Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate.

BACKGROUND: Ropivacaine has an optimal toxicity profile for epidural anesthesia in adults, but there are currently no studies concerning its pharmacokinetics during continuous infusion. The primary objective of this study was to evaluate the pharmacokinetics and safety of ropivacaine in adults during a 48-h continuous epidural infusion. MATERIALS AND METHODS: We enrolled 43 adults (ASA I-II) scheduled for major abdominal or urologic surgery with postoperative continuous epidural analgesia with ropivacaine 0.2% (5 mL/h) and sufentanil 0.75 µg/mL for 48 h. Ropivacaine blood samples were collected during continuous epidural infusion before the bolus and 3, 6, 12, 24, 48, 54, 60 h after the bolus; plasma concentrations were measured on HPLC-UV. The concentration-time relationship of ropivacaine levels was analyzed using a population pharmacokinetic method based on a mixed-effect-model approach (P-PHARM software). RESULTS: Mean plasma concentration of ropivacaine at the end of epidural infusion (C(48 h)) was 1.69 µg/mL (0.21-3.8 µg/mL). Mean (range) C(max) was 1.82 µg/mL (0.61-4.0 µg/mL); the area under the plasma concentration curve, AUC ((0-60)), was 67.48 ± 30.60 µg·h/mL. Total plasma ropivacaine concentrations fell mainly within (84%) or below (12%) the range reported to be safe in adults (1.0-3.0 µg/mL). Only two patients (5%) reached ropivacaine plasma levels higher than 3 µg/mL, namely 3.8 and 4.0 µg/mL at 48 and 54 h, respectively. Total ropivacaine concentrations up to 4.0 µg/mL were tolerated during long-term epidural ropivacaine infusion. Mean clearance for total ropivacaine was 5.33 L/h. Age was the only covariable to significantly reduce clearance variability: CL (L/h)=15.04-0.148 × age (years). The volume of distribution (Vd) was 92.15 L. The infusion dosing period half-life (t(1/2,DP)=0.693 × Vd/CL) was 10.8 h. CONCLUSIONS: Exposure to ropivacaine during epidural infusion is highly variable. The apparent infusion dosing half-life t(1/2,DP) is the most appropriate parameter to predict drug accumulation upon epidural infusion since it appears to better reflect the interplay interference between volume distribution and absorption rate during the accumulation phase. Prediction of ropivacaine accumulation can be improved by considering patient age.

Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy.

beta-thalassemia is a major health problem worldwide, and stem cell transplantation (SCT) is the only curative option. Oral Busulfan (Bu) based conditioning is widely used in this setting. Due to the variability of Bu systemic exposure, intravenous (i.v.) Bu has been proposed as a standard of care, with no need for drug monitoring and dose adjustment. Patients with beta-thalassemia from countries with limited resources might be at higher risk of erratic Bu metabolism because of liver dysfunction, severe iron overload, and specific ethnic/genetic features. We studied Bu pharmacokinetics in 53 children with advanced beta-thalassemia from Middle Eastern countries who underwent a total of 57 matched related donor SCTs. Forty-two percent of the children required dose adjustment because they did not achieve the therapeutic window after the first dose. With a Bu dose-adjustment policy, regimen-related toxicity was limited. At a median follow-up of 564 days, the probabilities of 2-year survival, current thalassemia-free survival, rejection, and treatment-related mortality were 96%, 88%, 21%, and 4%, respectively. Conditioning with i.v. Bu and dose adjustment is feasible and well tolerated, although recurrence of thalassemia remains an unsolved problem in children with advanced disease.

Levels and effectiveness of oral retinol supplementation in VLBW preterm infants.

Retinol palmitate oral administration is convenient, but it is difficult to assess/monitor its nutritional status in preterm infants and literature is controversial about the administration route and the effectiveness of vitamin A supplementation. We primarily evaluated retinol plasma levels to assess the vitamin A nutritional status in preterm infants (<1500 g; 32 weeks) after 28 days of oral supplementation (3000 IU/kg/day, retinol palmitate drops), in addition to vitamin A standard amount as suggested by European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines. We then observed the rate of typical preterm pathologies in the supplemented group (31 newborns) and in 10 matching preterm infants, hospitalized in neonatal intensive care unit (NICU) in the same period, who received neither vitamin A supplementation nor parents allowed plasma sampling. Oral integration resulted in constant retinol plasma concentration around the desired level of 200 ng/mL, but without statistical increase during the study period. Due to the complexity of vitamin A metabolism and the immaturity of preterm infant's organs, retinol supplementation may had first saturated other needy tissues; therefore, plasmatic measures may not be consistent with improved global vitamin A body distribution. Therefore, achieving a constant retinol concentration is a valuable result and supportive for oral administration: decreasing levels, even after parenteral/enteral supplementation, were reported in the literature. In spite of favourable trend and no adverse events, we did not report statistical difference in co-morbidities. This investigation confirms the necessity to perform further trials in preterm newborns, to find an index reflecting the complex nutritional retinol status after oral administration of vitamin A, highlighting its effectiveness/tolerability in correlated preterm infant's pathologies.

Monitoring of Busulphan Concentrations in Children Undergone Hematopoietic Stem Cell Transplantation: Unicentric Experience over 10 years.

BACKGROUND AND OBJECTIVES: The aim of this report is to describe the experience in the management of busulphan-based conditioning regimen administered before hematopoietic stem cell transplantation (HSCT) in children. METHODS: We report the values of the first dose AUC (area under the concentration-time curve, normal target between 3600 and 4800 ng·h/mL) in children treated with oral and intravenous busulphan, and we analyze the impact of some clinical variables in this cohort of patients. RESULTS: 82 children treated with busulphan before HSCT were eligible for the study: 57 received oral busulphan with a mean AUC of 3586 ng·h/mL, while 25 received intravenous busulphan with a mean AUC of 4158 ng·h/mL. Dose adjustment was based on first dose AUC. The dose was increased in 36 children (43.9%) and decreased in 26 patients (31.7%). Age at HSCT (P = 0.015), cumulative dose of busulphan as mg/m2 (P < 0.001), busulphan dose prescribed as mg/Kg (P = 0.001), intravenous busulphan administration (P < 0.001), type of stem source cells (P = 0.016), and type of HSCT (P = 0.03) were associated with AUC levels. No statistically significant differences were found between transplant-related toxicity, acute and chronic graft versus host disease, engraftment, and AUC levels. CONCLUSIONS: We concluded that older age at HSCT, intravenous administration of busulphan, cumulative, and prescribed dose of busulphan are associated with higher AUC levels. The absence of significant correlations between toxic events, graft failure, and AUC suggests the efficacy of busulphan concentrations monitoring in our patients.