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Phenytoin dosing guidelines

by D.McAuley, GlobalRPh Inc.

This initial program provides some general dosage guidelines based on population averages for the Michaelis Menten parameters !"m and #ma$%. The recommendations do not ta&e into account the follo'ing( !)% e$istence of interacting drugs !*% inter patient variability !*% e$isting disease states 'hich may significantly alter the eventual therapeutic dose. The program uses a maintenance dose of + to , mg-&g for all adults . ,/ years old. The elderly !defined as age0,/% on the other hand, e$hibit a saturation of metabolism at dosages that are usually 1/ 2 lo'er than in younger patients. 3or this reason, the program recommends initial dosages of * + mg-&g in this age group. !4ote( many studies have found only slight variations in "m 'ith regards to age, ho'ever, # ma$ has been found to decline steadily 'ith age most notably after the ,th decade%. The program also calculates an 5ad6usted dose5 for reported levels 'hen the serum albumin level is . +.7 g-dl. The program accomplishes this by utili8ing the 9heiner To8er e:uation( ; ad6 < ;reported -!/.1 $ serum albumin% = /.). In order to simplify the program, all dosages are based on the ad6usted body 'eight. This is especially important in obese patients 'here the utili8ation of total body 'eight 'ould result in an over estimation of dosage. Pro6ected loading doses re:uired to increase sub therapeutic concentrations to the therapeutic range are determined by using the follo'ing e:uation( ;ad6 < !;oncentration desired ;oncentration observed% $ #d, 'here #d < /.> $ ad6usted body 'eight. The usual range for #d is /.71 to /.>? @-&g. I must stress again the general nature of this program. 9ignificant inter patient variability may e$ist for many of the pharmaco&inetic parameters. Aere are some reported ranges( Vd( /.71 /.>? @-&g Vmax: , ? mg-&g-day Km: 7.+ ,.? mg-@. To ensure greater accuracy and appropriateness of dosing, individual determination of #ma$ and "m values for each patient based on steady state levels is recommended.

The maintenance dose can then be calculated using the follo'ing e:uation( MD !mg-day% < B ! #ma$ $ ;ss% - !9%!3%!"m = ;ss C
Ma$imum rate of drug metabolism ;oncentration at 'hich the rate of drug metabolism is 7/2 of #ma$ 9alt form factor !use /.D1 for capsules and in6ection and )./ for tablets E eli$ir% Fioavailability factor !Gse /.D7 for oral formulations and )./ for intravenous% Desired concentration at steady state

Vma$ Km S F

Css

Hther I:uations
The concentration at steady state can be estimated using the follo'ing e:uation if #ma$ and "m are &no'n !may use population averages if not available%( ;ss < B"m $ !9% $ !3% $ dose!mg-day%C - B#ma$ !9%!3% !dose!mg-day%%C.

Jith only one steady state serum level available, you can calculate a value for #ma$ if you assume a value for "m !4ote( some references assume a value of + mg-@ for "m% #ma$ < daily dose!mg-day% $ !"m-;ss = )% Derivation of above e:uation( !Input < Hutput% or

Daily dose!mg-day% < B !#ma$%!;ss% - "m = ;ssC To simplify further steps, Daily dose 'ill be abbreviated( dd. dd!"m = ;ss% < !#ma$%!;ss% dd!"m% = dd!;ss% < !#ma$%!;ss% Dividing by ;ss yields( Vma$ = dd + dd(Km)/Css or Vmax = daily dose(mg/day) x (Km/Css + 1)

If t'o steady state serum levels are available, it is possible to derive values for both #ma$ and "m. This is best achieved by the formation of an e:uation in the form of y < m$ = b. The final e:uation is( dd < "m!dd-;ss% = #ma$ !4ote( abbreviations are defined above% Jith this e:uation, the y intercept is e:ual to #ma$ and the slope of the line is e:ual to ! "m%. Remember that the e:uation for the slope of a line is !y) y1% - !$) $1%. The derivation is as follo's( !Input < Hutput% or Daily dose!mg-day% < B !#ma$%!;ss% - "m = ;ssC To simplify further steps, Daily dose 'ill be abbreviated( dd. dd!"m = ;ss% < !#ma$%!;ss% dd!"m% = dd!;ss% < !#ma$%!;ss% Dividing by ;ss yields( dd = !&m%!dd%-;ss < #ma$ and finally, dd = -Km(dd/Css) + Vmax
Graphing the al!es:

It is important to remember that since phenytoinKs elimination is a saturable process, and clearance decreases 'ith increasing concentrations, the steady state concentration is 4HT proportional to the maintenance dose !e.g. a non linear relationship e$ists%. Also, the half life has little value in estimating the time to steady state.

Additional Information
"ote: program uses ad6usted body 'eight for all calculations. #oading $ose (%V)( )/ 1/ mg-&g . Recommended infusion rate for adults( +/ 7/ mg-min. Ilderly !0,7%( Recommended infusion rate( 1/ 17 mg-min. &ral loading: Give in * to + divided doses at :1h intervals. !Divided doses increase bioavailability as 'ell as decrease potential for GI side effects such as 4E#%. The ma$imum single oral dose should not e$ceed +// mg in order to minimi8e GI side effects and also increase absorption !decrease li&elihood of concretions%. Sampling: )? to 1+ hours after the loading dose, and then every 7 to > days to assess trend. ' erage time to steady state: )/ )+ days. (al)-li)e: > to +1 hours !average < 1+ hours%. Con ersion to on*e daily dosing: ;onsider only after a divided dose regimen on e$tended phenytoin capsules is established. !Hnly e$tended release Dilantin caps are recommended for once daily administration.% A patient should ne er receive a once daily dose of eli$ir or in6ection as maintenance. +hen do yo! start the maintenan*e dose, The maintenance dose is started )? 1+ hours after the loading dose.

;apsules-in6ection< D12 phenytoin !sodium salt%. Ili$ir-tabs<)//2 phenytoin.


-.!ation !sed to estimate the dose re.!ired to in*rease *!rrent le el to normal range i) s!/therape!ti*: < B/.> $ IFJ $ !)7 current level% C /.D1L L !if capsules-in6ection used% 'd0!sted phenytoin *on*entration i) lo1 ser!m al/!min < measured total concentration - B !/.1 $ albumin% = /.)C

Population ranges !another source)%( !#ma$( 7.1? to ?.+) mg-&g-dayM "m( /.?* to +.)? mg-@M #d( /.>+ to /.D> )-&g%
). Allen NP, @udden TM, Furro' 9R, ;lementi JA, 9tavchans&y 9A. Phenytoin cumulation &inetics. ;lin Pharmacol Ther. )D>D HctM1,!+%(++7 ?.

;autions
!)% Al'ays remember that because phenytoinKs elimination is dose dependent !5capacity limited5%, that small increases in dosage can produce disproportionate increases in serum levels !possibly * to + fold%. !1% 4ever assume a linear relationship e$ists bet'een steady state concentrations and the dosage given. !*% ;hanges in the daily maintenance dose should be made in small increments !*/ )//mg ma$imum%. 9ample serum levels > to )/ days follo'ing each dosage change to assess the trend. 9teady state is usually achieved after )/ )+ days, ho'ever, it may be much longer than this in some patients. !+% Hnce therapeutic steady state levels are achieved, periodic levels based on clinical 6udgment should be obtained. 9ome studies have found fluctuations in steady state serum concentrations 0 )7/2 in patients receiving the same daily maintenance dose. All factors must be considered( addition of interacting drugs, changes in absorption !eg enteral feeding = oral administration of phenytoin%, concomitant disease state!s% 'hich may alter phenytoin &inetics, etc. !7% ;hanges in albumin levels or the binding affinity of phenytoin to albumin must be ta&en into account !total phenytoin levels are of little value if significant changes occur%. Determination of the free concentration is

recommended in these patients 'ith a target concentration of ) 1 mcg-ml. 3actors 'hich may reduce albumin levels include( hepatic cirrhosis, cache$ia, burns, malnutrition, and nephrotic syndrome. 3actors 'hich may decrease the affinity of phenytoin to albumin or cause displacement include( interacting drugs, increased bilirubin, renal failure ...%. The follo'ing e:uations can be used to ad6ust the serum concentrations based on either reduced albumin levels or presence of renal failure !crcl . )/ ml-min%. 9ome studies have found considerable underestimation of serum levels 'hile using these e:uations in some patients. Again, the most accurate assessment can be made by obtaining the actual unbound !free% level. The ad6ustment e:uations are estimations, and should be considered e$actly that. (ypoproteinemia
!9heiner To8er e:uation%( measured total concentration - B !/.1 $ albumin% = /.)C

2enal )ail!re:
;ad6usted < ;measured - B !/.) $ albumin% = /.)% C

References
). Allen NP, @udden TM, Furro' 9R, ;lementi JA, 9tavchans&y 9A. Phenytoin cumulation &inetics. ;lin Pharmacol Ther. )D>D HctM1,!+%(++7 ?. 1. Fachmann "A, Felloto RN Nr. Differential &inetics of phenytoin in elderly patients. Drugs Aging. )DDD 9epM)7!*%(1*7 7/. *. Fauer @A, Flouin RA. Age and phenytoin &inetics in adult epileptics. ;lin Pharmacol Ther. )D?1 MarM*)!*%(*/) +. +. Furton MI, #as&o MR, Frater D;. ;omparison of drug dosing methods. ;lin Pharmaco&inet. )D?7 Nan 3ebM)/!)%() *>. 7. Dager JI, Inciardi N3, Ao'e T@. Istimating phenytoin concentrations by the 9heiner To8er method in adults 'ith pronounced hypoalbuminemia. Ann Pharmacother. )DD7

Nul AugM1D!> ?%(,,> >/. ,. Dasgupta A, Dennen DA, Dean R, Mc@a'hon RJ. Prediction of free phenytoin levels based on Btotal phenytoinC-BalbuminC ratios. Potential errors 'ith hypoalbuminemia. Am N ;lin Pathol. )DD) 3ebMD7!1%(17* ,. 7. Dela ;ru8 3G, "anter MO, 3ischer NA, @ei&in NF. Ifficacy of individuali8ed phenytoin sodium loading doses administered by intravenous infusion. ;lin Pharm. )D?? MarM>!*%(1)D 1+. ?. 3lint 4, @ope8 @M, Robinson ND, Jilliams ;, 9alem RF. Related Articles;omparison of eight phenytoin dosing methods in institutionali8ed patients. Ther Drug Monit. )D?7M>!)%(>+ ?/. D. Grasela TA, 9heiner @F, Rambec& F, Foenig& AI, Dunlop A, Mullen PJ, Jads'orth N, Richens A, Ishi8a&i T, ;hiba ", et al. 9teady state pharmaco&inetics of phenytoin from routinely collected patient data )/. Gugler R, Manion ;#, A8arnoff D@. Phenytoin( pharmaco&inetics and bioavailability. ;lin Pharmacol Ther. )D>, 3ebM)D!1%()*7 +1. )). Aayes MN, @angman MN, 9hort AA. ;hanges in drug metabolism 'ith increasing age( 1. phenytoin clearance and protein binding. Fr N ;lin Pharmacol. )D>7 3ebM1!)%(>* D. )1. Audson 9A, 3ar:uhar D@, Thompson D, 9mith RG. Phenytoin dosage individuali8ation five methods compared in the elderly. N ;lin Pharm Ther. )DD/ 3ebM)7!)%(17 *+. )*. @iponi D3, Jinter MI, To8er T4. Renal function and therapeutic concentrations of phenytoin. 4eurology. )D?+ MarM*+!*%(*D7 >. )+. Mabuchi A, 4a&ahashi A. A ma6or inhibitor of phenytoin binding to serum protein in uremia. 4ephron. )D??M+?!+%( *)/ +. )7. Martin I, To8er T4, 9heiner @F, Riegelman 9. The clinical pharmaco&inetics of phenytoin. N Pharmaco&inet Fiopharm. )D>> DecM7!,%(7>D D,.

),. Martin I, Gambertoglio NG, Adler D9, To8er T4, Roman @A, Graus8 A. Removal of phenytoin by hemodialysis in uremic patients. NAMA. )D>> Hct )>M1*?!),%()>7/ *. )>. Mason GD, Jinter MI. Appropriateness of sampling times for therapeutic drug monitoring. Am N Aosp Pharm. )D?+ 9epM+)!D%()>D, ?/). )?. Mauro @9, Mauro #3, Fachmann "A, Aiggins NT. Accuracy of t'o e:uations in determining normali8ed phenytoin concentrations. DI;P. )D?D NanM1*!)%(,+ ?. )D. Mc;auley D@, To8er T4, Jinter MI. Time for phenytoin concentration to pea&( conse:uences of first order and 8ero order absorption. Ther Drug Monit. )D?D 9epM))!7%(7+/ 1. 1/. Mlynare& MI, Peterson I@, Oaro'it8 FN. Predicting unbound phenytoin concentrations in the critically ill neurosurgical patient. Ann Pharmacother. )DD, MarM*/!*%( 1)D 1*. 1). Peterson GM, "hoo FA, von Jitt RN. ;linical response in epilepsy in relation to total and free serum levels of phenytoin. Ther Drug Monit. )DD) 9epM)*!7%(+)7 D. 11. Pry&a RD, Rodvold "A, Irdman 9M. An updated comparison of drug dosing methods. Part I( Phenytoin. ;lin Pharmaco&inet. )DD) MarM1/!*%(1/D )>. 1*. 9a'chu& RN, Rector T9. 9teady state plasma concentrations as a function of the absorption rate and dosing interval for drugs e$hibiting concentration dependent clearance( conse:uences for phenytoin therapy. N Pharmaco&inet Fiopharm. )D>D DecM>!,%(7+* 77. 1+. 9heiner @F, Feal 9@. Ivaluation of methods for estimating population pharmaco&inetics parameters. I. Michaelis Menten model( routine clinical pharmaco&inetic data. N Pharmaco&inet Fiopharm. )D?/ DecM?!,%(77* >). 17. To8er T4, Jinter MI. Phenytoin. In( Ivans JI, 9chentag NN, Nus&o JN, eds. Applied Pharmaco&inetics( Principles of Therapeutic Drug Monitoring. *rd Id. #ancouver, JA( Applied TherapeuticsM )DD1( 17.) 17.++