The combination of exposure to Tacrolimus, mycophenolic acid, Inosine 5'-Monophosphate Dehydrogenase activity and inhibition in the first week define early histological outcomes in renal transplant recipients.

Therapeutic drug monitoring is routine for Tacrolimus, while levels are not routinely monitored for mycophenolic acid (MPA). This study investigated the effect of early post-transplant pharmacokinetics (PK) of MPA and Tacrolimus along with the pharmacodynamics (PD) of MPA on biopsy-proven acute rejection (BPAR) after renal transplantation. A prospective PK/PD study with limited sampling (three blood samples) was conducted in renal transplant recipients on week 1, around Day 6 (n = 42) and at the 3rd-month biopsy on Day 90 (n = 23). The partial exposures (area under curve [AUC]0-3.5 h ) of both MPA and Tacrolimus obtained during the first week were more predictive of rejection (combined clinical and subclinical rejection) by Day 90 than their trough concentrations or Day 90 exposures. Patients with rejection had significantly worse renal function (eGFR) and a comparatively lower exposure to MPA during the first post-transplant week. The lower MPA exposure was also associated with sub-optimal inosine monophosphate dehydrogenase (IMPDH) inhibition in patients with rejection, and the probability of rejection was higher in the presence of an increased pre-transplant IMPDH activity. A composite of parameters, including MPA exposure and IMPDH activity was found to predict acute rejection and may be beneficial along with tacrolimus monitoring early after renal transplantation.

Aerosolization of Second-generation Triazoles: In Vitro Evaluation and Application in Therapy of Invasive Airway Aspergillosis.

BACKGROUND: A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered. METHODS: Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. RESULTS: Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (<5.4 µm) of 2.8 µm, 2.0, 86%; 3.4 µm, 2.4, 78%; and 3.0 µm, 2.3, 79% for voriconazole and 6, 12 mg/mL of posaconazole, respectively. Aspergillus fumigatus isolate from the patient was more susceptible to voriconazole, and hence aerosolized voriconazole was introduced around the third month posttransplant at 40 mg TID for 1 week, 40 mg BID for 1 week, followed by 40 mg daily thereafter, along with IV caspofungin (50 mg/d) and liposomal amphotericin B (300 mg/d). The aerosol regimen was well tolerated by the patient with undetectable trough plasma levels of voriconazole. Bronchoscopy at the fourth month revealed improvement in anastomotic plaques with reduction in bronchoalveolar lavage galactomannan values (7.48-2.15 ng/mL). This consolidated aerosolized and intravenous regimen was maintained until 2.97 years posttransplant. CONCLUSIONS: The intravenous solutions of both second-generation triazoles showed characteristics that were suitable for aerosol delivery. Our report further adds to the therapeutic experience with the use of aerosolized voriconazole for IA in a lung transplant patient.