Phenytoin pht, sold under the brand name dilantin among others, is an antiseizure medication. Phenytoin is used to prevent and control seizures also called an anticonvulsant or antiepileptic drug. The recommended intravenous loading dose of phenytoin in the. Table 2 shows examples of the differences between dosing children and adults. Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic pbpk modelling software hannah batchelora, richard appletonb, daniel b. Phenytoin sodium is related to the barbiturates in chemical structure, but has a fivemembered ring.
Phenytoin dosing is critical in cancer patients as to decreased absorption secondary to chemotherapy. These patients also tend to have low serum albumin. If phenytoin level available prior to loading dose, use equation 1. This new version may be especially useful if the trough was drawn late and the next dose was delayed. The study authors used the bioavailability data and phenytoin pharmokinetic parameters obtained from 30 patients to simulate the impact of a % decrease or increase in auc 0 for phenytoin. Initially, 1 gm is divided into 3 doses 400 mg, 300 mg, 300 mg and administered at 2 hour intervals. Steadystate pharmacokinetics of phenytoin from routinely. Estimation of phenytoin pharmacokinetic parameters in saudi. Clinically important displacement can be caused by. It works by reducing the spread of seizure activity in the brain. Phenytoin dosing calculator and analysis globalrph. Pharmacokinetic pk models exist for most antiepileptic drugs aeds.
Pharmacokinetic phenytoin problems questions provided by michele splinter, pharmdquestion 1. Yet their use in clinical practice to assess interindividual differences and derive individualized doses has been limited. Establishing a clinical pharmacokinetic service for phenytoin dosing may benefit patient care in terms of maximizing both efficacy and safety. We applied such an integrated approach to characterize the pharmacokineticpharmacodynamic relationship of phenytoin.
These papers reported phenytoin concentrations at timepoints of 60180 min post administration of phenytoin and calculated the. For drugs with narrow safety margins, such as gentamicin or phenytoin, even small changes can cause serious toxicity. The dose is the same for all phenytoin products when initiating therapy. The substances of interest include any chemical xenobiotic such as. In general, aim for therapeutic levels between 2040 umoll. However, because phenytoin follows nonlinear pharmacokinetics, an 8% difference in dose can result in major changes in phenytoin serum concentrations. The intravenous form is used for status epilepticus that does not improve with benzodiazepines. The pharmacokinetic data from the current study considered in the context of reports of phenytoin. Determine an intravenous loading dose of phenytoin sodium injection for db, 61, 87 kg male, using a volume of distribution of 0. To roughly correct for this, use one of the following formulas. A phenytoin pharmacokinetic model was used in the simcyp populationbased adme simulator, simulating 100 children age 210 years receiving intravenous phenytoin 18 and 20 mgkg. The recommendations do not take into account the following. It is useful for the prevention of tonicclonic seizures and focal seizures, but not absence seizures. Around 90% of phenytoin is protein bound, so hypoalbuminemia leads to lower serum levels.
As a general rule, hold therapy 1 day for every 20umoll over 80umoll. Phenytoin may be given intravenously to patients who cannot receive the drug orally or who require rapid onset of drug effect. It also comes as an injectable medication thats given by a healthcare. Bioavailability is dependent upon particle size and problems of generic inequivalence have therefore arisen, particularly in scandinavia. Alternatively, you can create a pk or pd model using the graphical, tabular, or programmatic interfaces. Phenytoinpharmacokineticspopulation pkepilepsynonlinear.
Visual checks were used to evaluate the predictive performance of the candidate model. Hold dosage until levels are back within the therapeutic range then reduce dosage as per above. Use the method of iteration to derive individualised pharmacokinetic parameters from serum drug concentration data. Choice of an algorithm depends on the degree of risk from undertreatment and overtreatment, the availability of measurable, pharmacodynamic endpoints to guide dosage selection during. Steadystate pharmacokinetics of phenytoin from routinely collected patient data. Dosage adjustment phenytoin does not demonstrate a proportional relationship between drug levels and dose. The program is designed to use the pharmacokinetic data table in the appendix of goodman and gillmans the pharmacological basis of therapeutics not included. Cyp2c93 rs1057910 ac is associated with decreased metabolism of phenytoin in vitro and in vivo in pharmacokinetic studies of epileptic patients articles. Clinical and pharmacokinetic aspects, abstract phenytoin was administered intravenously in large doses mean 16. Standard michaelismenten pharmacokinetic phenytoin dosing equations. The drug has a moderately large volume of distribution and is approximately 90% bound to plasma proteins. The complete but practical guide to phenytoin dosing.
Vancomycin single level dosing by levels original calc if you would like to enter the time since the last dose was given, use this version. Pharmacokinetics from ancient greek pharmakon drug and kinetikos moving, putting in motion. Model options include number of compartments, dosing type, and elimination route. Simbiology pharmacokinetics software allows you to create a pk model by specifying your desired model options in the pk model wizard. With bayesian estimation, one can use only one blood sample at steadystate to estimate individual pharmacokinetic. Two studies have examined the safety and efficacy of phenytoin oral loading doses. Phenytoin is a relatively insoluble weak acid, usually administered as the sodium salt.
Acetaminophenrelated hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 0 mg to 6200 mg daily and phenytoin. Such phenomena can be caused by pharmacokinetic pk andor pharmacodynamic. Comparing paediatric intravenous phenytoin doses using. Clinical pharmacokinetics of phenytoin springerlink. The pharmacokinetic data, at least from this relatively healthy population, strongly support the use of once daily dosing of phenytoin at any age, if desired. Precautions and warnings with phenytoin there are many phenytoin precautions and warnings to be aware of before starting treatment with the drug, such as the safety of taking phenytoin while pregnant or nursing and people who should not take the drug at all. Pharmacokinetics and clinical effects of phenytoin and. In parallel, the anticonvulsant effect and the electroencephalogram eeg effect were used to determine the pharmacodynamics. However, if switching between these products the difference in. Useful pharmacokinetic equations symbols e d dose dosing interval cl clearance vd volume of distribution ke elimination rate constant ka absorption rate constant f fraction absorbed bioavailability k0 infusion rate t duration of infusion c plasma concentration. Dosing of monitorable drugs and anticoagulation management require independent. Menten pharmacokinetic dosing methods compared with physician. Phenytoin sodium is 92% phenytoin acid, so make dose adjustment accordingly for their different bioavailability fractions f1 for phenytoin acid and f0.
Due to its large surface area, the small intestine is the main site of phenytoin absorption. The case facilitates discussion of oral phenytoin loading dosing, which helps beginning learners start to think about what software programs in computerized physician order entry cpoe can help to prevent medication errors. The chemical name is sodium 5,5diphenyl2, 4imidazolidinedione, having the following structural formula. Phenytoin is poorly soluble in water and is therefore commonly given as phenytoin sodium salt, which dissolves more readily. Hawcuttc,d, a pharmacy andtherapeutics section, school ofclinical experimental medicine, medical.
Apply nonlinear pharmacokinetics to describe steadystate plasma concentrations following parenteral andor oral phenytoin therapy. It has been reported that a patient receiving chronic phenytoin therapy cpt or other antiepileptic drugs may possibly show a socalled resistance to the effects of nmba 28. The problem with an approach based on standard dosing for some drugs is illustrated in figure 1, which shows the frequency distribution of plasma phenytoin concentrations among 200 ambulatory patients chronically treated with 300 mg daily. Nonobese people are dosed on ideal body weight, and obese people are dosed using adjusted body weight. The following equation is a simple pharmacokinetic equation to estimate a loading dose or resulting serum concentration of a drug. In this study a pharmacokineticpharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. Previously reported routine phenytoin clinical pharmacokinetic data from japan, england, and germany were analysed to estimate population pharmacokinetic parameters. It may also be used for certain heart arrhythmias or neuropathic pain. By uniting healthcare, machine learning, and validated research, precisepk makes bayesianguided dosing easier than ever. Pharmacokinetic pharmacodynamic modeling of the influence. This dosing regimen should be reserved for patients in a clinic or hospital setting where phenytoin serum levels can be closely monitored.
Following the use of diazepam in patients having continuous seizures and in. Phenytoin sodium 50mgml solution for injection summary. There are 2 adjusted body weight equations depending on whether youre starting from scratch or not. In addition, they suggest that checking the serum level of phenytoin sooner than 2 weeks after a dose change, in either older or younger adults, will underestimate the effect of the change. However, serum drug levels should only be taken when there is a clear indication to. Phenytoin dosing calculator this initial program provides some general dosage guidelines based on population averages for the michaelismenten parameters km and vmax. Phenytoin dosing guidelines the concentration at steady state can be. However, serum drug levels should only be taken when there is a clear indication to guide patient management. In a patient having continuous seizure activity, as compared to the more common rapidly recurring seizures, i. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Links to pharmacokinetic software from other vendors. Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic pbpk modelling software article in seizure 33.
In this case, multiple seizures occur in a patient who was initially stable on phenytoin dosage prior to hospitalization. Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic pbpk modelling software. Due to zero order kinetics, dosage should not be increased by more than 50100mg increments. To provide guidance in drug dosage decisions, further studies are required to. There were 780 steadystate phenytoin concentrations and associated dosage rates mgday from 322 patients. Some of the factors complicating phenytoin dosing include a narrow therapeutic window, high degree of protein binding, and nonlinear pharmacokinetics. Impact of a phenytoin loading dose program in the emergency. Cyp2c93 is also associated with increased dose in patients with epilepsy article. Read 8 answers by scientists with recommendations from their colleagues to the question asked by srinivas pottella on jan 30, 2014. Pharmacokinetic algorithms for dosing range from practical nomograms and formulas to conventional or bayesian, weighted, leastsquares regression methods that adapt parametervalues to concentration data. Phenytoin does not demonstrate a proportional relationship between drug levels and dose.
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