Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation-A 10-Year Single-Center Experience.

Reaching target exposure of busulfan-based conditioning prior to hematopoietic stem cell transplantation is vital for favorable therapy outcomes. Yet, a wide inter-patient and inter-occasion variability in busulfan exposure has been reported, especially in children. We aimed to identify factors associated with the variability of busulfan pharmacokinetics in 124 consecutive patients transplanted at the University Children's Hospital Zurich between October 2010 and February 2020. Clinical data and busulfan plasma levels after twice-daily intravenous administration were analyzed retrospectively by population pharmacokinetic modeling. The volume of distribution correlated with total body water. The elimination rate constant followed an age-dependent maturation function, as previously suggested, and correlated with the levels of serum albumin. Acute lymphoblastic leukemia reduced busulfan clearance by 20%. Clearance significantly decreased by 17% on average from the start to the third day of busulfan administration, in agreement with other studies. An average reduction of 31% was found in patients with hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease. In conclusion, we demonstrate that in addition to known factors, underlying disease and serum albumin significantly impact busulfan pharmacokinetics in pediatric patients; yet, substantial unexplained variability in some patients remained. Thus, we consider repeated pharmacokinetic assessment essential to achieve the desired target exposure in twice-daily busulfan administration.

Kinetics of iron absorption from ferrous fumarate with and without galacto-oligosaccharides determined from stable isotope appearance curves in women.

BACKGROUND: Prebiotic galacto-oligosaccharides (GOS) are novel enhancers of iron absorption from ferrous fumarate (FeFum). However, the mechanism(s) of this effect, and whether it occurs in the proximal or distal gut, are uncertain. OBJECTIVES: We studied: 1) in vitro, the effect of GOS on iron solubility and dialyzability from FeFum; 2) in volunteers, the absorption kinetics of FeFum given with and without GOS using stable isotope appearance curves (SIAC). METHODS: We measured iron solubility at various pH and dialyzability from FeFum with and without GOS. In crossover design, iron-depleted women [n = 11; median serum ferritin (SF) 15.2; IQR: 12.6-21.2 µg/L] received 2 14-mg iron doses as labeled (57Fe,58Fe) FeFum 14 d apart with and without 15 g GOS in randomly assigned order. Multiple blood samples were collected over a time period of 24 h and 14 d later to determine SIAC and fractional iron absorption (FIA), respectively. SIAC data were fitted using nonlinear mixed effects modeling to a 1-compartment model with first-order absorption, and AUC and time of peak serum isotope concentration (tmax) were calculated. RESULTS: Iron dialyzability was 75% higher with GOS (P < 0.001) and iron solubility was more than doubled at pH 4 and 6 with GOS [both P < 0.001]. Mean ± SD AUC (5830.9 ± 4717.3 µg/min with GOS, 4454.0 ± 3260.7 µg/min for control), and median (IQR) FIA (20.3% (8.6%-38.7%) with GOS, and 15.6% (10.6%-24.8% f)or control) were not different with compared to without GOS (P = 0.064; P = 0.080). Mean ±SD tmax was not altered with GOS (3.08 ± 0.47 h with GOS; 2.80 ±0.50 h for control; P = 0.096). Iron bioavailability significantly increased with decreasing SF and this effect was significantly enhanced by GOS (P = 0.037, interaction of GOS with SF). CONCLUSIONS: GOS increases iron solubility from FeFum at physiological pH characteristic of the proximal duodenum. The absorption kinetics in vivo are consistent with effects on iron absorption in the proximal, rather than distal, parts of the gut. There was no overall effect of GOS on FIA in vivo, but the interaction of GOS and SF on FIA might benefit iron-deficient women, an effect potentially mediated by the higher solubility shown in vitro. This study was registered at clinicaltrials.gov as NCT03996421.

Gentamicin Population Pharmacokinetics in Pediatric Patients-A Prospective Study with Data Analysis Using the saemix Package in R.

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children's Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPKcdw platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0-21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were <1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment.

[11C]mHED PET follows a two-tissue compartment model in mouse myocardium with norepinephrine transporter (NET)-dependent uptake, while [18F]LMI1195 uptake is NET-independent.

PURPOSE: Clinical positron emission tomography (PET) imaging of the presynaptic norepinephrine transporter (NET) function provides valuable diagnostic information on sympathetic outflow and neuronal status. As data on the NET-targeting PET tracers [11C]meta-hydroxyephedrine ([11C]mHED) and [18F]LMI1195 ([18F]flubrobenguane) in murine experimental models are scarce or lacking, we performed a detailed characterization of their myocardial uptake pattern and investigated [11C]mHED uptake by kinetic modelling. METHODS: [11C]mHED and [18F]LMI1195 accumulation in the heart was studied by PET/CT in FVB/N mice. To test for specific uptake by NET, desipramine, a selective NET inhibitor, was administered by intraperitoneal injection. [11C]mHED kinetic modelling with input function from an arteriovenous shunt was performed in three mice. RESULTS: Both tracers accumulated in the mouse myocardium; however, only [11C]mHED uptake was significantly reduced by excess amount of desipramine. Myocardial [11C]mHED uptake was half-saturated at 88.3 nmol/kg of combined mHED and metaraminol residual. After [11C]mHED injection, a radiometabolite was detected in plasma and urine, but not in the myocardium. [11C]mHED kinetics followed serial two-tissue compartment models with desipramine-sensitive K1. CONCLUSION: PET with [11C]mHED but not [18F]LMI1195 provides information on NET function in the mouse heart. [11C]mHED PET is dose-independent in the mouse myocardium at < 10 nmol/kg of combined mHED and metaraminol. [11C]mHED kinetics followed serial two-tissue compartment models with K1 representing NET transport. Myocardial [11C]mHED uptake obtained from PET images may be used to assess cardiac sympathetic integrity in mouse models of cardiovascular disease.