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Ivermectin has been used since the 1980s as an anthelmintic and antiectoparasite agent worldwide. Currently, the only available oral formulation is tablets designed for adult patients. A patient‐friendly orodispersible tablet formulation designed for pediatric use (CHILD‐IVITAB) has been developed and is entering early phase clinical trials. To inform the pediatric program of CHILD‐IVITAB, 16 healthy adults were enrolled in a phase I, single‐center, open‐label, randomized, 2‐period, crossover, single‐dose trial which aimed to compare palatability, tolerability, and bioavailability and pharmacokinetics of CHILD‐IVITAB and their variability against the marketed ivermectin tablets (STROMECTOL) at a single dose of 12 mg in a fasting state. Palatability with CHILD‐IVITAB was considerably enhanced as compared to STROMECTOL. Both ivermectin formulations were well tolerated and safe. Relative bioavailability of CHILD‐IVITAB compared to STROMECTOL was estimated as the ratios of geometric means for Cmax, AUC 0‐∞, and AUC0‐last, which were 1.52 [90% CI: 1.13‐2.04], 1.27 [0.99‐1.62], and 1.29 [1.00‐1.66], respectively. Maximum drug concentrations occurred earlier with the CHILD‐IVITAB formulation, with a median Tmax at 3.0 h [range 2.0‐4.0 h] versus 4.0 h [range 2.0‐5.0 h] with STROMECTOL (P =.004). With CHILD‐IVITAB, variability in exposure was cut in half (coefficient of variation: 37% vs 70%) compared to STROMECTOL. Consistent with a more controlled absorption process, CHILD‐IVITAB was associated with reduced variability in drug exposure as compared to STROMECTOL. Together with a favorable palatability and tolerability profile, these findings motivate for further clinical studies to evaluate benefits of such a patient‐friendly ODT formulation in pediatric patients with a parasitic disease, including infants and young children <15 kg. [ABSTRACT FROM AUTHOR]

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off‐label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of the active metabolites 4‐methylaminoantipyrine (4‐MAA) and 4‐aminoantipyrine (4‐AA) was performed. Various reduced plasma sampling scenarios were evaluated by PMX simulations. Saliva and plasma samples from 25 children were included (age range, 5–70 months; weight range, 8.7–24.8 kg). Distribution of metamizole metabolites between plasma and saliva was without delay. Estimated mean (individual range) saliva/plasma fractions of 4‐MAA and 4‐AA were 0.32 (0.05–0.57) and 0.57 (0.25–0.70), respectively. Residual variability of 4‐MAA (4‐AA) in saliva was 47% (28%) versus 17% (11%) in plasma. A simplified sampling scenario with up to 6 saliva samples combined with 1 plasma sample was associated with similar PK parameter estimates as the full plasma sampling scenario. This case study with metamizole shows increased PK variability in saliva compared to plasma, compromising its suitability as single matrix for PK studies in infants. Nonetheless, rich saliva sampling can reduce the number of plasma samples required for PK characterization, thereby facilitating the conduct of PK studies to optimize dosing in pediatric patients. [ABSTRACT FROM AUTHOR]

Purpose: Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7alpha-thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age. Methods: The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites, and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed‐effects modelling software Monolix 2018R2. Results: A total of 150 spironolactone, 158 TMS, and 158 CAN concentrations from 23 patients (ages: 3 days–21 months; median weight 4.3 kg (2.2–12.6)) were available for PK analysis. A one-compartment model for spironolactone, TMS, and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9–138.1) L/h for spironolactone, 9.7 (1.5–66.9) L/h for TMS, and 1.0 (0.2–5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size of the patient: body weight explained 22% of inter-individual variability of spironolactone clearance. None of the undesirable effects of spironolactone was documented during the study period. Conclusion: The pharmacokinetics of spironolactone and its metabolites was highly variable between patients below 2 years of age. Body weight explained a significant part of this variability; this highlights the need to take it into account for dosing prescription in this population. (Clinical trial Registration Number 2013–001189-40). [ABSTRACT FROM AUTHOR]

An association between QT prolongation (Bazett's corrected QT interval, QTcB) of 7 milliseconds and nocturnal hypoglycemia, compared with euglycemia, has been observed in children with type 1 diabetes (T1D). The objective of this pharmacometric analysis was to understand this association and other sources of QTc variability quantitatively. Data originate from a prospective observational study (25 cardiac healthy children with T1D, aged 8.1‐17.6 years) with continuous subcutaneous glucose and electrocardiogram measurements for 5 consecutive nights. Mixed‐effect modeling was used to compare QTcB with individual heart‐rate correction (QTcI). Covariate models accounting for circadian variation, age, and sex were evaluated, followed by an investigation of glucose–QTc relationships (with univariable and combined adjusted analysis). Factors potentially modifying sensitivity to QTc lengthening were explored. Random inter‐individual variability was reduced in the QTcI versus QTcB model (±12.6 vs 14.1 milliseconds), and was further reduced in the adjusted covariate model (±9.7 milliseconds), accounting for the significantly (P <.01) shortened QTc in adolescent boys (–14.6 milliseconds), circadian variation (amplitude, 19.2 milliseconds; shift, 2.9 hours), and linear glucose–QTc relationship (delay rate, 0.56−h; slope, 0.76 milliseconds [95%CI 0.67‐ 0.85 milliseconds] per 1 mmol/L decrease in glucose). Differing sensitivity was suggested to depend upon hemoglobin A1c (HbA1c), T1D duration, and time spent in nocturnal hypoglycemia. In conclusion, a clinically mild association of QTc prolongation with nocturnal hypoglycemia was confirmed and quantified in this pharmacometric analysis, and the longest QTc interval was around 03:00 a.m. The characterized delayed association with glucose highlights the relevance of both the extent and the duration of hypoglycemia. Further clinical studies are warranted to investigate whether these factors contribute to increased risk of hypoglycemia‐associated cardiac arrhythmia in children with T1D. [ABSTRACT FROM AUTHOR]

Background: Hemodialysis (HD) dose targets and ultrafiltration rate (UFR) limits for pediatric patients on chronic HD are not known and are derived from adults (spKt/V>1.4 and <13 ml/kg/h). We aimed to characterize how delivered HD dose and UFR are associated with survival in a large cohort of patients who started HD in childhood. Methods: Retrospective analysis on a cohort of patients <30 years, on chronic HD since childhood (<19 years), having received thrice-weekly HD 2004–2016 in outpatient DaVita centers. Outcome: Survival while remaining on HD. Predictors: (I) primary analysis: mean delivered dialysis dose stratified as spKt/V ≤1.4/1.4–1.6/>1.6 (Kaplan–Meier analysis), (II) secondary analyses: UFR and alternative dialysis adequacy measures [eKt/V, body-surface normalized Kt/BSA] on continuous scale (Weibull regression model). Results: A total of 1780 patients were included (age at the start of HD: 0–12y: n=321, >12–18y: n=1459; median spKt/V=1.55, eKt/V=1.31, Kt/BSA=31.2 L/m2, UFR=10.6 mL/kg/h). (I) spKt/V<1.4 was associated with lower survival compared to spKt/V>1.4–1.6 (P<0.001, log-rank test), and spKt/V>1.6 (P<0.001), with 10-year survival of 69.3% (59.4–80.9%) versus 83.0% (76.8–89.8%) and 84.0% (79.6–88.5%), respectively. (II) Kt/BSA was a better predictor of survival than spKt/V or eKt/V. UFR was additionally associated with survival (P<0.001), with increased mortality <10/>18 mL/kg/h. Associations did not alter significantly following adjustment for demographic characteristics (age, etiology of kidney disease, and ethnicity). Conclusions: Our results suggest usefulness of targeting Kt/BSA>30 L/m2 for best long-term outcomes, corresponding to spKt/V>1.4 (>12 years) and >1.6 (<12 years). In contrast to adults, higher UFR of 10–18 ml/kg/h was not associated with greater mortality in this population. [ABSTRACT FROM AUTHOR]

Background: Characterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr) as a measure of kidney function in extremely low birth weight (≤ 1000 g; ELBW) neonates remains challenging. Methods: We performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to 6 weeks after birth. Change of Scr and inter-individual variability was characterized with nonlinear mixed-effect modeling. Key covariates such as gestational age (GA), mode of delivery (MOD), and treatment with ibuprofen or inotropic agents were investigated. Results: A total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), and GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease (≤ 5%) was quantified during ibuprofen treatment. For a GA of 27 weeks, mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth. Conclusions: We report the first mathematical model able to characterize Scr and CLcr in ELBW neonates during the first 6 weeks of life in a quantitative manner as a function of GA, MOD, and ibuprofen treatment. This model allows the derivation of GA-adjusted reference ranges for ELBW neonates and provides a rationale for normative Scr concentrations, and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Purpose: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3–72 months. Methods: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC0–inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3–23 months, 2–6 years) and compared with the 80–125% range of adult dose–adjusted reference exposure (AUCref). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure. Results: A total of 25 children aged 5 months–5.8 years (7.8–24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC0–inf of 4-methylaminoantipyrine in children 2–6 years was 29.9 mg/L/h (95% CI 23.4–38.2), significantly lower than AUCref (80–125% range 39.2–61.2 mg/L/h). AUC0–inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8–119.0), comparable with AUCref, while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age. Conclusions: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight–based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10–20 mg/kg) to achieve equivalent adult exposure. Trial registration: ClinicalTrials.gov identifier: NCT02660177. [ABSTRACT FROM AUTHOR]