Bilbao‑Mesegue e al.
Jou nal o In ensi e Ca e (2022) 10:21
h ps://doi.o g/10.1186/s40560‑022‑00611‑w
RESEARCH
Op imiza ion o le e i ace am dosing
egimen inc i ically ill pa ien s wi haugmen ed
enal clea ance: aMon e Ca lo simula ion s udy
Idoia Bilbao‑Mesegue 1,3, Helena Ba asa4,5, Alicia Rod íguez‑Gascón1,2, Edua do Asín‑P ie o6,8, Ja ie Mayna 4,5,
José Ángel Sánchez‑Izquie do7, Ma ía Ángeles Solinís1,2* and A an xazu Isla1,2*
Abs ac
Backg ound: Le e i ace am pha macokine ics is ex ensi ely al e ed in c i ically ill pa ien s wi h augmen ed enal
clea ance (ARC). Consequen ly, he dosage egimens commonly used in clinical p ac ice may no be su icien o
achie e a ge plasma concen a ions. The aim o his s udy is o p opose al e na i e dosage egimens able o achie e
a ge concen a ions in his popula ion. Fu he mo e, he easibili y o he p oposed dosing egimens will be dis‑
cussed om a clinical poin o iew.
Me hods: Di e en dosage egimens o le e i ace am we e e alua ed in c i ically ill pa ien s wi h ARC. Mon e Ca lo
simula ions we e conduc ed wi h ex ended o con inuous in usions and/o high d ug doses using a p e iously de el‑
oped popula ion pha macokine ic model. To assess he clinical easibili y o he p oposed dosages, we ca ied ou a
li e a u e sea ch o e alua e he in o ma ion on oxici y and e icacy o con inuous adminis a ion o high doses, as
well as he pos ‑dilu ion s abili y o le e i ace am.
Resul s: Acco ding o he simula ions, a ge concen a ions in pa ien s wi h C Cl o 160 o 200 mL/min can be
achie ed wi h he 3000 mg daily dose by p olonging he in usion ime o le e i ace am. Fo pa ien s wi h C Cl o
240 mL/min, i would be necessa y o adminis e doses highe han he maximum ecommended. A ailable e idence
sugges s ha le e i ace am adminis a ion in con inuous in usion o a highe doses han hose app o ed seems o
be sa e. I would be desi able o e‑examina e he cu en ecommenda ions abou d ug s abili y and o achie e a
consensus in his issue.
Conclusions: Con en ional dosage egimens o le e i ace am (500–1500 mg wice daily in a sho in usion) do no
allow ob aining d ug plasma concen a ions among he de ined a ge in c i ically ill pa ien s wi h ARC. The e o e,
new dosing guidelines wi h speci ic ecommenda ions o pa ien s in his subpopula ion a e needed. This s udy
p oposes new dosages o le e i ace am, including ex ended (4 o 6 h) in usions, con inuous in usions o he admin‑
is a ion o doses highe han he ecommended in he summa y o p oduc cha ac e is ics (> 3000 mg). These new
dosage ecommenda ions ake in o accoun biopha maceu ical and pha macokine ic aspec s and mee easibili y
c i e ia, which allow hem o be ans e ed o he clinical en i onmen wi h sa e y and e icacy. Ne e heless, u he
clinical s udies a e needed o con i m hese esul s.
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Open Access
*Co espondence: [email p o ec ed]; [email p o ec ed]
1 Pha macokine ic, Nano echnology and Gene The apy G oup
(Pha maNanoGene), Facul y o Pha macy, Cen o de In es igación
Lasca ay Ike gunea, Uni e si y o he Basque Coun y UPV/EHU, Paseo de
la Uni e sidad 7, 01006 Vi o ia‑Gas eiz, Spain
Full lis o au ho in o ma ion is a ailable a he end o he a icle
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Bilbao‑Mesegue e al. Jou nal o In ensi e Ca e (2022) 10:21
Backg ound
Since le e i ace am was in oduced in Eu ope, i has
become a e y equen ly used an iseizu e medica ion
in he in ensi e ca e uni s (ICUs). I is used bo h in
he ea men o ocal and gene alized onse seizu es,
and in he second line ea men o s a us epilep icus.
Mo eo e , despi e he lack o a obus ecommenda-
ion, le e i ace am has been inc easingly used in he
ICUs in many clinical scena ios (a e c anio omy, sub-
a achnoid hemo hage (SAH) o auma ic b ain inju y
(TBI)) due o i s ela i e ease o use, e icacy, and low
side e ec s p o ile [1]. The e is no clea di e en ia ion
be ween p ophylac ic and he apeu ic doses. Thus, in
gene al, i is ecommended o s a wi h 500mg wice
daily and inc ease he dose un il he he apeu ic e ec
is achie ed up o a maximum o 1500mg wice daily.
This could jus i y ha he mos equen ly used dose in
p ophylaxis is 500mg/12h [2].
The al e ed pa hophysiology in c i ically ill pa ien s
can ha e a majo impac on he pha macokine ic
pa ame e s o d ugs [3–5]. One o he phenomena in
his popula ion ha is gaining ele ance is augmen ed
enal clea ance (ARC). ARC is de ined as a c ea inine
clea ance (C Cl) > 130 mL/min/1.73 m2. I is p esen
in 20–65% o c i ically ill pa ien s wi h younge age,
poly auma and lowe se e i y illness being iden i ied
as isk ac o s [6]. Fu he mo e, i seems o be mo e
common in ce ain si ua ions, such as TBI and SAH,
clinical condi ions ha usually jus i y he use o an i-
con ulsan s ei he p ophylac ically o he apeu ically
[7–10]. The p esence o ARC in c i ically ill pa ien s
has been consis en ly associa ed wi h sub he apeu ic
an imic obial plasma concen a ions and i may ha e a
nega i e impac on he a ainmen o he apeu ic le els
o many d ugs [11–15]. Al hough i s in luence has been
s udied mainly in he con ex o an imic obial he apy,
ARC has he po en ial o in luence he pha macokine ic
p o ile o any d ug ha is enally clea ed and known o
ha e a di ec co ela ion be ween hei enal clea ance
(CL) and C Cl, such as le e i ace am.
The e e ence ange o le e i ace am ough con-
cen a ions is 12–46mg/L a s eady s a e, as ecom-
mended by he In e na ional League Agains Epilepsy
(ILAE) [16]. To da e, se e al s udies on le e i ace am in
c i ically ill pa ien s indica e ha he dosages egimens
commonly used a e no su icien o achie e plasma
concen a ions wi hin his ange, speci ically in c i i-
cally ill pa ien s wi h ARC [17–20].
These esul s a e in line wi h a ecen ly published sys-
ema ic e iew and me a-analysis (30 s udies, n = 7609
pa ien s), which assesses he use o le e i ace am com-
pa ed wi h no an iseizu e medica ion o wi h a di e -
en an iseizu e medica ion o he p e en ion o i s
seizu e ac oss neu oc i ical pa ien s [2]. They could no
demons a e signi ican educ ions in seizu e incidence
and, nei he suppo no e u e he use o le e i ace am
p ophylaxis in TBI, SAH, in ace eb al hemo hage o
sup a en o ial neu osu ge y. Howe e , hei da a sug-
ges ed ha le e i ace am migh be supe io o o he
seizu e medica ions ollowing sup a en o ial neu o-
su ge y. They hypo hesized ha he use o low-dosage
le e i ace am, wi h 500mg wice daily being he mos
common dosage used ac oss he s udies, migh no gen-
e a e he apeu ic le els. These esul s sugges ed he need
o es ablish new dosage guidelines ha allow eaching
he he apeu ic objec i e in his popula ion.
The e o e, he aim o his s udy is o pu o wa d al e -
na i e dosage egimens, using s ochas ic simula ions,
able o achie e a ge concen a ions in c i ically ill
pa ien s wi h ARC ecei ing le e i ace am. Fu he mo e,
he easibili y o he p oposed dosing egimens will be
discussed om a clinical poin o iew conside ing he
po en ial oxici y and e icacy o he doses and mode o
adminis a ion e alua ed, as well as he s abili y o he
pha maceu ical p epa a ion.
Me hods
Op imized dosage egimen p oposals o c i ically ill
pa ien s wi hARC in ea men wi hle e i ace am
New dosage egimens o le e i ace am we e simula ed
in c i ically ill pa ien s wi h ARC (C CL o 160, 200 and
240mL/min). Dosing p oposals include he use o con-
inuous in usion, ex ended in usion imes (4 o 6h) and/
o he adminis a ion o inc easing doses ( om 3000mg
up o 6000mg daily). S ochas ic dosing simula ions we e
pe o med by a popula ion pha macokine ic model
(PPK) ecen ly published by ou g oup [17]. This PPK
model was de eloped om a mul icen ic open-label
p ospec i e s udy conduc ed in 27 c i ically ill pa ien s
ea ed wi h le e i ace am and wi h a C Cl > 50mL/min
( ange 54–239mL/min) measu ed in u ine. The model is
desc ibed in Table1.
Mon e Ca lo simula ions we e pe o med in
NONMEN® ( .7.4) o gene a e he concen a ion–
ime p o iles in 1000 i ual subjec s. The pe cen iles
o s eady-s a e ough concen a ions by he simula ed
Keywo ds: Le e i ace am, Dosing, Pha macokine ics, Pha macodynamics, Mon e Ca lo simula ion, Augmen ed enal
clea ance, C i ically ill pa ien , Neu oc i ical ca e
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Bilbao‑Mesegue e al. Jou nal o In ensi e Ca e (2022) 10:21
dosing egimens we e subsequen ly de e mined in R
( .4.0.2). The p obabili ies o achie ing a ge ough con-
cen a ions we e es ima ed o he e e ence ange o
12–46mg/L.
E alua ion o dosage egimens easibili y
To assess he clinical easibili y o p oposed dosages o
le e i ace am, we ca ied ou an e alua ion o he ol-
lowing aspec s: (1) e idence o oxici y o e icacy o
ex ended o con inuous adminis a ion mode, (2) e i-
dence o oxici y o e icacy o high doses and (3) s abili y
issues.
To ga he in o ma ion on hese aspec s, wo e ia y
da abases, UpToDa e® [21] and Mic omedex® [22] we e
consul ed. In addi ion, o e alua e he ex ended o con-
inuous in usion mode, a bibliog aphic sea ch was ca -
ied ou in MEDLINE, om incep ion un il Oc obe
2021. The ollowing e ms we e used: (“le e i ace am”
OR “kepp a”) AND (“ex ended” OR “con inuous”) AND
“in usion”. Fo s abili y e alua ion h ee elec onic d ug
compa ibili y e e ences (King Guide® o Pa en e al
Admix u es® [23], T issel’s 2 Clinical Pha maceu ics
Da abase® [24] and S abilis® da abase [25]) and manu-
ac u e s’ online labeling we e also consul ed [26–28].
Finally, o he e e ences conside ed o be ele an we e
iden i ied in a non-sys ema ic li e a u e sea ch.
Resul s
Op imized dosage egimen p oposals o c i ically ill
pa ien s wi hARC in ea men wi hle e i ace am
Table2 summa izes he p obabili ies o a ge a ainmen
(PTA), ha is, he pe cen age o i ual pa ien s ha
main ained ough d ug concen a ions a s eady s a e
abo e 12mg/L and below 46mg/L.
Based on ou simula ions, o pa ien s wi h C Cl o
160mL/min, i would be possible o achie e a PTA o
a leas 80% wi h 1000mg in used o e 4h e e y 8h o
wi h 1500mg o e 30min e e y 8h. Fo pa ien s wi h
C Cl o 200mL/min, i would be necessa y o adminis e
3000mg in con inuous in usion, 1500mg o e 4h e e y
8h o 2000mg o e 30min e e y 8h. Fo pa ien s wi h
C Cl o 240mL/min, i would be necessa y o adminis-
e 4500mg in con inuous in usion o 2000mg o e 4h
e e y 8h. Wi h hose dosing egimens, he p obabili y o
Cmin o exceed he alue o 46mg/L is < 5%.
E alua ion o dosing egimens easibili y
Mode o adminis a ion: ex ended o con inuous in usion
Cu en ly, he e is expe ience on he use o le e i ace am
in con inuous in usion, bo h in a enously and sub-
cu aneously. O e all, al hough mo e s udies would be
necessa y, le e i ace am gi en as a con inuous in usion
appea s o be e ec i e and well ole a ed.
Ou sea ch iden i ied wo publica ions ha include
pa ien s ecei ing in a enous le e i ace am in con-
inuous in usion. Moodle e al. [29], made a e o-
spec i e s udy o 36 pa ien s wi h diagnosis o s a us
epilep icus and who had been ea ed wi h in a enous
le e i ace am. Thi y pa ien s ecei ed le e i ace am
as bolus in usions and 6 as con inuous in usion. E i-
cacy was highe i a bolus was adminis e ed compa ed
wi h con inuous in usions wi hou ini ial loading bolus
(p = 0.002). The aim o he s udy was no o in es iga e
he di e en ial e icacy o bo h me hods o adminis a-
ion and plasma le els we e no measu ed. Ne e heless,
au ho s hypo hesized ha in he con ex o s a us epilep-
icus peak le els a e apid le e i ace am in usions migh
be esponsible o highe e ec i eness o bolus compa ed
wi h con inuous pump in usions. No se e e ad e se
e ec s ela ed o le e i ace am in usion we e desc ibed
and ea men was o e all well ole a ed. Bu akgazi e al.
[30] published a e ospec i e s udy wi h 33 pa ien s who
ecei ed in a enous le e i ace am (16 as bolus and 17 as
con inuous in usion) o ea men o p e en ion o sei-
zu es wi h he aim o discussing i s sa e y and ole abili y.
They concluded ha in a enous le e i ace am, ega d-
less o he me hod o adminis a ion, was no associa ed
wi h any ad e se e en s in hospi alized pa ien s.
The e a e also case epo s assessing he adminis a ion
o le e i ace am in subcu aneous con inuous in usion
in he con ex o pallia i e ca e. In his se ing, le e i-
ace am subcu aneous in usion seems o be an e ec i e
op ion o seizu e con ol wi h good ad e se e ec p o-
ile [31–34]. Howe e , andomized con olled ials a e
needed o es ablish he e icacy and ole abili y o subcu-
aneous le e i ace am adminis a ion.
Table 1 Popula ion pha macokine ic model used in he
simula ions
CL clea ance, C Cl c ea inine clea ance, V1 cen al olume o dis ibu ion, Q
in e compa men al clea ance, V2 pe iphe al olume o dis ibu ion, IIV in e ‑
indi idual a iabili y, RE esidual e o , RSE ela i e s anda d e o s
Pa ame e Model
es ima e
(RSE (%))
CL (L/h) = θn + (C Cl/120)θ –
θn 3.5 (9)
θ 2.5 (17)
V1 (L) 20.7 (18)
Q (L/h) 31.9 (22)
V2 (L) 33.5 (13)
IIV_CL (%) 32.7 (21)
IIV_V1 (%) 56.1 (29)
RE_p opo ional (%) 22.3 (15)
Page 4 o 8
Bilbao‑Mesegue e al. Jou nal o In ensi e Ca e (2022) 10:21
Mic omedex® [22] includes he s udy o Bu akgazi
e al. [30] in i s in o ma ion, while UpToDa e® [21] does
no make e e ences o his me hod o adminis a ion in
i s monog aph o le e i ace am.
The use o high doses
The in o ma ion con ained in he summa y o p oduc
cha ac e is ics (SPC) es ablishes a maximum dose o
3000mg pe day [26, 27], based on phase III ials wi h
ixed dose egimens. E en ha he e alua ion o a dose–
e ec ela ionship was no he p ima y objec i e o hese
ials, he esul s gi e an indica ion o a dose–e ec ela-
ionship in his dose ange [35–37].
Howe e , o highe doses (up o 4000 mg) i has
been conside ed ha hey did no inc ease e icacy bu
inc eased he a e o side e ec s [38, 39]. This is based on
s udies ha compa ed di e ing le e i ace am ixed doses
acco ding o a g oup compa ison. A mo e ecen e o-
spec i e s udy [40], which included 61 pa ien s ea ed
wi h le e i ace am, analyzed indi idual esponse o a le -
e i ace am dose inc emen . I concluded ha dose esca-
la ion imp o ed ea men ou comes wi hou addi ional
sa e y haza ds. The inal daily doses anged om 1000 o
6000mg.
In e ia y da abases [21, 22], he maximum dose ec-
ommended in he ea men o ocal and gene alized
onse seizu es o p ophylac ically i is also 3000mg pe
day.
S abili y o le e i ace am in usion solu ions
Acco ding o he Eu opean SPC o Kepp a® [26], in a-
enous le e i ace am is physically compa ible and
chemically s able o a leas 24h a oom empe a-
u e. In he case o he SPC au ho ized by FDA [27], he
in o ma ion was he same un il 2016, when i was mod-
i ied. Cu en ly i s a es ha he dilu ed solu ion should
no be s o ed o mo e han 4h a con olled oom
empe a u e. Howe e , he e a e o he FDA-app o ed
le e i ace am medica ions ha main ain 24-h s abili y
and he e a e also p e-dilu ed al e na i es [28].
The in o ma ion ega ding s abili y o le e i ace am
solu ions ound in he consul ed elec onic da abases is
sca ce and di e s be ween hem. While in King Guide
o Pa en e al Admix u es® [23], a 24h a oom em-
pe a u e s abili y is g an ed, T issel’s 2 Clinical Pha -
maceu ics Da abase® [24] only gi es a s abili y o 4h
a oom empe a u e based on he SPC o Kepp a®
au ho ized by FDA. S abilis® da abase [25] does no
p o ide in o ma ion on s abili y a oom empe a u e.
Table 2 P obabili y o a ge a ainmen based on Mon e Ca lo simula ions
Cmin minimum le e i ace am concen a ion, C Cl c ea inine clea ance. In bold, PTA (p obabili y o Cmin highe han 12mg/L) > 80%
C Cl (mL/min) To al daily dose
(mg) Dose (mg) Dosing in e al
(h) Pe usion du a ion
(h) P obabili y o Cmin (%)
> 12mg/L > 46mg/mL
160 3000 1500 12 0.5 51 0
4 62 < 0.5
6 70 < 0.5
1000 8 0.5 65 0
481 < 0.5
688 1
3000 24 24 98 1
4500 1500 8 0.5 89 5
200 3000 1000 8 6 69 < 0.5
3000 24 24 89 < 0.5
4500 1500 8 4 84 1
692 2
6000 2000 8 0.5 84 5
240 3000 3000 24 24 68 < 0.5
4500 1500 8 4 61 < 0.5
6 74 < 0.5
4500 24 24 96 1
6000 2000 8 4 80 2
689 3
6000 24 24 99 7
Page 5 o 8
Bilbao‑Mesegue e al. Jou nal o In ensi e Ca e (2022) 10:21
Discussion
This s udy is, o he bes o ou knowledge, he i s o
p opose al e na i e dosing egimens o le e i ace am
in c i ically ill pa ien s wi h ARC. Dosing simula ions
sugges he need o adminis e up o 6000mg o le e i-
ace am daily o each he a ge plasma le el. Ou esul s
indica e ha i is necessa y o op imize he dosage egi-
men in e ms o inc easing he dose and/o in usion ime
o each he a ge plasma concen a ions in his g oup
o pa ien s. Conside ing his e idence, i is wo h won-
de ing whe he we a e using le e i ace am adequa ely in
c i ically ill pa ien s, especially in hose wi h ARC. This
should be an issue o be aken in o accoun in daily clini-
cal p ac ice, because ARC has been iden i ied in 20–65%
o ICU pa ien s and in up o 85% o neu oc i ical pa ien s
[6–10].
Cu en ly, he e e ence ange o le e i ace am ough
concen a ions has been s ablished by he ILAE in
12–46mg/L [16]. Howe e , s udies ca ied ou in c i i-
cally ill pa ien s ha e shown ha hese plasma concen a-
ions a e no achie ed wi h he au ho ized adul dosing
egimen. To da e, ou PPK s udies o le e i ace am ha e
been iden i ied in neu oc i ical ca e pa ien s. Spence
e al. [19] included 12 adul pa ien s who ecei ed le -
e i ace am. They es ima ed a highe le e i ace am CL
and a sho e hal -li e compa ed wi h p e iously pub-
lished esul s in heal hy olun ee s. Jus one pa ien ,
wi h enal impai men (C Cl 42 mL/min), achie ed a
s eady-s a e ough concen a ion g ea e han 6mg/L.
Sime e al. [18] de eloped a popula ion pha macoki-
ne ics model in 30 c i ically ill pa ien s wi h se e e TBI
o SAH wi hou enal dys unc ion. Fo e e y 40 mL/
min/1.73 m2 inc ease in u ina y C Cl, le e i ace am CL
inc eased by 50% and he median ough concen a ions
we e educed by 50%. They pe o med dosing simula-
ions wi h dosages anging om 1000mg e e y 12h o
2000mg e e y 8h and concluded ha o u ina y C Cl
g ea e ha 120mL/min/1.73 m2, none o he simula ed
egimens had a p obabili y o 80% o abo e o achie ing
ough concen a ions highe han 12 mg/L. Simila ly,
Ong e al. [20] de eloped a PPK model in 20 neu osu -
gical pa ien s. They also pe o med Mon e Ca lo simu-
la ions showing a low p obabili y o eaching ough
concen a ions > 6mg/L wi h he 500mg wice daily dos-
ing egimen. Finally, ou g oup also epo ed a popula-
ion pha macokine ic model in 27 c i ically ill pa ien s
[17], no es ic ed o neu oc i ical pa ien s. C Cl dem-
ons a ed a signi ican in luence on he le e i ace am CL.
Dosing simula ions showed ha he adminis a ion o a
leas 500mg e e y 8h o 1000mg e e y 12h would be
needed in pa ien s wi h no mal enal unc ion and ha
highe doses o sho e dosing in e al would be needed
in pa ien s wi h ARC.
Acco ding o hese PPK models, he dosage egimen
o 500mg e e y 12h is insu icien o achie e a PTA o
a leas 80% in ICU pa ien s wi h a no mal enal unc-
ion. Howe e , his is a widely used dosage in clinical
p ac ice, especially in he p ophylac ic con ex , whe e
be ween 34 and 100% o pa ien s ecei ed his dosage
[17–20]. Fu he mo e, he maximum dosage app o ed
o le e i ace am, 3000mg daily in sho in usion, also
esul ed in sub he apeu ic le els in pa ien s wi h ARC.
Ou esul s con i m ha he a ge plasma le els would
only be eached in ARC pa ien s wi h he adminis a ion
o a leas 3000mg in 4-h in usion (in pa ien s wi h C Cl
o 160mL/min) o in con inuous in usion (in pa ien s
wi h C Cl o 200mL/min). Al hough ex ended and con-
inuous in usions a e no included in he SPC o le e i-
ace am, hey may be an al e na i e ha a oids he use
o doses highe han 3000mg. Howe e , in pa ien s wi h
C Cl o 240mL/min, i is no possible o each he a ge
plasma le els wi h he maximum au ho ized dose ega d-
less o he mode o adminis a ion, and highe doses a e
compulso y.
Fo an adequa e managemen o hese pa ien s, how-
e e , he ARC should be conside ed as a dynamic and
empo a y si ua ion and, consequen ly, pa ien s’ enal
unc ion should be assessed daily o adjus dosing
egimens i necessa y [6, 16]. Equa ions ha es ima e
glome ula il a ion a e ha e been shown o be inap-
p op ia e in c i ically ill pa ien s [41], and speci ically
in pa ien s wi h ARC as hey end o unde es ima e he
alue o C Cl in his popula ion [6]. Fo his eason, c e-
a inine clea ance measu ed in u ine should be he ou-
ine echnique o calcula ing C Cl in ICU pa ien s, and
his alue should be used o adjus he dosing egimens o
d ugs a ec ed, such as le e i ace am.
Se e al ac o s a e needed o be conside ed be o e
conside ing applying in he clinical p ac ice hese esul s
ob ained by means o pha macokine ic simula ions,
ha is, he easibili y o he p oposed dosage s a egies
mus be ponde ed om di e en app oaches. In he
case o le e i ace am, he e is su icien expe ience o
conside sa e i s adminis a ion in p olonged in usions
[29–34]. Howe e , i is impo an o ake in o accoun
ha ex ended in usions do no allow eaching he apeu-
ic le els om he beginning o he ea men ; he e o e,
in pa ien s who we e no unde going p e ious ea men
wi h he d ug, i is necessa y o conside a loading dose.
Conside ing le e i ace am Vd is no a ec ed by pa ien `s
C Cl, he equi ed loading dose would be he same as
in pa ien s wi hou ARC (1000–1500mg). On he o he
hand, i should be no ed ha he adminis a ion in
ex ended o con inuous in usion makes sense insi ua-
ions in which we wan o main ain s able d ug le els in
he blood o p olonged ime. The e o e, hese s a egies
Page 6 o 8
Bilbao‑Mesegue e al. Jou nal o In ensi e Ca e (2022) 10:21
would no be sui able o example in he acu e ea men
o s a us epilep icus, whe e high single dose bolus is usu-
ally ecommended (1 o 3g a a a e o 2 o 5mg/kg/min
o 40 o 60mg/kg as a single dose in used o e 5–15min
in combina ion wi h a pa en e al benzodiazepine, and
wi h a maximum dose o 4.5g) [21]. Finally, one po en-
ial d awback o p olonged o con inuous in usion is
he need o a enous access si e in pa ien s wi h limi ed
lumens a ailable.
The sa e y o adminis e ing doses highe han hose
au ho ized in he SPC mus be conside ed. Ou dosing
simula ions sugges he need o adminis e up o 6000mg
o le e i ace am daily o each he a ge plasma le el. To
da e, a ailable e idence shows a good sa e y p o ile wi h
he use o high doses o le e i ace am [40]. Ne e heless,
he objec i e o ou simula ions is o each le els wi hin
he he apeu ic ange in a g oup o pa ien s in which,
due o hei cha ac e is ics, he clea ance o he d ug is
inc eased. Fo his eason, he use o high doses in his
con ex can be conside ed sa e, al hough i is necessa y o
closely moni o pa ien s and, i possible, pe o m he a-
peu ic moni o ing o he d ug.
Finally, when adminis e ing a d ug in ex ended o con-
inuous in usion, he in o ma ion on d ug s abili y is
c i ical. Indeed, sho pos -dilu ion s abili y can p e en
he d ug om being adminis e ed in his way. Howe e ,
di e en s abili ies ha e been se o le e i ace am by di -
e en egula o y agencies, which can condi ion he p o-
posal o new dosage egimens. On he one hand, EMA
[20] accep ed ha le e i ace am is s able o a leas 24h
a oom empe a u e; on he o he hand, FDA [21] lim-
i ed i o 4h. This disc epancy migh suppose he use o
ex ended and p olonged pe usions impossible unde
FDA c i e ia, whe eas easible in Eu ope. The e o e, i
would be desi able o e-examina e he cu en ecom-
menda ions abou d ug s abili y and o achie e an in e -
na ional consensus ega ding his issue.
Al hough his esea ch eached i s aims, i has ce -
ain limi a ion: i s o all, he e is a limi ed numbe o
PPK s udies o le e i ace am including ARC condi ion
and all he esul s a e ob ained om simula ions based
on a p e iously published s udy ca ied ou in a ela-
i ely small popula ion, which included pa ien s wi h
C CL > 50 mL/min, bu only 37% had ARC. Second,
he objec i e o ou simula ions was o e alua e he
adequacy o cu en ly le e i ace am dosage egimens
o achie e plasma le els wi hin he ange es ablished by
he ILAE. Howe e , he e is a lack o consensus abou
which he a ge concen a ions o le e i ace am ea -
men a e, and no speci ic a ge has been de ined in
p ophylac ic use. Al hough, he dosage egimens used
in p ophylac ic con ex a e usually he same as hose
lis ed o seizu e ea men and he majo i y o clinical
ials in which he e icacy o le e i ace am in p ophy-
laxis has been e alua ed use same guidelines, he ela-
ionship be ween le e i ace am plasma le els and i s
e icacy o oxici y needs o be u he cha ac e ized
in bo h si ua ions. Tha is, e en i he e a e s udies ha
analyze he in luence o he ARC in he achie emen o
plasma le els wi hin he cu en ly accep ed ange, he e
is no da a linking his si ua ion wi h highe incidence o
seizu es. The e o e, u he in es iga ions o e coming
hese limi a ions a e needed o con i m hese esul s in
he clinical se ing.
Conclusions
This s udy s a es ha con en ional dosage egimens do
no allow ob aining d ug plasma concen a ions among
he he apeu ic ange o le e i ace am in c i ically ill
pa ien s wi h ARC, and highligh s he need o imple-
men new dosing guidelines ha include speci ic ec-
ommenda ions o pa ien s in his subpopula ion. The
ecommended egimens mus ake in o accoun biop-
ha maceu ical and pha macokine ic aspec s ha con-
di ion he p obabili y o ea men success, such as he
con o e sial s abili y o he d ug in solu ion o he du a-
ion o pe usion. We p oposed new dosage ecommen-
da ions, o be implemen ed in c i ically ill pa ien s wi h
ARC, which mee easibili y c i e ia ha allow hem o
be ans e ed o he clinical en i onmen wi h sa e y
and e icacy. Acco ding o simula ion esul s, some imes
ex ended o con inuous in usions would be needed, and
in o he si ua ions, i would be necessa y o adminis e
doses highe han hose au ho ized. Ne e heless, u he
clinical s udies a e needed o con i m hese esul s.
Abb e ia ions
ARC : Augmen ed enal clea ance; CL: Clea ance; C Cl: C ea inine clea ance;
ICU: In ensi e ca e uni ; ILAE: In e na ional League Agains Epilepsy; PPK:
Popula ion pha macokine ic model; PTA: P obabili y o a ge a ainmen ;
SAH: Suba achnoid hemo hage; SPC: Summa y o p oduc cha ac e is ics; TBI:
T auma ic b ain inju y.
Acknowledgemen s
No applicable.
Au ho con ibu ions
IB, AI, MAS, AR and HB concei ed he s udy. HB, JM and JASI ca ied ou da a
collec ion. IB and EA pe o med da a analysis. IB, HB, MS and AI d a ed he
manusc ip . All au ho s ead and app o ed he inal manusc ip .
Funding
This esea ch was unded by Depa men o Educa ion o he Basque Go e n‑
men (PIBA 2019‑57) and by he Uni e si y o he Basque Coun y UPV/EHU
(GIU20/048).
Decla a ions
E hics app o al and consen o pa icipa e
No applicable.
Page 7 o 8
Bilbao‑Mesegue e al. Jou nal o In ensi e Ca e (2022) 10:21
Consen o publica ion
No applicable.
A ailabili y o da a and ma e ials
The da a se s used and/o analyzed du ing he cu en s udy a e a ailable
om he co esponding au ho on easonable eques . The popula ion PK
model used o simula ions has been published a : Bilbao‑Mesegue e al. [17].
Compe ing in e es s
The au ho s decla e ha hey ha e no compe ing in e es s.
Au ho de ails
1 Pha macokine ic, Nano echnology and Gene The apy G oup (Pha maNano‑
Gene), Facul y o Pha macy, Cen o de In es igación Lasca ay Ike gunea, Uni‑
e si y o he Basque Coun y UPV/EHU, Paseo de la Uni e sidad 7, 01006 Vi o‑
ia‑Gas eiz, Spain. 2 Bioa aba, Mic obiology, In ec ious Disease, An imic obial
Agen s, and Gene The apy, Vi o ia‑Gas eiz, Spain. 3 Depa men o Pha macy,
C uces Uni e si y Hospi al, Plaza de C uces 12, Ba akaldo, 48903 Bizkaia, Spain.
4 Bioa aba, In ensi e Ca e Uni , Vi o ia‑Gas eiz, Spain. 5 Osakide za Basque
Heal h Se ice, A aba Uni e si y Hospi al, In ensi e Ca e Uni , c/ Olaguibel no.
29, Vi o ia‑Gas eiz, Spain. 6 Inse m U1070: Pha macologie des an i‑in ec ieux,
Pôle Biologie San é‑Bâ imen B36, Uni e si é de Poi ie s, 1 ue Geo ges Bonne ,
86022 Poi ie s, F ance. 7 In ensi e Ca e Uni , Doce de Oc ub e Hospi al, A da
de Có doba, s/n, 28041 Mad id, Spain. 8 P esen Add ess: Pha maMa , A da. De
los Reyes, 1, Pol. Ind. La Mina‑No e, Colmena Viejo, 28770 Mad id, Spain.
Recei ed: 21 Feb ua y 2022 Accep ed: 5 Ap il 2022
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as , con enien online submission
•
ho ough pee e iew by expe ienced esea che s in you ield
•
apid publica ion on accep ance
•
suppo o esea ch da a, including la ge and complex da a ypes
•
gold Open Access which os e s wide collabo a ion and inc eased ci a ions
maximum isibili y o you esea ch: o e 100M websi e iews pe yea
•
A BMC, esea ch is always in p og ess.
Lea n mo e biomedcen al.com/submissions
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Publishe ’s No e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in pub‑
lished maps and ins i u ional a ilia ions.
