rifampin and posaconazole

Mucormycosis is an emerging mycotic infection with high mortality. We described the clinical presentation, evolution and treatment of 5 patients with diagnosis of mucormycosis.. La mucormicosis es una micosis emergente, de elevada mortalidad. El objetivo del estudio es presentar las características clínicas y evolución de los casos asistidos en el Sanatorio Allende, de la Ciudad de Córdoba República Argentina y hacer una actualización bibliografíca. Se presentan 5 pacientes con mucormicosis con diferentes formas clínicas de presentación. El diagnóstico clínico se confirmó por histopatología y/o cultivo de los tejidos. Concluimos que en la actualidad la sospecha clínica basada en la forma de presentación y los factores de riesgo siguen siendo claves para establecer la sospecha clínica y realizar el diagnóstico temprano. En cuanto al tratamiento se basa fundamentalmente en el desbridamiento quirúrgico para eliminación del tejido necrótico y Anfotericina liposomal como antifúngico de elección. El posaconazol nuevo triazol tendría un rol importante en la consolidación del tratamiento una vez que el paciente logra la estabilización clínica o como tratamiento de rescate.

Topics: Adolescent; Adult; Amphotericin B; Antifungal Agents; Fatal Outcome; Female; Humans; Male; Middle Aged; Mucormycosis; Rifampin; Risk Factors; Triazoles; Young Adult

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Midazolam; Middle Aged; Piperidines; Receptor Protein-Tyrosine Kinases; Rifampin; Treatment Outcome; Triazoles; Young Adult

Topics: Antifungal Agents; Rifampin; Triazoles

Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drug-drug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.

Topics: Adult; Anti-HIV Agents; Anticonvulsants; Antiemetics; Antifungal Agents; Biological Availability; Carbamates; Drug Interactions; Drug Therapy, Combination; Furans; Healthy Volunteers; Humans; Metoclopramide; Nucleic Acid Synthesis Inhibitors; Organophosphates; Phenytoin; Proton Pump Inhibitors; Rifampin; Sulfonamides; Triazoles

Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H(2) antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Australia; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; Fungi; Humans; Logistic Models; Male; Metoclopramide; Middle Aged; Mycoses; Phenytoin; Ranitidine; Retrospective Studies; Rifampin; Triazoles

Topics: Antifungal Agents; Drug Interactions; Humans; Male; Rifampin; Serum; Triazoles; Young Adult