Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole.

In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., Ͻ79 mg · h/liter, a Ն20% lower AUC 0 -24 ), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC 0 -24 at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC 0 -24 (Ͻ79 mg · h/liter) was seen in 10 patients. The AUC 0 -24 was significantly and positively correlated with the caspofungin dose in mg/kg/day (P ϭ 0.011). The median AUC 0 -24 with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.)

e Invasive aspergillosis and candidemia are important causes of morbidity and mortality in immunocompromised and critically ill patients. The triazoles voriconazole, fluconazole, and posaconazole are widely used for the treatment and prophylaxis of these fungal infections. Due to the variability of the pharmacokinetics of the triazoles among and within individual patients, therapeutic drug monitoring is important for optimizing the efficacy and safety of antifungal treatment. A dried blood spot (DBS) analysis was developed and was clinically validated for voriconazole, fluconazole, and posaconazole in 28 patients. Furthermore, a questionnaire was administered to evaluate the patients' opinions of the sampling method. The DBS analytical method showed linearity over the concentration range measured for all triazoles. Results for accuracy and precision were within accepted ranges; samples were stable at room temperature for at least 12 days; and different hematocrit values and blood spot volumes had no significant influence. The ratio of the drug concentration in DBS samples to that in plasma was 1.0 for voriconazole and fluconazole and 0.9 for posaconazole. Sixty percent of the patients preferred DBS analysis as a sampling method; 15% preferred venous blood sampling; and 25% had no preferred method. There was significantly less perception of pain with the DBS sampling method (P ‫؍‬ 0.021). In conclusion, DBS analysis is a reliable alternative to venous blood sampling and can be used for therapeutic drug monitoring of voriconazole, fluconazole, and posaconazole. Patients were satisfied with DBS sampling and had less pain than with venous sampling. Most patients preferred DBS sampling to venous blood sampling.

The addition of fludarabine to cyclophosphamide as lymphodepleting regimen prior to CD19 chimeric antigen receptor (CAR) T cell therapy significantly improved outcome in patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL). Fludarabine exposure, previously shown to be highly variable when dosing is based on body surface area, is a predictor for survival in allogeneic hematopoietic cell transplantation. Hence, we hypothesized that an optimal exposure of fludarabine might be of clinical importance in CD19 CAR T cell treatment. We examined the effect of cumulative fludarabine exposure during lymphodepletion defined as concentration-time curve (AUC) on clinical outcome and lymphocyte kinetics. A retrospective analysis was conducted with data from 26 patients receiving tisagenlecleucel for r/r B-ALL. Exposure of fludarabine was shown to be a predictor for leukemia-free survival, B cell aplasia, and CD19-positive relapse following CAR T cell infusion. Minimal event probability was observed at a cumulative fludarabine AUCT0−∞ ≥14 mg*h/L and underexposure was defined as an AUCT0−∞ <14 mg*h/L. In the underexposed group, the median leukemia-free survival was 1.8 months and the occurrence of CD19-positive relapse within 1 year was 100%, which was higher compared to the group with an AUCT0−∞ ≥14 mg*h/L (12.9 months; p<.001 and 27.4%; p=.0001, respectively). Furthermore, the duration of B cell aplasia within 6 months was shorter in the underexposed group (77.3% versus 37.3%; p=.009). These results suggest that optimizing fludarabine exposure may have a relevant impact on leukemia-free survival following CAR T cell therapy, which needs to be validated in a prospective clinical trial.

Candida infections in the elderly are an important and expanding clinical problem, with significantly higher mortality in this group than in younger patients. The increasing problem of invasive Candida infections may be related to higher prevalence of immunocompromised older people and the emergence of treatment resistance. Older people, especially the frail and critically ill, are at higher risk of medication-related harmful effects due to changes in pharmacokinetics and pharmacodynamics, which may be further complicated by organ dysfunction, diminished homeostatic control, co-morbidities and polypharmacy. Here, we review the available options for the treatment of Candida infections and provide insights into the challenges surrounding the optimal use of antifungal drugs in the elderly.

The fluconazole concentration is not sufficient in pediatric cancer patients with the currently recommended dose regimen, and a higher fluconazole dose is required to achieve adequate drug exposure. Therapeutic drug monitoring of fluconazole can be a valuable tool to detect possible underexposure in critically ill children.

Posaconazole exposure is insufficient in more than 40% of patients at risk of or with invasive fungal disease, and posaconazole exposure is positively correlated with a successful treatment outcome. Therapeutic drug monitoring of posaconazole can detect underexposure and can be helpful in treatment optimization.

The method developed has a straightforward sample preparation and uses a structural analog as the internal standard. This method has been applied successfully for the measurement of anidulafungin and caspofungin concentrations in patient samples, both for clinical practice and for research.