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, 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.

A multistep (semi)-continuous biocatalytic setup for the production of polycaprolactone.

Biocatalysis has gained increasing importance as an eco-friendly alternative for the production of bulk and fine chemicals. Within this paradigm, Baeyer Villiger monoxygenases (BVMOs) serve as enzymatic catalysts that provide a safe and sustainable route to the conventional synthesis of lactones, such as caprolactone, which is employed for the production of polycaprolactone (PCL), a biocompatible polymer for medicinal applications. In this work, we present a three-step, semi-continuous production of PCL using an entirely biocatalytic process, highlighting the merits of continuous manufacturing for enhancing biocatalysis. First, caprolactone is produced in batch from cyclohexanol using a coenzymatic cascade involving an alcohol dehydrogenase (ADH) and BVMO. Different process parameters and aeration modes were explored to optimize the cascade's productivity. Secondly, the continuous extraction of caprolactone into an organic solvent, needed for the polymerization step, was optimized. 3D-printed mixers were applied to enhance the mass transfer between the organic and the aqueous phases. Lastly, we investigated the ring-opening polymerization of caprolactone to PCL catalyzed by Candida antarctica lipase B (CAL-B), with a focus on eco-friendly solvents like cyclopentyl-methyl-ether (CPME). Space-time-yields up to 58.5 g L-1 h-1 were achieved with our overall setup. By optimizing the individual process steps, we present an efficient and sustainable pathway for PCL production.