The Use of Newer Antiepileptic Drugs in Patients With Renal Failure

Anyzeila Diaz; Beverly Deliz; Selim R Benbadis

Expert Rev Neurother. 2012;12(1):99-105.

Brivaracetam

Brivaracetam is an orphan drug for the treatment of symptomatic myoclonus. It is a novel high-affinity SV2A ligand that also displays inhibitory activity at neuronal voltage-dependent sodium channels. It possesses a selective binding affinity for SV2A, 13 times higher than that of levetiracetam, and also shows an ability to inhibit sodium channels.^[23]

Brivaracetam has nearly complete bioavailability after oral administration. The half-life is approximately 8 h. Brivaracetam is primarily metabolized via hydrolysis of the acetamide group and CYP2C8-mediated hydroxylation. Its metabolites are not pharmacologically active. Brivaracetam is weakly bound to plasma proteins, at approximately 17.5%. Excretion of over 95% of the dose, including metabolites, occurs renally within 72 h of administration.

The pharmacokinetic profile of brivaracetam is unaltered in patients with impaired renal function or by hemodialysis. It is not necessary to adjust treatment initiation doses or to administer supplemental doses after hemodialysis.^[24]

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Table 1. Summary of recommended antiepileptic drug doses for patients with renal impairment.
Drug	Molecular weight	CrCl (ml/min)				HD dose
Drug	Molecular weight	50–80	30–50	>10 to <30	<15	HD dose
Vigabatrin	129.2	25% decrease	50% decrease	75% decrease		Up to 60% removed; replace based on clinical judgment or dose after
Rufinamide	238.2	No change	No change	No change		Supplement 30% of dose
Lacosamide	250.3	No change	No change	Max dose 300 mg/day		Up to 50% replacement dose
Ezogabine	303.3	No change	Initiate 50 mg t.i.d., max 200 mg t.i.d.	Initiate 50 mg t.i.d., max 200 mg t.i.d.		Not established
Eslicarbazepine	296.3	No change	400 mg QOD × 2 weeks then 400 mg daily; 600 mg daily max	400 mg QOD × 2 weeks then 400 mg daily; 600 mg daily max		Not established, metabolites are removed
Perampanel	349.4	Not established	Not established	Not established		Not established
Clobazam	300.7	No change	No change	No change		Not affected by HD
Pregabalin	159.2	600 mg/day max dose^†	300 mg/day max dose^‡	150 mg/day^§	75 mg/day max dose	Replacement dose 25–150 mg

^†CrCl = >60 ml/min.
^‡CrCl = 30–60 ml/min.
^§CrCl = 15–30 ml/min.
CrCl: Creatinine clearance; HD: Hemodialysis; Max: Maximum; QOD: Every other day; t.i.d.: Three times daily.

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Key Issues

Pharmacokinetics and pharmacodynamic properties of a parent drug and its active or inactive metabolites are greatly affected in patients with kidney disease and its resulting uremia. Hemodialysis (HD)-related factors also alter drug clearance.
Vigabatrin: in patients with renal impairment the dose should be decreased based on creatinine clearance. The effect of dialysis on vigabatrin clearance has not been adequately studied.
Rufinamide: patients with a creatinine clearance less than 30 ml/min do not require dosage adjustments. HD may reduce plasma concentrations by approximately 30%.
Lacosamide: no dose adjustment is considered necessary in patients with mild or moderate renal impairment. A maximum dose of 300 mg/day should not be exceeded in patients with severe renal impairment or in patients with end-stage renal disease. A supplemental dose of up to 50% following HD should be considered.
Pregabalin: for patients with renal failure, the pregabalin daily dose should be adjusted based on creatinine clearance. A supplemental dose should be administered immediately following each HD treatment.
Ezogabine (retigabine): a single-dose study shows that ezogabine exposure is increased and plasma and renal clearance are decreased as the severity of renal impairment increases. The effect of HD on ezogabine clearance has not been adequately established.
Eslicarbazepine: systemic exposure to antiepileptic drugs is increased in patients with mild-to-moderate renal impairment. The dose of eslicarbazepine should be reduced in patients with a creatinine clearance less than or equal to 50 ml/min. Patients may require supplemental doses after HD.
Brivaracetam: the pharmacokinetic profile of brivaracetam is unaltered in patients with impaired renal function or by HD.
Perampanel: the use of perampanel in patients with altered renal function has not been studied.
Clobazam: dosage adjustment should not be necessary in patients with impaired renal function.

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