“…The estimated half-life of conversion from fosphenytoin to phenytoin calculated from K 12 , which was approximately 8 min, was consistent with the half-life proposed by Boucher et al [9]. …”
Section: Discussionsupporting
confidence: 88%
“…The basic pharmacokinetic parameters were total clearance (CL, L/h); central volume of distribution (V 2 , L); inter-compartmental clearance (Q, L/h); peripheral volume of distribution (V 3 , L); and metabolism rate constant (K 12 , h −1 ). The bioavailability of phenytoin derived from intravenous fosphenytoin sodium injection is approximately 1 [9]. Fig.…”
PurposeWe performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.MethodsWe used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL.ResultsWe used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.ConclusionsThe pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.
“…The estimated half-life of conversion from fosphenytoin to phenytoin calculated from K 12 , which was approximately 8 min, was consistent with the half-life proposed by Boucher et al [9]. …”
Section: Discussionsupporting
confidence: 88%
“…The basic pharmacokinetic parameters were total clearance (CL, L/h); central volume of distribution (V 2 , L); inter-compartmental clearance (Q, L/h); peripheral volume of distribution (V 3 , L); and metabolism rate constant (K 12 , h −1 ). The bioavailability of phenytoin derived from intravenous fosphenytoin sodium injection is approximately 1 [9]. Fig.…”
PurposeWe performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.MethodsWe used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL.ResultsWe used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.ConclusionsThe pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.
“…FOS parameter values from our control subjects are similar to those previously reported for healthy subjects (15)(16)(17)(18). In our control subjects, FOS plasma clearance averaged 3.5 ml/min/kg compared with 3.0-4.0 mllminikg for published values; FOS protein binding averaged 95% (unbound fraction, 5%), consistent with values of 95-99% reported in the literature (12,16); FOS half-life averaged 9.5 min, similar to values of 8-12 min reported in the earlier literature.…”
Summary: Purpose:The pharmacokinetic behavior of fosphenytoin (FOS), the water-soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT.Methods: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4). and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated.Results: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects.Conclusions: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly. Key Words: FosphenytoinPhenytoin-Renal disease-Hepatic disease-pharmacokinetics.Parenteral phenytoin (PHT) is widely used for the treatment of acute seizures and status epilepticus and for prevention of seizures in epilepsy and neurosurgical patients. Because of its poor water solubility, PHT is dissolved in an alkaline vehicle (pH -12) containing 40% propylene glycol and 10% ethanol. Complications of parenteral PHT include injection-site reactions and cardiovascular complications (1-3). The vehicle used to solubilize parenteral PHT is likely to contribute to these adverse effects.Fosphenytoin (FOS, Cerebyx; Parke-Davis) is a watersoluble phosphate-ester prodrug of phenytoin that was developed as a replacement for parenteral PHT (4). like PHT, FOS requires only a simple aqueous buffer (pH -8.8) as a vehicle. FOS is metabolized to its active metabolite, PHT, by ubiquitous nonspecific phosphatases (4,5). The advantages of FOS include compatibility with common aqueous i.v. solutions; less pain and local irritation on administration; faster rates of administration (shorter infusion periods); and rapid, predictable absorption after i.m. administration (6-8).After i.v. infusion, conversion of FOS to PHT is rapid and complete, with a half-life of -15 min (9-11). Conversi...
“…The greater (> lOOO-fold) water solubility of fosphenytoin overcomes many of the problems and limitations associated with parenteral phenytoin sodium administration. The advantages of fosphenytoin are (12,(13)(14)(15)(16)(17): (a) It can be administered either i.m or i.v and, since the injection contains no propylene glycol and is not buffered at high pH, causes fewer side effects compared with phenytoin; (b) It offers improved compatibility with commonly used intravenous fluids, and causes less irritation and phlebitis at the injection site; (c) It can be administered at infusion rates up to three times the maximum rate for phenytoin (150 mg phenytoin equivalents/min for fosphenytoin versus 50 mg phenytoin/min for phenytoin sodium); (d) It is rapidly and completely absorbed from the i.m site; and (e) It is rapidly and completely hydrolyzed in vivo by blood and tissue phosphatases to generate phenytoin after i.v or i.m administration, with approximately 100% bioavailability (18). Thus, fosphenytoin may offer both practical and clinical advantages over intravenous phenytoin.…”
The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration may not be feasible.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
