#####
Author Video based on Basic & Applied Pharmacokinetics Self Assessment book by John E. Murphy

Welcome to the chapter on phenytoin dosing and drug concentration predictions phenytoin has been used for many years as an anticonvulsant and consequently a fairly large number of patients still receive the drug patients with new onset seizures are more frequently started on other medications these days the most interesting aspect of phenytoin pharmacokinetics

Is its central elimination most drugs follow first order elimination patterns but phenytoin elimination is best described by a michaelis-menten saturation pattern at low concentrations it is primarily first-order whereas at high concentrations it is better represented by zero order elimination due to this elimination small changes in daily dose can produce a

Large changes in concentration particularly at the upper end of the therapeutic range in this video we will estimate concentrations based on an administered dosing schedule and consider the impact of saturable elimination on average steady-state concentrations enjoy the video as i discussed previously phenytoin follows michaelis menten elimination or saturable

Elimination when we have a drug that follows first order elimination and we give a dose it produces a certain concentration if we double the dose the concentration is doubled this makes it easy to adjust doses and concentrations by using the proportionality of dose and concentration when a drug follows saturable metabolism or michaelis menten elimination what

Happens is that the concentration initially follows first order elimination patterns but as the concentration goes it begins to saturate and once we approach v-max concentrations go up very rapidly with fairly small changes in dosage let’s do a patient case to show how phenytoin can be dosed and the impact of small changes in dosing we’ll begin with a 25 year old

Male patient who weighs 90 kilograms and whose ideal body weight is 70 kilograms we’re going to give him phenytoin for new onset seizures what i want to do is determine a loading dose of phosphonate wine which is given intravenously for an estimated post load concentration of 15 milligrams per liter we’re going to treat it as if it’s given as an iv bolus though

The dose would actually be given over several minutes due to the low clearance of phenytoin the impact of using the iv bolus formula is over 1 that allows for an infusion is very limited for a 25 year-old the volume of distribution for phenytoin is 0.65 liters per kilogram of actual weight unless the patient is obese so to determine that pharmacokinetic parameter

From the population for this patient we’re going to first look and determine if the patient is overweight or obese his actual body weight is 90 kilograms and his ideal body weight is 70 so that a bw / ibw is 1.2 9 because of this we’re going to use an equation for determining volume of distribution in the obese and that equation is that the b and liters is 0.65

Liters per kilogram times ideal body weight plus 1.33 times the difference between actual and ideal body weight when we plug in the values of his ideal body weight of 70 kilos and the difference between 90 and 70 the volume of distribution is sixty two point seven nine liters to determine the iv bolus loading day we use the following formula which says see change

Is equal to s times dos over volume of distribution because it’s an iv bolus or an iv dose we don’t need the bioavailability fraction f but that could be in there if an oral loading dose was used to solve for dose we convert the equation to dose equals sea change times v divided by s and if you remember s is the fraction of dose that is equal to phenytoin for plus

Phenytoin the s is 0.92 so let’s plug in the values the concentration change that we desire is 15 milligrams per liter because we’re starting at zero and our desired concentration is 15 the volume of distribution is 62 point seven nine liters and the s fraction is 0.92 when we saw that it gives us a dose of one thousand and twenty three point seven five milligrams

And that would be rounded to a thousand milligrams of course if we round the concentration down from the ones that we predicted for 15 then the predicted sea change would also be affected so we can go back into the original formula up here and solve for the sea change estimated using one thousand milligrams and that would be fourteen point seven milligrams per

Liter we could also do this by ratio which would be 15 times one thousand over one thousand twenty three point seven five so our target concentration is fifteen milligrams per liter our dose to produce that concentration as figured as we did before and what that would look like if we gave an iv bolus of something like this where the c0 would be fifteen milligrams

Per liter and after we gave the bolus the concentration would decay away now i tried to point out here the difference that you might see when a drug has saturable pharmacokinetics and the first portion of the curve would might be where we were actually under zero order elimination or a fixed amount eliminated per time and then later on as the concentration drops

Way below v-max we go into a first order situation where a fixed fraction is eliminated per time let’s continue our patient case now we’re going to determine a maintenance dose and i want it to be an exact dose of phenytoin suspension that we’re gonna give every 12 hours for a predicted css average of 15 milligrams per liter to do that we need to get the population

Pharmacokinetic parameters let’s show what it would look like thoroughly for the average concentration at steady-state for a drug with saturable elimination given everytown hours here’s the equation if we were solving for css average based on a dose we were using and this is what it might look like with the css average developing what we actually want to do is

Determine the dose of the drug in this case a drug with saturable elimination that’s given every towel hours to produce a css average so after the equation is manipulated it comes up to be this where the dose is equal to the vm or maximum velocity of elimination times the average steady-state concentration desired divided by km which is the michaelis menten constant

Plus css average multiplied by tau and divided by s times f so let’s get the pharmacokinetic parameters for a 25 year old patient the michaelis constant or km is 4.3 milligrams per liter and the v-max is 7 milligrams per kilogram per day to calculate v-max we use 7 milligrams per kilogram per day and we want to use ideal body weight because it’s been shown that

Ideal body weight is a better predictor of v-max than his actual body weight in this case seven times the ideal body weight of 70 gives us a v-max of 490 milligrams per day and the v-max is supposed to be the maximum amount of drug that could be eliminated over the period of time all right let’s see what happens when we give the dosing with phenytoin suspension

Which has an s equal to one remember s is the fraction of dose that is phenytoin in this case and for phenytoin suspension and phenytoin tablets it s is equal one whereas for phenytoin capsules and phenytoin iv as well as phosphate at time s equals 0.92 so here’s the formula we use to solve for the dose to produce the desired css average as you can see here we

Plug in 490 milligrams per day for the v-max which is essentially considered to be the maximum amount of phenytoin that the body could get rid of in a given day 15 milligrams per liter for css average 4.3 milligrams per liter for km the michaelis constant and what you can see here is i’ve used 0.5 days for my dosing interval the reason i use 0.5 days is so that i

Can cancel out the units from b max or day i could convert b max to 490 milligrams per 24 hours and then use 12 hours here either way would allow us to eliminate the unit’s appropriately when i do the calculations the dose equals 190 point 4 milligrams every 12 hours and that would generally be rounded to 200 milligrams as always when we use a different dose than

The one predicted to produce a desired concentration we want to calculate the impact of different dos on the predicted concentration here’s where you will see the large impact on steady-state concentrations from very small changes in dose here’s the impact of using 200 milligrams of phenytoin suspension again with s equals 1 the formula we want to use is this

One which calculates the css average and when we plug in our units km 4.3 milligrams per liter and a vm a 490 milligrams per day and again using 0.5 days as the interval which could be done in a different way you could also use 400 milligrams per day and that would cancel out the units as well the css average is predicted to be nineteen point one milligrams per

Liter so look at that the difference between using 190 point four milligrams and 200 milligrams every 12 hours results in almost a 30% increase in the concentration predicted so for about a 5% increase in dose we got a 27% increase in concentration demonstrating how important it is to be careful in dosage adjustment with phenytoin particularly as concentrations are

Higher now it’s likely we wouldn’t leave a patient on suspension for a long term especially if they could take capsules or tablets so let’s see what happens if we switch them to 200 milligrams of phenytoin capsules a day so with the capsules as you remember the s is equal to 0.92 again we go in with use the appropriate formula to solve for css average plug in the

Important data and for this one the more important piece is the 0.92 for s actually then 1/8 milligram decrease per each 100 milligram of dos and the css average is predicted to be 13 milligrams per liter so by decreasing the dose 8% from the full 200 milligrams that one would get with suspension and an s of 1 292 milligrams for each 100 milligram capsule we go

From a predicted concentration of 19 point one all the way down to 13 so we’ve dropped our concentration to approximately 2/3 just by that very small decrease in dose again demonstrating how small changes can have large impacting concentrations with a drug that follows saturable elimination patterns

Transcribed from video

Phenytoin By ASHPOfficial