Pharmacokinetic investigations of isavuconazole in paediatric cancer patients show reduced exposure of isavuconazole after opening capsules for administration via a nasogastric tube.

OBJECTIVES: To study the isavuconazole pharmacokinetics in a real-life paediatric cohort and confirm whether the isavuconazole exposures are within the adult exposure range. Furthermore, we are the first to describe unbound isavuconazole pharmacokinetics. METHODS: In this prospective, observational study, the isavuconazole dosing regimen was as follows (IV/oral/nasogastric tube): 5.4 mg/kg isavuconazole (maximum 200 mg/dose) three times daily on Days 1 and 2, followed by 5.4 mg/kg isavuconazole (maximum 200 mg/dose) once daily. At least one pharmacokinetic curve was assessed. Non-linear mixed effects modelling was used for analysis. Monte Carlo simulations were performed with the above mentioned maintenance dose for IV administrations and a weight band dosing regimen for oral/nasogastric tube administrations: I) <18 kg (100 mg daily); II) 18-37 kg (150 mg daily); III)>37 kg (200 mg daily). RESULTS: Seventeen paediatric patients with a median age of 9 years (range 1-17) and median weight of 26.0 kg (range 8.4-78.5) were evaluated. A two-compartment model describing linear pharmacokinetics of the unbound concentrations and saturable protein binding fitted the isavuconazole concentrations best. The absolute bioavailability of isavuconazole was 41.0% (95% CI: 32.4%-50.8%). The median (IQR) simulated exposures (AUC0-24h, SS) of the total isavuconazole concentrations after IV and oral/nasogastric tube administration were 87.7 mg·h/L (70.5-105.1) and 50.3 mg·h/L (39.0-62.4), respectively. The unbound isavuconazole fraction (unbound/total) ranged from 0.5% to 2.3%. CONCLUSIONS: This study revealed low bioavailability after nasogastric tube administration with opened capsules. Isavuconazole exposures were in the expected range following IV administration. Total and unbound isavuconazole pharmacokinetics were reported with a 5-fold range in the unbound fraction.

Posaconazole bioavailability of the solid oral tablet is reduced during severe intestinal mucositis.

OBJECTIVES: This study aimed to describe the absolute oral bioavailability of the solid oral formulation of posaconazole and the impact of severe intestinal mucositis in haematology patients. This study also aimed to describe posaconazole protein binding in haematology patients. METHODS: A pharmacokinetic study was performed of patients receiving induction chemotherapy or a haematopoietic cell transplantation who were randomized to receive 7 days of intravenous posaconazole therapy followed by 9 days of oral therapy, or vice versa. Patients received a posaconazole licensed dose until day 12, after which a reduced once-daily dose of 200 mg was given. At days 7, 12, and 16, blood samples were obtained for pharmacokinetic curves, and trough samples were collected on all other days. Total and unbound posaconazole pharmacokinetics were analyzed by population pharmacokinetic modelling. The presence of severe intestinal mucositis was assessed by plasma citrulline levels and analyzed as a binary covariate using 10 µmol/L as the cut-off. Monte Carlo simulations were performed to simulate posaconazole exposure at a steady state. RESULTS: Twenty-three patients were included for analysis, with 581 total posaconazole concentrations and 91 paired unbound concentrations. Absolute bioavailability in the final model was estimated at 51.4% (percentage relative standard error (%RSE): 56.5) and 67.6% (%RSE: 75.0) in patients with and without severe intestinal mucositis, respectively. Posaconazole unbound fraction was estimated at 2.7% (%RSE: 3.9). DISCUSSION: Posaconazole bioavailability is reduced in haematological patients with severe intestinal mucositis, requiring an increase in oral posaconazole dose to 400 mg twice daily on day 1, followed by 400 mg once daily or a switch to intravenous therapy.

Pharmacokinetic evaluation of twice-a-week micafungin for prophylaxis of invasive fungal disease in children with acute lymphoblastic leukaemia: a prospective observational cohort study.

OBJECTIVES: To determine the pharmacokinetics of twice-a-week micafungin prophylaxis in paediatric leukaemic patients to provide the rationale for this approach. METHODS: Twice-a-week micafungin at a dose of 9 mg/kg (maximum 300 mg) was given during the leukaemic induction treatment with at least one pharmacokinetic assessment. Non-linear mixed-effects modelling was used for analysis. For model building, our paediatric data were strengthened with existing adult data. Monte Carlo simulations were performed with twice-a-week dosing regimens of 5, 7 and 9 mg/kg and flat dosing per weight band. Simulated paediatric exposures were compared with the exposure in adults after a once-daily 100 mg regimen. RESULTS: Sixty-one paediatric patients were included with a median age and weight of 4.0 years (range 1.0-17) and 19.5 kg (range 8.60-182), respectively. A two-compartment model best fitted the data. CL and central Vd were lower (P < 0.01) in paediatric patients compared with adults. Predicted exposures (AUC0-168 h) for the 5, 7 and 9 mg/kg and flat dosing per weight band regimens exceeded the adult reference exposure. CONCLUSIONS: All twice-a-week regimens appeared to result in adequate exposure for Candida therapy, with simulated exposures well above the adult reference exposure. These findings provide the rationale for the pharmacokinetic equivalence of twice-a-week and once-daily micafungin regimens. The greater micafungin exposures seem to be caused by a slower-than-anticipated CL in our paediatric leukaemic patients. The generalizability of our results for Aspergillus prophylaxis cannot be provided without assumptions on target concentrations and within-class identical efficacy.

Clinical Pharmacokinetics of Triazoles in Pediatric Patients.

Triazoles represent an important class of antifungal drugs in the prophylaxis and treatment of invasive fungal disease in pediatric patients. Understanding the pharmacokinetics of triazoles in children is crucial to providing optimal care for this vulnerable population. While the pharmacokinetics is extensively studied in adult populations, knowledge on pharmacokinetics of triazoles in children is limited. New data are still emerging despite drugs already going off patent. This review aims to provide readers with the most current knowledge on the pharmacokinetics of the triazoles: fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. In addition, factors that have to be taken into account to select the optimal dose are summarized and knowledge gaps are identified that require further research. We hope it will provide clinicians guidance to optimally deploy these drugs in the setting of a life-threatening disease in pediatric patients.

A Multidisciplinary Approach to Fungal Infections: One-Year Experiences of a Center of Expertise in Mycology.

Invasive fungal diseases (IFDs) often represent complicated infections in complex patient populations. The Center of Expertise in Mycology Radboudumc/CWZ (EMRC) organizes a biweekly multidisciplinary mycology meeting to discuss patients with severe fungal infections and to provide comprehensive advice regarding diagnosis and treatment. Here, we describe the patient population discussed at these meetings during a one-year period with regards to their past medical history, diagnosis, microbiological and other diagnostic test results and antifungal therapy. The majority of patients discussed were adults (83.1%), 62.5% of whom suffered from pulmonary infections or signs/symptoms, 10.9% from otorhinolaryngeal infections and/or oesophagitis, 9.4% from systemic infections and 9.4% from central nervous system infections. Among children, 53.8% had pulmonary infections or signs/symptoms, 23.1% systemic fungal infections and 23.1% other, miscellaneous fungal infections. 52.5% of adult patients with pulmonary infections/symptoms fulfilled diagnostic criteria for chronic pulmonary aspergillosis (CPA). Culture or polymerase chain reaction (PCR) demonstrated fungal pathogens in 81.8% of patients, most commonly Aspergillus. A multidisciplinary mycology meeting can be a useful addition to the care for patients with (I)FDs and can potentially aid in identifying healthcare and research needs regarding the field of fungal infections. The majority of patients discussed at the multidisciplinary meetings suffered from pulmonary infections, predominantly CPA.

Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time To Rethink Dosing.

Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.).

Mucuna Pruriens Combined with Carbidopa in Parkinson's Disease: A Case Report.

We present a 48-year-old woman with Parkinson's disease in whom carbidopa was added to Mucuna pruriens, resulting in marked motor improvement (documented on video and using MDS-UPDRS motor scores). This case report shows that adding a dopa-decarboxylase inhibitor (DDCI) to Mucuna pruriens could fit well in a personalized approach for patients who are reluctant to start levodopa. Meanwhile, larger trials with a longer follow-up are needed to establish the true effects and tolerability of Mucuna pruriens plus a DDCI.

Clinical Pharmacokinetics and Pharmacodynamics of Micafungin.

Micafungin is a selective inhibitor of the synthesis of fungal 1,3-ß-D-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0.15-8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol-O-methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40-80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4-10 mg/kg in premature neonates and 2-4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.

Flucloxacillin Results in Suboptimal Plasma Voriconazole Concentrations.

Combining voriconazole and flucloxacillin is indicated in patient cohorts experiencing both invasive aspergillosis and Gram-positive infections (e.g., patients with chronic granulomatous disease or postinfluenza pulmonary aspergillosis). We report a highly relevant interaction between voriconazole and flucloxacillin, resulting in subtherapeutic plasma voriconazole concentrations in more than 50% of patients, that poses a severe threat if not managed properly.

Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.

BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies. METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL. CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.

Impact of special patient populations on the pharmacokinetics of echinocandins.

Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.

Liquid chromatography-tandem mass spectrometric assay for therapeutic drug monitoring of the tyrosine kinase inhibitor pazopanib in human plasma.

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric assay for the tyrosine kinase inhibitor pazopanib was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing pazopanib-d(4) as internal standard. The extract was injected into the chromatographic system after dilution with water (1:9, v/v). The system consisted of a sub-2 µm particle, trifunctional bonded octadecyl silica column with isocratic elution using 0.005% (v/v) of formic acid in a mixture of water (76%, v/v) and acetonitrile (24%, v/v). The analyte was quantified using the selected reaction monitoring mode of a triple quadrupole mass spectrometer with a heated electrospray interface. The assay was validated in a 0.1-100 µg/ml calibration range. Within day precisions were 3.6-5.2%, between day precisions 4.0-8.3% and accuracies between 106% and 113% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients treated with pazopanib.

Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis.

Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 +/- 2.7%, 10.0 +/- 3.0 pg/mumol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 +/- 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.