Nejvíce citovaný článek - PubMed ID 15212851
BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.
- MeSH
- biologické modely MeSH
- dítě MeSH
- dospělí MeSH
- inotuzumab ozogamicin * farmakokinetika aplikace a dávkování MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- pre-B-buněčná leukemie * farmakoterapie krev MeSH
- předškolní dítě MeSH
- protinádorové látky imunologicky aktivní * farmakokinetika aplikace a dávkování terapeutické užití MeSH
- recidiva MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Názvy látek
- inotuzumab ozogamicin * MeSH
- protinádorové látky imunologicky aktivní * MeSH
This study aimed to characterize the impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of meropenem in neonates and children and to provide recommendations for meropenem dosing in this specific population of patients. Therapeutic drug monitoring (152 meropenem plasma concentrations) data from 45 patients (38 received ECMO) with a body weight (BW) of 7.88 (3.62-11.97) kg (median (interquartile range)) and postnatal age of 3 (0-465) days were collected. The population PK analysis was performed using NONMEM V7.3.0. Monte Carlo simulations were performed to assess the probability of target achievement (PTA) for 40% of time the free drug remained above the minimum inhibitory concentration (fT > MIC) and 100% fT > MIC. BW was found to be a significant covariate for the volume of distribution (Vd) and clearance (CL). Additionally, continuous renal replacement therapy (CRRT) was associated with a two-fold increase in Vd. In the final model, the CL and Vd for a typical patient with a median BW of 7.88 kg that was off CRRT were 1.09 L/h (RSE = 8%) and 3.98 L (14%), respectively. ECMO did not affect meropenem PK, while superimposed CRRT significantly increased Vd. We concluded that current dosing regimens provide acceptably high PTA for MIC ≤ 4 mg/L for 40% fT > MIC, but individual dose adjustments are needed for 100% fT > MIC.
- Klíčová slova
- Monte Carlo simulations, children, continuous renal replacement therapy, extracorporeal membrane oxygenation, meropenem, neonates,
- Publikační typ
- časopisecké články MeSH
Peritonitis is a limiting complication of peritoneal dialysis, which is treated by intraperitoneal administration of antibiotics. Various dosing strategies are recommended for intraperitoneally administered vancomycin, which leads to large differences in intraperitoneal vancomycin exposure. Based on data from therapeutic drug monitoring, we developed the first-ever population pharmacokinetic model for intraperitoneally administered vancomycin to evaluate intraperitoneal and plasma exposure after dosing schedules recommended by the International Society for Peritoneal Dialysis. According to our model, currently recommended dosing schedules lead to possible underdosing of a large proportion of patients. To prevent this, we suggest avoiding intermittent intraperitoneal vancomycin administration, and for the continuous dosing regimen, we suggest a loading dose of 20 mg/kg followed by maintenance doses of 50 mg/L in each dwell to improve the intraperitoneal exposure. Vancomycin plasma level measurement on the fifth day of treatment with subsequent dose adjustment would prevent it from reaching toxic levels in the few patients who are susceptible to overdose.
PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.
- Klíčová slova
- Fondaparinux, Hemodialysis, Peritoneal dialysis, Population pharmacokinetics-pharmacodynamics, Therapeutic plasma exchange,
- MeSH
- chronická renální insuficience metabolismus terapie MeSH
- fondaparinux farmakokinetika farmakologie MeSH
- inhibitory faktoru Xa farmakokinetika farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- náhrada funkce ledvin * MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- tělesná hmotnost MeSH
- věkové faktory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Názvy látek
- fondaparinux MeSH
- inhibitory faktoru Xa MeSH
The aim of this prospective PK study was to evaluate the pharmacokinetics of ciprofloxacin dosed within the first 36 h (early phase) and after 3 days of treatment (delayed phase) using individual and population PK analysis. The secondary aim of the study was to evaluate possible dosing implications of the observed PK differences between early and delayed phases to achieve a PK/PD target for ciprofloxacin of AUC24/MIC ≥ 125. Blood concentrations of ciprofloxacin (1 and 4 h after dose and trough) were monitored in critically ill adults in the early and delayed phases of the treatment. Individual and population PK analyses were performed. Complete concentration-time profiles in the early phase, delayed phase, and both phases were obtained from 29, 15, and 14 patients, respectively. No systematic changes in ciprofloxacin PK parameters between the early and delayed phases were observed, although variability was higher at the early phase. Both individual and population analyses provided similar results. Simulations showed that after standard dosing, it is practically impossible to reach the recommended ciprofloxacin PK/PD target (AUC/MIC ≥ 125) for pathogens with MIC ≥ 0.5 mg/L. A dosing nomogram utilizing patients' creatinine clearance and MIC values was constructed. Both individual and population analyses provided similar results. Therapeutic drug monitoring should be implemented to safeguard the optimal ciprofloxacin exposure.
- Klíčová slova
- NONMEM, ciprofloxacin, covariates, dosing, pharmacokinetics, renal function,
- Publikační typ
- časopisecké články MeSH
