Background: Meltdose tacrolimus (Envarsus (R)) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose... Show moreBackground: Meltdose tacrolimus (Envarsus (R)) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose individualization is essential. Relaxation of the upper age limits for kidney transplantations has resulted in larger numbers of elderly patients receiving tacrolimus. However, due to the physiological changes caused by aging, the tacrolimus pharmacokinetics (PK) might be altered. The primary aim was to develop a population PK model in elderly kidney transplant recipients. Secondary aims were the development and evaluation of a limited sampling strategy (LSS) for AUC estimation. Methods: A total of 34 kidney transplant recipients aged >= 65 years, starting on meltdose tacrolimus directly after transplantation, were included. An eight-point whole blood AUC0-24h and an abbreviated dried blood spot (DBS) AUC0-24h were obtained. The PK data were analyzed using nonlinear mixed effect modeling methods. Results: The PK data were best described using a two-compartment model, including three transit compartments and a mixture model for oral absorption. The best three-sample LSS was T = 0, 2, 6 h. The best four-sample LSSs were T = 0, 2, 6, 8 h and T = 0, 1, 6, 8 h. Conclusions: The developed population PK model adequately described the tacrolimus PK data in a population of elderly kidney transplant recipients. In addition, the developed population PK model and LSS showed an adequate estimation of tacrolimus exposure, and may therefore be used to aid in tacrolimus dose individualization. Show less
Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal... Show moreCeftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T->MIC) (for efficacy purposes and 100% T->4xMIC and 100% T->5xMIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T->MIC during hypothermia (33.7 degrees C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T->MIC during normothermia (36.7 degrees C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T->4xMIC and 100% T->5xMIC are desired. Show less
Martial, L.C.; Biewenga, M.; Ruijter, B.N.; Keizer, R.; Swen, J.J.; Hoek, B. van; Moes, D.J.A.R. 2021
Aims Meltdose tacrolimus (Envarsus) is marketed as a formulation with a more consistent exposure. Due to the narrow therapeutic window, therapeutic drug monitoring is essential to maintain adequate... Show moreAims Meltdose tacrolimus (Envarsus) is marketed as a formulation with a more consistent exposure. Due to the narrow therapeutic window, therapeutic drug monitoring is essential to maintain adequate exposure. The primary objective of this study was to develop a population pharmacokinetic (PK) model of Envarsus among liver transplant patients and select a limited sampling strategy (LSS) for AUC estimation. The secondary objective was to investigate potential covariates including CYP3A/IL genotype suitable for initial dose optimization when converting to Envarsus.Methods Adult liver transplant patients were converted from prolonged release tacrolimus (Advagraf) to Envarsus and blood samples were obtained using whole blood and dried blood spot sampling. Subsequently the population PK parameters were estimated using nonlinear-mixed effect modelling. Demographic factors, and recipient and donor CYP3A4, CYP3A5, IL-6, -10 and -18 genotype were tested as potential covariates to explain interindividual variability.Results Fifty-five patients were included. A 2-compartment model with delayed absorption was the most suitable to describe population PK parameters. The population PK parameters were as follows: clearance, 3.27 L/h; intercompartmental clearance, 9.6 L/h; volume of distribution of compartments 1 and 2, 95 and 500 L, respectively. No covariates were found to significantly decrease interindividual variability. The best 3-point LSS was t = 0,4,8 with a median bias of 1.8% (-12.5-12.5).Conclusions The LSS can be used to adequately predict the AUC. No clinically relevant covariates known to influence the PK of Envarsus, including CYP3A status, were identified and therefore do not seem useful for initial dose optimization. Show less
Kamp, J.; Jonkman, K.; Velzen, M. van; Aarts, L.; Niesters, M.; Dahan, A.; Olofsen, E. 2020
Background: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of... Show moreBackground: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers.Methods: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach.Results: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics.Conclusions: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites. Show less
Yin, O.; Wagner, A.J.; Kang, J.; Knebel, W.; Zahir, H.; Sande, M. van de; ... ; Stacchiotti, S. 2020
Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A... Show morePexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2-compartment model with sequential zero- and first-order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L/h in a typical patient with reference covariates (male, non-Asian, weight = 80 kg, creatinine clearance >= 90 mL/min, aspartate aminotransferase <= 80 U/L, and total bilirubin <= 20.5 mu mol/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady-state area under the curve values from 0 to 24 hours (AUC(0-24,ss)). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC(0-24,ss)were generally <20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC(0-24,ss)than those with normal renal function. The effects of covariates on ZAAD exposure were similar to those on pexidartinib. These results indicate small and generally clinically nonmeaningful effects of patient demographic and clinical characteristics on pexidartinib and ZAAD PK profiles. Show less
AbstractIn this prospective study, we examined the pharmacokinetics of 1 and 2 mg/kg liposomal amphotericin B in 16 morbidly obese individuals (104–177 kg). Body size had no effect on clearance. We... Show moreAbstractIn this prospective study, we examined the pharmacokinetics of 1 and 2 mg/kg liposomal amphotericin B in 16 morbidly obese individuals (104–177 kg). Body size had no effect on clearance. We recommend a fixed dose in patients ≥100 kg (ie, 300 or 500 mg rather than the current dose of 3 and 5 mg/kg, respectively).Clinical Trials Registration NCT02320604. Show less
Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of... Show moreChildren undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92–944], body weight, 6.1 kg [4.0–12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8–hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1‐compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher. Show less
