The Safety,Tolerability, and Pharmacokinetics of Fosphenytoin after Intramuscular and Intravenous Administration in Neurosurgery Patients

Study Objective . To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water-soluble phenytoin prodrug, after intramuscular and intravenous administration. Design . Open-label study of intramuscular administration, and double-blind, randomized study of intravenous administration. Setting . Six and ten hospitals throughout the United States for the intramuscular and intravenous multicenter studies, respectively. Patients . Neurosurgical patients who required anticonvulsant prophylaxis or treatment. Interventions . In the intramuscular study, 118 patients received loading doses ranging from 480–1500 mg phenytoin equivalents (PE) and daily maintenance doses ranging from 130–1250 mg PE for 3–14 days. In the intravenous study, 88 patients received fosphenytoin and 28 received phenytoin sodium for 3–14 days. Mean ± SD loading doses and maintenance doses of intravenous fosphenytoin and phenytoin were 1082 ± 299 mg PE and 411 ± 221 mg PE, and 1082 ± 299 mg and 422 ± 197 mg, respectively. Trough phenytoin concentrations were measured daily in all patients. Measurements and Main Results . Intramuscular fosphenytoin was safe and well tolerated, with no irritation found for 99% of all injection site evaluations. Adverse events associated with the drug occurred in 9% of patients, commonly those typical of the parent drug. For intravenous treatment, the frequency of mild irritation at the infusion site was significantly lower in the fosphenytoin group (6%) than in the phenytoin group (25%, p<0.05). Reductions in infusion rates were required in 17% and 36% of fosphenytoin and phenytoin recipients, respectively. No significant difference was observed relative to adverse events or seizure frequency between the groups. Trough plasma phenytoin concentrations were approximately 10 μg/ml or greater in patients receiving at least 3 days of intramuscular and intravenous fosphenytoin. Trough phenytoin concentrations were similar between patients receiving intravenous phenytoin and fosphenytoin on all study days. Conclusion . Fosphenytoin can be administered intramuscularly and intravenously in neurosurgical patients to achieve and maintain therapeutic phenytoin concentrations for up to 14 days. Both routes are safe and well tolerated. Intravenous fosphenytoin is significantly better tolerated than intravenous phenytoin sodium in this patient subset.     

Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures

Fosphenytoin is a phosphate ester prodrug developed as an alternative to intravenous phenytoin for acute treatment of seizures. Advantages include more convenient and rapid intravenous administration, availability for intramuscular injection, and low potential for adverse local reactions at injection sites. Drawbacks include the occurrence of transient paraesthesias and pruritus at rapid infusion rates, and cost. Fosphenytoin is highly bound (93-98%) to plasma proteins. Saturable binding at higher plasma concentrations accounts for an increase in its distribution volume and clearance with increasing dose and infusion rate. Fosphenytoin is entirely eliminated through metabolism to phenytoin by blood and tissue phosphatases. The bioavailability of the derived phenytoin relative to intravenous phenytoin is approximately 100% following intravenous or intramuscular administration. The half-life for conversion of fosphenytoin to phenytoin ranges from 7-15 minutes. Faster intravenous infusion rates and competitive displacement of derived phenytoin from plasma protein binding sites by fosphenytoin compensate for the expected conversion-related delay in appearance of phenytoin in the plasma. Unbound phenytoin plasma concentrations achieved with intravenous fosphenytoin loading doses of 100-150 or 50-100mg phenytoin sodium equivalents/min are comparable, and achieved at similar times, to those with equimolar doses of intravenous phenytoin at 50 (maximum recommended rate) or 20-40 mg/min, respectively. The rapid achievement of effective concentrations permits the use of fosphenytoin in emergency situations, such as status epilepticus. Following intramuscular administration, therapeutic phenytoin plasma concentrations are observed within 30 minutes and maximum plasma concentrations occur at approximately 30 minutes for fosphenytoin and at 2-4 hours for derived phenytoin. Plasma concentration profiles for fosphenytoin and total and unbound phenytoin in infants and children closely approximate those in adults following intravenous or intramuscular fosphenytoin at comparable doses and infusion rates. Earlier and higher unbound phenytoin plasma concentrations, and thus an increase in systemic adverse effects, may occur following intravenous fosphenytoin loading doses in patients with a decreased ability to bind fosphenytoin and phenytoin (renal or hepatic disease, hypoalbuminaemia, the elderly). Close monitoring and reduction in the infusion rate by 25-50% are recommended when intravenous loading doses of fosphenytoin are administered in these patients. The potential exists for clinically significant interactions when fosphenytoin is coadministered with other highly protein bound drugs. The pharmacokinetic properties of fosphenytoin permit the drug to serve as a well tolerated and effective alternative to parenteral phenytoin in the emergency and non-emergency management of acute seizures in children and adults.     

Fosphenytoin. Pharmacoeconomic implications of therapy.

Advantages and disadvantages of Fosphenytoin. Advantages. More rapid intravenous administration than phenytoin and no need for an in-line filter. May be administered by intramuscular injection. Lower potential for local tissue and cardiac toxicity than phenytoin. Associated with less pain and phlebitis at the injection site, fewer reductions in infusion rate and fewer changes of administration site because of injection site complications than phenytoin. Benefits in terms of ease of administration and improved tolerability vs phenytoin have pharmacoeconomic implications which may translate into an overall cost advantage. Disadvantages. Approximately 10-fold higher acquisition cost vs phenytoin. Fosphenytoin is a parenterally administered prodrug of phenytoin, used in the treatment of patients with seizures. Advantages of fosphenytoin over phenytoin include more rapid intravenous administration, no need for an intravenous filter, and a lower potential for local tissue and cardiac toxicity. Unlike phenytoin, fosphenytoin may also be administered by intramuscular injection. Pharmacoeconomic data from a small study of patients with acute seizures in a US emergency department showed an overall cost advantage of fosphenytoin over phenytoin, despite a considerably greater acquisition cost of fosphenytoin. The main cost drivers for phenytoin therapy were treatment costs associated with adverse events. In view of the limited pharmacoeconomic data currently available, it is in the interests of individual institutions to conduct their own formal pharmacoeconomic studies applying local cost data and patterns of clinical practise to determine whether fosphenytoin should replace phenytoin on their formularly list.     

Fosphenytoin: A Novel Phenytoin Prodrug

Fosphenytoin is a phenytoin prodrug that received an approvable letter from the Food and Drug Administration in February 1996. It was designed to overcome many of the shortcomings associated with parenteral phenytoin sodium. Specifically, fosphenytoin is a highly water-soluble, phosphate ester of phenytoin that has no known pharmacologic activity before its conversion to phenytoin. Dosing of fosphenytoin uses phenytoin equivalents (PE) to minimize dosage errors when converting from the conventional formulation. Pharmacokinetic studies documented that the agent is rapidly and completely converted to phenytoin after intravenous and intramuscular dosing. Reported conversion half-lives after intravenous administration range from 8–15 minutes. The absorption rate appears to be the rate-limiting step in the conversion of fosphenytoin to phenytoin after intramuscular administration (half-life range 22–41 min). Bioavailability of phenytoin derived from both intravenous and intramuscular fosphenytoin is essentially 100%. As a consequence of concentration-dependent protein binding, fosphenytoin is bioequivalent to phenytoin sodium at intravenous infusion rates of 100–150 mg PE/minute and 50 mg/minute, respectively. In clinical studies to date, fosphenytoin is safe and significantly better tolerated than phenytoin sodium when administered intravenously. It is also well tolerated when given intramuscularly, and this is a valuable alternative route of administration when intravenous access or cardiographic monitoring is unavailable. Its pharmacoeconomic advantages over phenytoin have not been documented in formal studies to date, although the likelihood of savings based on cost-effectiveness analyses is high. Hence, fosphenytoin has the potential as a safe, well-tolerated, and effective means of delivering phenytoin parenterally in a variety of clinical settings.     

Fosphenytoin for the treatment of status epilepticus: an evidence-based assessment of its clinical and economic outcomes

INTRODUCTION: Status epilepticus (SE) is a life-threatening condition requiring prompt treatment in the emergency department to control seizures and limit potential neurologic damage. Fosphenytoin is a water-soluble prodrug of phenytoin (an established treatment option for SE) that has been developed to overcome the often severe venous adverse events that can occur following the intravenous administration of phenytoin. AIMS: The objective of this article is to review the evidence for the use of fosphenytoin in the treatment of SE. EVIDENCE REVIEW: Fosphenytoin can be infused more rapidly than phenytoin and there is evidence that therapeutic drug levels are achieved at least at a similar rate. Although few studies have been conducted in SE patients, there is evidence that fosphenytoin is at least as effective as phenytoin in terms of response and control of SE. There is also moderate evidence that there are fewer vascular adverse events following intravenous fosphenytoin compared with phenytoin administration when both drugs are infused at the recommended dosage and rate. Evidence from pharmacoeconomic studies indicates that a reduction in the incidence of adverse events and their subsequent management are critical factors for cost-effectiveness with fosphenytoin. CLINICAL VALUE: In conclusion, fosphenytoin is a valuable treatment option for the rapid treatment of SE; the risk of venous adverse events is lower than with phenytoin when administered at the recommended rate.     

Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers

Purpose

We 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.

Methods

We 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.

Results

We 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.

Conclusions

The 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.     

Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus

AIMS: Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. METHODS: Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. RESULTS: After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. CONCLUSIONS: Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.     

磷苯妥英钠注射液人体药代动力学研究

目的：研究健康受试者单次静脉滴注不同剂量磷苯妥英钠注射液后磷苯妥英及其活性代谢物苯妥英的体内药动学特征。方法：24名健康受试者分别接受静脉滴注600 mg和900 mg剂量的磷苯妥英钠注射液,HPLC法测定血药浓度,使用DAS2.0软件计算药动学参数。结果：受试者静脉注射600 mg和900 mg剂量磷苯妥英钠注射液后磷苯妥英主要药动学参数Cmax分别为（89.3±14.9）、（110.5 ± 17.2）mg？L-1;Tmax分别为（0.46 ± 0.08）、（0.46 ± 0.08）h;AUC0-t分别为（56.5 ± 11.3）、（71.2 ± 13.8） mg？h？L-1;苯妥英主要药动学参数Cmax分别为（8.36 ± 0.92）、（11.98 ± 1.07）？L-1;Tmax分别为（1.1 ± 0.3）、（1.3 ± 0.3）h;AUC0-t分别为（222.7 ± 47.8）、（355.9 ± 72.6）mg？h？L-1。结论：单次静脉滴注600 mg-900 mg剂量范围内的磷苯妥英钠注射液,其母药磷苯妥英及其活性代谢产物苯妥英的药动学特征均符合1级动力学。磷苯妥英钠注射液在中国人体内的药动学行为与外国文献报道基本一致。     

Phenytoin prodrugs VI: In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats

Tissue damage caused by subcutaneous and intramuscular administration of three phenytoin prodrugs to rats was assessed. Since two of the prodrugs caused significant irritation, only 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester might be useful as a nonirritant phenytoin prodrug suitable for parenteral administration. To confirm the release of phenytoin from this prodrug, phenytoin availability after intramuscular and intravenous administrations of the phosphate prodrug was evaluated in rats and compared with sodium phenytoin. The prodrug quantitatively released phenytoin after intravenous administration, and phenytoin levels from intramuscular administration of the prodrug were far superior to those generated from similarly administered sodium phenytoin. Based on this and earlier studies, it was concluded that this prodrug should be further assessed as a parenteral form of phenytoin.     

Probabilistic approach to the establishment of maximal content limits of impurities in drug formulations: the case of parenteral diphenylhydantoic acid

Diphenylhydantoic acid (DPHA) is a degradation product in parenteral formulations of the anticonvulsant phenytoin and the prodrug fosphenytoin. DPHA has also been reported to be a minor metabolite of phenytoin. Levels found in the urine of various species, including humans, after oral or intravenous (iv) phenytoin ranged from undetected to a few percent of administered dose. In the present analysis, the toxicologic profile of DPHA was integrated with exposure data in order to characterize its safety under recommended clinical regimens of fosphenytoin administration. In preclinical safety studies, DPHA was without effect in the Ames assay and at concentrations up to 3000 microg/plate in the presence or absence of metabolic activation, and in the in vitro micronucleus test with acute and 2-week repeated dose studies in Wistar rats at iv doses up to 15 mg/kg. In 4-week studies conducted in rats and dogs receiving fosphenytoin containing DPHA levels up to 1.1%, and in an in vitro structural chromosome aberration test with DPHA levels up to 2.0%, all findings were consistent with known effects of phenytoin (such as CNS signs and increased liver weight), and none were attributed to DPHA. Reports in the literature indicate that in murine in vivo and in vitro models, DPHA has much lower potential for reproductive toxicity than phenytoin. A no-observed-effect level (NOEL) of 15 mg/kg established from the 2-week study in rats was used with probabilistic techniques to estimate tolerable daily doses (TDDs) of DPHA. In this approach, interspecies correction was performed by allometrically scaling the NOEL based on a distributional power of body weight while intraindividual variability was accounted for by selecting the lower percentiles of the population-based distribution of TDDs. The results indicate that a DPHA content limit of 3.0% in an administered dose of fosphenytoin is unlikely to cause adverse effects in patients.     

Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit.

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.     

Fosphenytoin and phenytoin in patients with status epilepticus: improved tolerability versus increased costs.

Tonic-clonic status epilepticus (TCSE) is the most common neurological emergency and affects approximately 60000 patients each year in the US. The risk of complications increases substantially as TCSE lasts longer than 60 minutes. Ideally, drugs used to treat this condition should be well tolerated when administered as rapid intravenous infusions and should not interfere with patients' state of consciousness or cardiovascular and respiratory functions. Because of its efficacy, absence of sedation or respiratory suppression, intravenous phenytoin has largely replaced phenobarbital (phenobarbitone) as the second agent of choice (following the administration of a benzodiazepine) in the treatment of TCSE. While the efficacy of phenytoin in the treatment of acute seizures and TCSE is well established, the parenteral formulation of phenytoin has several inherent shortcomings which compromise its tolerability and limit the rate of administration. Intravenous phenytoin has been associated with fatal haemodynamic complications and serious reactions at the injection site including skin necrosis and amputation of extremities. Fosphenytoin, a phenytoin prodrug, has the same pharmacological properties as phenytoin but none of the injection site and cardiac rhythm complications of intravenous infusions of phenytoin. While fosphenytoin costs more than intravenous phenytoin, treating the acute and chronic complications of TCSE itself, and the complications of intravenous phenytoin can also be costly. All other factors being equal, there is no doubt that fosphenytoin is better tolerated and can be delivered faster than intravenous phenytoin; 2 measures that clearly improve outcome in patients with TCSE. The tolerability of intramuscular fosphenytoin also extends its use to clinical situations where prompt administration of a nondepressing anticonvulsant is indicated but secure intravenous access and cardiac monitoring are not available, such as treatment of seizures by rescue squads in the field and serial seizures in the institutionalised, elderly and other patients with intractable epilepsy.     

Safety, tolerance and pharmacokinetics of intravenous doses of the phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin: a new prodrug of phenytoin

A new prodrug of phenytoin, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin (ACC-9653), was administered intravenously over 30 minutes to four different groups of volunteers at doses of 150, 300, 600, and 1200 mg. The prodrug and phenytoin were measured in plasma samples, collected at specified times, by specific high performance liquid chromatography (HPLC) assays. The prodrug, after achieving a maximum concentration at the end of the 30-minute infusion (Cmax 20, 36, 75, 129 micrograms/mL) declined rapidly with a half-life (t1/2) of about 8 minutes. The area under the plasma concentration-time curve (10, 19, 43, 77 mg.hr/L) was proportional to dose whereas the total clearance, 14 L/hr, was independent of dose. The volume of distribution of the prodrug, a polar, water-soluble molecule was about 2.6 L, indicating that most of the dose remained in the plasma. The concentration of phenytoin reached 90% of its maximum about 12 minutes after the end of the infusion of ACC-9653. At the dose of 1200 mg of prodrug, the average peak concentration of phenytoin was about 17 micrograms/mL, near the upper limit of the therapeutic range. Adverse reactions (lightheadedness, nystagmus, incoordination) were minor and attributed to phenytoin. No significant abnormalities in ECG, Holter monitoring, or EEG were noted after the infusion of ACC-9653.     

Considerations on prevention of phlebitis and venous pain from intravenous prostaglandin E(1) administration by adjusting solution pH: in vitro manipulations affecting pH

Prostaglandin E(1) (PGE(1); Alprostadil Alfadex) is a potent vasodilator and inhibitor of platelet aggregation used to treat patients with peripheral vascular disease. The main adverse effects of intravenous PGE(1) administration, phlebitis and venous pain, arise from the unphysiologically low pH of infusion solutions. When PGE(1) infusion solutions with a pH value greater then 6 are used, phlebitis and venous pain are considered to be avoidable. Beginning with a PGE(1) infusion solution with pH greater than 6, we add the amount of 7% sodium bicarbonate needed to bring the solution to pH 7.4 if phlebitis or venous pain develops. In the present study we established a convenient nomogram showing the relationship between the titratable acidity of various infusion solutions and the volume of 7% sodium bicarbonate required to attain pH 7.4 for preventing the phlebitis and venous pain associated with PGE(1) infusion.     

Clinical use of intravenous phenytoin sodium infusions

The safety of administering phenytoin sodium by intermittent intravenous infusion was evaluated. Twenty-eight adult patients in a neurosurgical intensive-care unit were studied; most patients had head trauma. Ninety-three doses of phenytoin sodium 300 mg in 0.9% sodium chloride injection 50 ml were administered according to hospital-approved guidelines, which included administration over 30-60 minutes, initiation of infusion within one hour of solution preparation, and use of a 5-microns inline filter. All patients were monitored for adverse reactions and were on continuous ECG monitoring. Analysis of clinical data before and immediately after phenytoin infusions showed no statistically significant change in blood pressure and a small but significant drop in mean heart rate. There were no cases of hypotension, arrhythmias, bradycardia, or phlebitis. Single occurrences of hypertension, nystagmus, and pain at the i.v. site were noted. It is concluded that careful infusion of phenytoin sodium in 0.9% sodium chloride injection is safe. The use of approved written guidelines to govern important factors of preparation and administration are recommended.     

Lack of pharmacokinetic interaction between lansoprazole and intravenously administered phenytoin

The objective of this randomized, double-blind, two-period crossover study was to investigate whether concomitant steady-state lansoprazole influences the pharmacokinetics of CYP2C9 substrates using single intravenously dosed phenytoin as a model substrate. In addition, the safety of concomitant administration of these two drugs was evaluated. Twelve healthy, nonsmoking, adult male subjects received 60 mg lansoprazole or placebo once daily for 9 days during each study period. On the morning of day 7, each subject received a single 250 mg intravenous phenytoin dose. There were no statistically significant differences between the two regimens for mean phenytoin Cmax or tmax. There was a minor (< 3%) but statistically significant difference between the two regimens for phenytoin AUC resulting from a very low intrasubject coefficient of variation (2.3%). The treatment and control mean plasma concentration phenytoin profiles were virtually super-imposable. In conclusion, concomitant multidose lansoprazole administration is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2C9 substrates in general or intravenous phenytoin specifically.     

Pharmacokinetics of tilidine and metabolites in man

Tilidine is a prodrug from which the active metabolite nortilidine is formed by demethylation. The pharmacokinetics of tilidine (T), nortilidine (NT) and bisnortilidine (BNT) were studied in nine healthy subjects following single intravenous (10 min infusion) and oral 50 mg T-HCl dose as well as following multiple 50 mg T-HCl oral doses. Systemic availability of the parent substance was 6% and of the active metabolite NT 99%. The terminal half-life of NT was 3.3 h following single oral administration, 4.9 h following intravenous administration and 3.6 h following multiple dosing. Following intravenous infusion, concentrations of unchanged substance were found which were 30 times higher than following oral administration. BNT was eliminated with half-lives of 5 h after oral administration and 6.9 h after intravenous administration. Renal elimination of unchanged substance was 1.6% of the dose following intravenous administration and less than 0.1% of the dose following oral administration. Approximately 3% were recovered in urine as NT and 5% as BNT following both routes of administration.     

Phenytoin pharmacokinetics and clinical effects in African children following fosphenytoin and chloramphenicol coadministration

AIMS: Some children with malaria and convulsions also have concurrent bacterial meningitis. Chloramphenicol is used to treat the latter whereas phenytoin is used for convulsions. Since chloramphenicol inhibits the metabolism of phenytoin in vivo, we studied the effects of chloramphenicol on phenytoin pharmacokinetics in children with malaria. METHODS: Multiple intravenous (i.v.) doses of chloramphenicol succinate (CAP) (25 mg kg-1 6 hourly for 72 h) and a single intramuscular (i.m.) seizure prophylactic dose of fosphenytoin (18 mg kg-1 phenytoin sodium equivalents) were concomitantly administered to 15 African children with malaria. Control children (n = 13) with malaria received a similar dose of fosphenytoin and multiple i.v. doses (25 mg kg-1 8 hourly for 72 h) of cefotaxime (CEF). Blood pressure, heart rate, respiratory rate, oxygen saturation, level of consciousness and convulsion episodes were monitored. Cerebrospinal fluid (CSF) and plasma phenytoin concentrations were determined. RESULTS: The area under the plasma unbound phenytoin concentration-time curve (AUC(0, infinity ); means (CAP, CEF): 58.5, 47.6 micro g ml-1 h; 95% CI for difference between means: -35.0, 11.4), the peak unbound phenytoin concentrations (Cmax; medians: 1.12, 1.29 micro g ml-1; 95% CI: -0.5, 0.04), the times to Cmax (tmax; medians: 4.0, 4.0 h; 95% CI: -2.0, 3.7), the CSF:plasma phenytoin ratios (means: 0.21, 0.22; 95% CI: -0.8, 0.10), the fraction of phenytoin unbound (means: 0.06, 0.09; 95% CI: -0.01, 0.07) and the cardiovascular parameters were not significantly different between CAP and CEF groups. However, mean terminal elimination half-life (t1/2,z) was significantly longer (23.7, 15.5 h; 95% CI: 1.71, 14.98) in the CAP group compared with the CEF group. Seventy per cent of the children had no convulsions during the study period. CONCLUSIONS: Concomitant administration of chloramphenicol and a single i.m. dose of fosphenytoin alters the t1/2,z but not the other pharmacokinetic parameters or clinical effects of phenytoin in African children with severe malaria. Moreover, a single i.m. dose of fosphenytoin provides anticonvulsant prophylaxis in the majority of the children over 72 h. However, a larger study would be needed to investigate the effect of concomitant administration of multiple doses of the two drugs in this population of patients.     

Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects.

As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single-dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open-label, randomized, three-period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 +/- 0.77 micrograms/mL at 1.0 +/- 0.3 h]) than following oral ganciclovir (0.47 +/- 0.17 microgram/mL and 2.2 +/- 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 +/- 1.2 and 10.8 +/- 1.9 micrograms-h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 +/- 3.8 micrograms-h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.     

Induction of tirilazad clearance by phenytoin

Tirilazad is a membrane lipid peroxidation inhibitor being studied for the management of subarachnoid hemorrhage; phenytoin is used for seizure prophylaxis in the same disorder. The induction of tirilazad clearance by phenytoin was assessed in 12 volunteers (6 male, 6 female). Subjects received phenytoin orally every 8 h for 7 days (200 mg for nine doses and 100 mg for 13 doses) in one phase of a crossover study. In both study phases, 1.5 mg kg⁻¹ tirilazad mesylate was administered by IV infusion every 6 h for 29 doses. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. After the final dose, tirilazad clearance was increased by 91.8% in subjects receiving phenytoin+tirilazad versus tirilazad alone. AUC_0–6 for U-89678 after the last tirilazad dose was reduced by 93.1% by concomitant phenytoin. These effects were statistically significant. The time course of induction was consistent with that of phenytoin's effect on the ratio of urinary 6β -hydroxycortisol to cortisol, a measure of hepatic CYP3A activity. The results show that phenytoin induces metabolism of tirilazad and U-89678 in healthy subjects and that, under these conditions, tirilazad clearance approaches liver blood flow. © 1998 John Wiley & Sons, Ltd.