Broadening mould-active strategies in paediatric haemato-oncology patients

Invasive mould disease (IMD) is a life-threatening infection in immunocompromised and hospitalized pediatric patients, particularly in those with haematological malignancies. This research aimed to develop and/or optimize mould-active dosing strategies for preventing and treating IMD in paediatric cancer patients. In Chapter 2 the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with acute lymphoblastic leukaemia (ALL) are described from 2012-2018. Among 643 patients, the incidence rate of probable and proven IMD was 7.3% during early ALL treatment, with Aspergillosis diagnosed in 89.4% of cases. Our data suggests that patients with IMD were generally older than those not developing IMD. Serum galactomannan was the trigger for diagnostic workup in only 11% of the episodes, questioning its screening value. Persistent fever and respiratory symptoms were common at presentation, with the lungs involved in 94% of the patients and a remarkably high CNS involvement(34%). Half of the patients with CNS involvement were asymptomatic at the time of diagnosis. The combination of liposomal amphotericin B and voriconazole seems to be justified given the azole resistance frequency for Aspergillus isolates of 21%. The 6- and 12-week mortality rates after IMD diagnosis were 10.6% and 14.9%, respectively. These findings highlight the importance of effective prophylaxis and early brain imaging in children even in the absence of neurological symptoms. A review of the pharmacokinetic data of triazoles in paediatric patient populations is provided in Chapter 3. This review shows that fluconazole is extensively studied in the neonatal population and voriconazole in children and adolescents, while isavuconazole, itraconazole and posaconazole are studied to a limited extend. Fluconazole data in children and adolescents are understated, and there is an urgent need for pharmacokinetic studies of other triazoles in neonates and infants. Future studies should address the pharmacokinetics of newer triazoles the bioavailability of available formulations, foor interaction, administration over a nasogastric tube, the effect of CYP genotypes, other metabolic routes, unbound drug concentrations, the development and pharmacokinetics of new children-friendly formulations, the pharmacokinetics of triazoles in critically ill patients, and the impact of dialysis, ECMO, renal or hepatic impairment. Better understanding of the pharmacokinetics is necessary for optimal clinical care. The pharmacokinetics of isavuconazole in Dutch paediatric cancer patients is examined in Chapter 4, revealing a reduced isavuconazole bioavailability of 41% when administered via a nasogastric tube with opened capsules. The administration of the reconstituted injection formulation over a nasogastric tube, demonstrating bioequivalence compared to oral administration, in combination with TDM should be considered. This study reported a five-fold range in unbound isavuconazolefraction, advocating for using unbound concentrations for TDM and for defining target concentrations. In Chapter 5 the pharmacokinetics of a twice-a-week micafungin regimen in Dutch paediatric patients with ALL are explored. The pharmacokinetic data obtained from this large paediatric (n=61) cohort were combined with an adult (n=20) cohort and supported the pharmacokinetically equivalence to a daily regimen. The predicted exposures (AUC0-168) for varying dosing regimens exceeded the adult reference exposure, likely caused by a slower clearance in our cohort. The efficacy of thistwice-a-week micafungin regimen for Aspergillus prophylaxis in Dutch paediatric patients with ALL was studied in Chapter 6. A twice-a-week micafungin regimen during early ALL treatment significantly reduced proven and probable Aspergillus infections in the micafungin cohort (1.2%; n=169) compared to the historical cohort (5.8%; n=643). This regimen was generally well tolerated, suggesting it as a viable option for a patient-friendly Aspergillus prophylaxis regimen during early ALL treatment in high-incidence areas. This thesis provides an overview of invasive mould disease in paediatric patients with ALL, covering the epidemiology, the pharmacokinetics of new mould-active agents, and the efficacy of new prophylactic and treatment strategies

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

Clinical presentation and outcome of invasive mould disease in paediatric patients with acute lymphoblastic leukaemia

Background: Childhood acute lymphoblastic leukaemia (ALL) cure rates have improved, but invasive mould disease (IMD) remains a life-threatening complication. Here, we evaluate the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with ALL. Methods: Patients (1–18 years) treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol from 2012–2021 were analysed for probable and proven IMD. Data was extracted from the Dutch national registry and the electronic health care system. Results: Among 643 patients with ALL, 47 (7.3%) were diagnosed with a probable (n = 29) or proven (n = 18) IMD. Aspergillosis was diagnosed in 42 (89%) patients. Forty-one episodes (87%) occurred during the induction (n = 20) and first consolidation (n = 21) course. The median age at ALL diagnosis was 5 years [IQR 3–10] in the overall group versus 14 years [IQR 7–16] in the IMD group. Two-third of the patients did not receive mould-active prophylaxis. The most prevalent clinical symptoms at presentation were persistent fever and respiratory symptoms. The lungs were the most common site of infection with involvement in 44 (94%) patients, followed by the CNS in 16 (34%) patients. The 6-week and 12-week mortality rate after IMD diagnosis was 10.6% and 14.9%, respectively. Discussion and conclusion: In our paediatric cohort a notable incidence of probable and proven IMD was observed during the early stages of treatment. Remarkable is the high frequency of CNS involvement. These findings highlight the importance of effective prophylactic strategies and warrant early brain imaging

Dietary intake of fibers: differential effects in men and women on perceived general health and immune functioning

Background: It has been reported previously that dietary fiber intake provides health benefits. Nevertheless, only a limited number of human studies have investigated whether gender differences exist in the relationship between fiber intake and perceived health and immune status. Objective: To investigate potential gender differences in the effects of dietary fiber intake on perceived health and immune status of healthy young adults. Design: A survey was conducted among university students in Utrecht, the Netherlands. Data were collected on perceived general health status and perceived immune functioning. Dietary intake of fibers was assessed using a food frequency questionnaire. Perceived general health status and immune functioning were associated with daily intake of fibers using nonparametric (Spearman) correlations. Statistical analyses were conducted for the group as a whole, and for men and women separately. Results: N = 509 subjects completed the survey. Mean (SD) age was 20.8 (2.6) years old. 71.9% of the samples were females. Mean daily dietary fiber intake was 15.5 (6.9) g. Daily dietary fiber intake correlated significantly with general health rate (r = 0.171, p = 0.0001) and perceived immune functioning (r = 0.124, p = 0.008). After controlling for total caloric intake, the partial correlation between fiber intake and general health remained significant (r = 0.151, p = 0.002). In men, dietary fiber intake correlated significantly with perceived general health status (r = 0.320, p = 0.0001) and immune functioning (r = 0.281, p = 0.002). After controlling for caloric intake, the association between dietary fiber intake and perceived general health (r = 0.261, p = 0.005) remained significant. Remarkably, no significant correlations were observed in women. Conclusion: A significant association between daily dietary fiber intake and perceived general health status and immune rate was found in men, but not in women. Future studies should further address the nature and causes of the observed gender differences, including validated biomarkers for immune responsiveness

Dietary intake of fibers: differential effects in men and women on perceived general health and immune functioning

Background: It has been reported previously that dietary fiber intake provides health benefits. Nevertheless, only a limited number of human studies have investigated whether gender differences exist in the relationship between fiber intake and perceived health and immune status. Objective: To investigate potential gender differences in the effects of dietary fiber intake on perceived health and immune status of healthy young adults. Design: A survey was conducted among university students in Utrecht, the Netherlands. Data were collected on perceived general health status and perceived immune functioning. Dietary intake of fibers was assessed using a food frequency questionnaire. Perceived general health status and immune functioning were associated with daily intake of fibers using nonparametric (Spearman) correlations. Statistical analyses were conducted for the group as a whole, and for men and women separately. Results: N = 509 subjects completed the survey. Mean (SD) age was 20.8 (2.6) years old. 71.9% of the samples were females. Mean daily dietary fiber intake was 15.5 (6.9) g. Daily dietary fiber intake correlated significantly with general health rate (r = 0.171, p = 0.0001) and perceived immune functioning (r = 0.124, p = 0.008). After controlling for total caloric intake, the partial correlation between fiber intake and general health remained significant (r = 0.151, p = 0.002). In men, dietary fiber intake correlated significantly with perceived general health status (r = 0.320, p = 0.0001) and immune functioning (r = 0.281, p = 0.002). After controlling for caloric intake, the association between dietary fiber intake and perceived general health (r = 0.261, p = 0.005) remained significant. Remarkably, no significant correlations were observed in women. Conclusion: A significant association between daily dietary fiber intake and perceived general health status and immune rate was found in men, but not in women. Future studies should further address the nature and causes of the observed gender differences, including validated biomarkers for immune responsiveness

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) &lt;18 kg (100 mg daily); II) 18–37 kg (150 mg daily); III) &gt;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.</p

Clinical presentation and outcome of invasive mould disease in paediatric patients with acute lymphoblastic leukaemia

Background: Childhood acute lymphoblastic leukaemia (ALL) cure rates have improved, but invasive mould disease (IMD) remains a life-threatening complication. Here, we evaluate the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with ALL. Methods: Patients (1–18 years) treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol from 2012–2021 were analysed for probable and proven IMD. Data was extracted from the Dutch national registry and the electronic health care system. Results: Among 643 patients with ALL, 47 (7.3%) were diagnosed with a probable (n = 29) or proven (n = 18) IMD. Aspergillosis was diagnosed in 42 (89%) patients. Forty-one episodes (87%) occurred during the induction (n = 20) and first consolidation (n = 21) course. The median age at ALL diagnosis was 5 years [IQR 3–10] in the overall group versus 14 years [IQR 7–16] in the IMD group. Two-third of the patients did not receive mould-active prophylaxis. The most prevalent clinical symptoms at presentation were persistent fever and respiratory symptoms. The lungs were the most common site of infection with involvement in 44 (94%) patients, followed by the CNS in 16 (34%) patients. The 6-week and 12-week mortality rate after IMD diagnosis was 10.6% and 14.9%, respectively. Discussion and conclusion: In our paediatric cohort a notable incidence of probable and proven IMD was observed during the early stages of treatment. Remarkable is the high frequency of CNS involvement. These findings highlight the importance of effective prophylactic strategies and warrant early brain imaging

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 V-d were lower (P < 0.01) in paediatric patients compared with adults. Predicted exposures (AUC(0-168 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

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults

AIM: There is accumulating evidence that neutropenic patients require higher dosages of vancomycin. To prevent sub-therapeutic drug exposure, it is of utmost importance to obtain adequate exposure from the first dose onwards. We aimed to quantify the effect of neutropenia on the pharmacokinetics of vancomycin. METHODS: Data were extracted from a matched patient cohort of patients known with (1) hematological disease, (2) solid malignancy, and (3) patients not known with cancer. Pharmacokinetic analysis was performed using non-linear mixed effects modeling with neutropenia investigated as a binary covariate on clearance and volume of distribution of vancomycin. RESULTS: A total of 116 patients were included (39 hematologic patients, 39 solid tumor patients, and 38 patients not known with cancer). In total, 742 paired time-concentration observations were available for the pharmacokinetic analysis. Presence of neutropenia showed to significantly (p = 0.00157) increase the clearance of vancomycin by 27.7% (95% CI 10.2-46.2%), whereas it did not impact the volume of distribution (p = 0.704). CONCLUSIONS: This study shows that vancomycin clearance is increased in patients with neutropenia by 27.7%. Therefore, the vancomycin maintenance dose should be pragmatically increased by 25% in neutropenic patients at the start of treatment. Since the volume of distribution appeared unaffected, no adjustment in loading dose is required. These dose adjustments do not rule out the necessity of further dose individualization by means of therapeutic drug monitoring

The effect of neutropenia on the clinical pharmacokinetics of vancomycin in adults

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