained by gain-of-function single nucleotide polymorphism (SNP) *17 for CYP2C19 (at least in the Caucasian population) [9][10][11][12], comedication by enzymatic inducers [13], or non-observance [10], the determinants of supratherapeutic VRC C min have been less investigated.…”