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Neuroprotective effect of poly(lactic-co-glycolic acid) nanoparticle-bound brain-derived neurotrophic factor in a permanent middle cerebral artery occlusion model of ischemia in rats

Maznychenko, Andriy V.

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Treatment with lacosamide or levetiracetam in patients with renal 
replacement therapy. What is really known?
Maya Cuhls1, Julian Bösel1, Johannes Rösche1,2
1 Klinik für Neurologie, Klinikum Kassel, Kassel, Germany
2 Klinik und Poliklinik für Neurologie, Universitätsmedizin Rostock,  
 Rostock, Germany
Correspondence
Johannes Rösche
Klinik für Neurologie, Klinikum Kassel
Mönchebergstraße 41-43,34125 Kassel, Germany
Phone: 00 49 561 980 40 51
Fax 00 49 561 980 69 79
e-mail: johannes.roesche@med.uni-rostock.de.de
SUMMARY
Background. Lacosamide and levetiracetam are commonly used in critically ill patients, who need an 
antiepileptic treatment in addition to several other medications. Since both drugs are eliminated via the 
kidneys, dosage has to be adapted to renal function especially in renal replacement therapy (RRT). In 2016 
recommendations of dosage in this condition were based on three case reports only.
Aim. To elucidate the current data basis for recommendations on the dosage of Lacosamide and leveti-
racetam in patients on renal replacement therapy.
Material and methods. A search in MEDLINE and Web of Science with several core terms was performed. 
Papers reporting on doses and concentrations of lacosamide or levetiracetam in patients with renal re-
placement therapy were analysed.
Results and discussion. One phase-I study and three case reports concerning lacosamide and one case 
series with 22 patients and nine case reports concerning levetiracetam were identified. Whether 200 mg 
Lacosamide twice/day results in trough concentrations at least in the lower therapeutic range depends 
on the replacement rate used in continuous venovenous haemofiltration. Peritoneal dialysis seems to 
remove only a small portion of levetiracetam. Levetiracetam (1000 mg) every 12 hours may generate a 
trough concentration in the lower therapeutic range in continuous venovenous haemofiltration.
Conclusion. Due to the sparse and low quality data, current recommendations on dosing lacosamide or 
levetiracetam in patients undergoing renal replacement therapy have to be considered with caution and 
therapeutic drug monitoring may be useful in guiding patient management.
Keywords: peritoneal dialysis • intermittent haemodialysis • continuous venovenous haemofiltration
BACKGROUND
Lacosamide (LCM) was t approved in 2008 for the man-
agement of partial-onset seizures. Plasma protein bind-
ing for LCM is low (approximately < 15%) in healthy 
subjects. Approximately 40% of the dose is eliminat-
ed in the urine as unchanged active drug. Overall, 94% 
of the dose is eliminated in the urine within 168 hours, 
mainly as inactive metabolites. It has demonstrated no 
clinically relevant pharmacokinetic drug-drug interac-
tions (Cawello, 2015). Levetiracetam (LEV) obtained 
initial approval from the FDA in 1999. It is not pro-
tein bound. 66% of the dose is eliminated unchanged 
and 27% is excreted in urine as an inactive metabolite 
within 48 hours. It shows very few drug–drug inter-
actions as well (Patsalos, 2004). Therefore, both oral-
ly and intravenously applicable drugs are commonly 
used in those critically ill patients, who need antiepi-
leptic drugs (AEDs) in addition to several other medi-
cations. A therapeutic range is recommended for LCM 
Received January 13, 2020 
Accepted for publication on-line March 26, 2020 
Published on-line April 4, 2020
Copyright and photocopying by Foundation of Epileptology, 2020
Journal of Epileptology • 2020 • 28 • 10.21307/jepil-2020-004
34
of 5 mg/l–10 mg/l and for LEV of 12 mg/l–46 mg/l (Ja-
cob and Nair, 2016). Since both drugs are eliminat-
ed via the kidneys, the dosage has to be adapted to re-
nal function especially in renal replacement therapy 
(RRT). A comprehensive evaluation of literature con-
cerning the effect of RRT on the pharmacokinetics of 
AEDs performed in May 25th 2016 (Smetana et al., 2016) 
identified just one paper on the use of LCM during in-
termittent haemodialysis (IHD) (Cawello et al., 2013) 
and two case reports on the use of LEV with contin-
uous venovenous haemofiltration (CVVH) (Nei et al., 
2015; New et al., 2016). Based on these data it was rec-
ommended to prescribe 200–600 mg/d LCM divided 
in 2 to 3 doses and LEV 1000 mg every 12 h respective-
ly in patients with RRT.
AIM
To investigate the current data that constitute the basis 
for recommendations on the dosage of LCM and LEV 
in patients undergoing RRT.
MATERIAL AND METHODS
On September 15th, 2019 we searched in MEDLINE 
and Web of Science with the following core terms: (La-
cosamide OR Levetiracetam) AND (Dialysis OR He-
modialys* OR Haemodialys* OR Renal Replacement). 
No date restriction was imposed on the search strate-
gy. All papers reporting on dosages and plasma con-
centrations of these two AEDs undergoing RRT were 
included in the analysis. The reporting of the papers 
was grouped according to their reference to peritoneal 
dialysis (PD), IHD and CVVH.
RESULTS AND DISCUSSION
Lacosamide
No reports were found about the influence of PD on 
the pharmacokinetics of LCM. Two papers on the use 
of LCM in patients undergoing IHD were identified. 
In a phase 1 study (Cawello et al., 2013), eight patients 
with end-stage renal disease, receiving haemodialysis 
were administered 100 mg of LCM. They received 100 
mg of LCM 2.5 hours before a 4-hour session. It was 
observed that haemodialysis removed 50.9 ± 6.3 g LCM 
which represented more than 50% of circulating LCM 
reaching a mean concentration of 0.89 mg/l compared 
with 2.19 mg/l when haemodialysis free. An anuric 
patient with acute kidney injury received a daily dose 
of 100 mg of LCM and an additional dose of 150 mg 
post-haemodialysis. The concentration values were be-
tween 8.6 mg/l and 8.8 mg/l on dialysis days and also 
on non-dialysis days alike (Nei et al., 2019).
Two patients receiving LCM while undergoing 
CVVH have been published. One patient received 
200 mg LCM twice/day intravenously (Franquiz et al., 
2018) resulting in a peak concentration at steady state of 
7.7 mg/l and a trough concentration of 5.9 mg/l. With 
the same dose of LCM in another patient a peak con-
centration of 7.4 mg/l and a trough concentration of 
3.7 mg/l (Wieruszewski et al., 2018b) were measured. 
The lower trough concentration in the second case may 
be due to the higher replacement rate of 30 ml/kg/hr 
(Wieruszewski et al., 2018b) in contrast to 20 ml/kg/hr 
(Franquiz et al., 2018).
Levetiracetam
Two papers have reported on the effect of PD on LEV 
pharmacokinetics. In one patient 1000 mg LEV dai-
ly and 10-hour PD peak concentrations ranged from 
42 mg/l to 56 mg/l and trough concentrations from 
27 mg/l to 49 mg/l (Ratté et al., 2018). There was only 
a small amount of LEV removal by PD. This observa-
tion is supported by the case of a 73-year-old man (160 
cm, 93 kg), who had been undergoing PD for two years. 
Eight weeks after being put on LEV 500 mg twice/day 
he presented to an emergency department with a Glas-
gow Coma Scale of 10. Unfortunately, no LEV con-
centrations were measured at this point. But even 24 
hours after discontinuation of LEV. a concentration of 
29.8 mg/l was recorded (Bathe et al., 2014).
We found two case reports on LEV treatment and 
IHD. A 43-year-old lean woman (158 cm, 48.1 kg) 
(Wieruszewski et al., 2018a) received a loading dose 
of 2000 mg, continuing with 500 mg of LEV daily 
and a supplemental dose of 750 mg post-dialysis. On 
off-dialysis days a peak concentration at steady state 
of 20.2 mg/l and a trough concentration of 12.2 mg/l 
were documented. About 85% of LEV was cleared with-
in a 3-hour-dialysis session. A peak concentration of 
31.2 mg/l and a trough concentration of just 4.47 mg/l 
were measured. A second 25-year-old lean women (40 
kg) developed seizures during IHD when given 500 mg 
LEV daily and a 250 mg supplementary dose after HD 
(Company-Albir et al., 2017) were given. After increas-
ing the supplementary dose to 500 mg, peak concentra-
tions ranging from 20 mg/l to 35 mg/l and trough con-
centrations ranging from 3.7 mg/l to 9.4 mg/l were meas-
ured. To achieve seizure freedom valproate was added.
Maya Cuhls et al.
35
Additionally, a case series of 14 patients receiving 
doses ranging from 250 mg to 1000 mg LEV twice/day 
and 8 patients receiving 500 mg to 1500 mg daily with 
a supplementary dose after haemodialysis was pub-
lished (Shive et al., 2017). LEV twice/day resulted in 
higher peak and trough concentrations than LEV dai-
ly. Since patients with LEV twice/day received a mean 
daily dose of 1367 mg and patients with LEV daily 1219 
mg on days with dialysis and 812.5 mg on dialysis-off 
days, this difference may be explained by the differenc-
es in dosage. No recommendation for a specific LEV 
dose can be derived from this study.
Five case reports on patients receiving LEV while on 
CCVH have been published. In one 51-year-old wom-
an who was administered a dose of 1000 mg LEV in-
travenously every 12 hours, trough concentrations of 
19 mg/l were obtained (Louie et al., 2015). In a strongly 
built (175 cm, 116.9 kg) 67-year old man after a loading 
dose of 2000 mg LEV and maintenance doses of 1000 
mg LEV every 12 hours were administered (Nei et al., 
2015). Peak concentrations ranged from 26.5 mg/l af-
ter the loading dose to 39.8 mg/l at steady state. Trough 
concentrations ranged from 13.9 mg/l to 18.2 mg/l at 
steady state. In a 59-year-old tall man (187 cm, 83.4 kg) 
administered 1000 mg LEV every 12 hours, a peak con-
centration of 32.2 mg/l and a trough concentration of 
16.1 mg/l (New et al., 2016) were measured. In a 78-year-
old (93.2 kg) man treated with the same LEV dosage, 
a peak concentration of 30.7 mg/l and a trough concen-
tration of 16.1 mg/l (Van Matre et al., 2017) were meas-
ured. In a 79-year-old man (175 cm, 90 kg) treated with 
a dose of LEV 1000 mg twice/day, a median concentra-
tion of 12.4 mg/l was measured (le Noble et al., 2017).
Unfortunately, the authors do not state the levels of 
peak concentrations and trough concentrations sepa-
rately. But to avoid the large differences between peak 
concentrations and trough concentrations they rec-
ommended continuous LEV infusion of 2000 mg/24 h.
CONCLUSION
Due to the sparse and low quality data, current recom-
mendations on dosing lacosamide or levetiracetam in 
patients undergoing renal replacement therapy have 
to be considered with caution and therapeutic drug 
monitoring may be useful in guiding patient manage-
ment (table 1).
CONFLICT OF INTEREST
J. Rösche reports speaker honoraria from Eisai unre-
lated to this work. J. Bösel reports speaker honorar-
ia and travel support from Bard, Zoll, and Boehringer 
Ingelheim unrelated to this work. M. Cuhls has noth-
ing to declare.
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Table 1. Summary of recommendations  data on lacosamide and levetiracetam  use in renal replacement therapy
Renal replacement therapy Lacosamide Levetiracetam
Peritoneal dialysis No data With a dose of 1000 mg daily, a trough 
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36
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Maya Cuhls et al.
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