The Use of Newer Antiepileptic Drugs in Patients With Renal Failure
Abstract and Introduction
Abstract
Seizures and chronic kidney disease are both common and often coexist. Treating seizures in patients with renal failure, including those on dialysis, is a challenge that is frequently encountered, especially in the inpatient setting. For the newer antiepileptic drugs, there are limited data available, so an understanding of how each drug is affected by kidney disease and dialysis is critical in order to make rational choices qualitatively (which drug) and quantitatively (dosing). Generally, newer (second-generation) antiepileptic drugs are associated with fewer systemic side effects and drug–drug interactions, so they tend to be preferred in this population. The landscape of antiepileptic drugs is constantly evolving, with new compounds being released on a regular basis. Thus, several new agents have become available since the last review of this topic (in 2006) and these are the ones discussed here. Most require dosage adjustment according to the degree of renal failure, and most require extra doses after dialysis.
Introduction
Epilepsy has a prevalence of 1%, the lifetime prevalence of a single seizure is approximately 9%, and seizures are also common in renal failure. Seizures occur in approximately 30% of patients with uremic encephalopathy.[1] Therefore, the use of antiepileptic drugs (AEDs) in patients with chronic kidney disease (CKD) is a common problem in neurological practice, to which the clinical neurologist is sure to be confronted, in both inpatient and outpatient settings. There are few data and systematic reviews on the use of AEDs in patients with renal failure, including patients on dialysis.[2] In addition, the landscape of available AEDs is constantly evolving, with new drugs being added to the market on a regular basis. In the absence of data, often the management will rely on a good understanding of the drug’s metabolism or ‘dialysability’.
This article will focus on the agents that have become available since the last review of this topic,[2] which include vigabatrin, rufinamide, lacosamide, pregabalin, ezogabine, eslicarbazepine, brivaracetam, perampanel and clobazam.
This review is meant as a practical guide to help clinicians (internists, nephrologists and neurologists) in this relatively common situation. We will first review the general principles of drug treatments in patients with CKD, and then turn to individual AEDs (summarized in Table 1), with an emphasis on recently released and soon to be available compounds. Many AEDs are indicated for conditions other than seizures (e.g., gabapentin and pregabalin for chronic pain, topiramate and valproate for migraine, and lamotrigine for bipolar disease), but these indications are less ‘acute’ than seizures, so the main focus here will be for the purpose of seizure control.
Principles of Drug Therapy in Renal Failure
In 2002, the Kidney Disease Outcomes Quality Initiative developed guidelines that classify CKD into five stages. It is challenging to estimate the total CKD population, as early-to-moderate CKD is usually asymptomatic and a decline in kidney function is an inherent part of the aging process. The prevalence of CKD and end-stage renal disease (ESRD) is difficult to predict as it is based on population studies that are extrapolated to the available census data. In addition, cross-country comparisons are difficult, as there are differences in study design, CKD definitions used and laboratory calibration. The prevalent population of ESRD in the USA in 2009 was 370,274.[3] These statistics become important not only for the nephrologist and primary care physician of CKD patients, but also for any physician who prescribes medications to this population.
CKD stage 1 is defined as having a normal GFR and some evidence of kidney damage (pathologic abnormalities or markers of damage). CKD stage 2 is defined as a mild decrease in GFR (60–89 ml/min per 1.73 m2). CKD stage 3 is defined as having a GFR of 30–59 ml/min per 1.73 m2, and this can be considered to be moderate renal impairment. CKD stage 4 is defined as having a GFR of 15–29 ml/min per 1.73 m2, and this can be considered to be severe renal impairment. CKD stage 5 is defined as a GFR of <15 ml/min per 1.73 m2 and in this stage renal replacement therapy in the form of dialysis or transplantation has to be considered to sustain life.[4]
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. In general, dosage reduction is indicated in patients with CKD when ≥30% of a drug or active metabolite appears unchanged in the urine. In terms of absorption, renal disease can affect it directly or indirectly, and thus alter the bioavailability of oral medications. An example is in cases of gastrointestinal (GI) neuropathy (due to diabetes mellitus or aging) with its concomitant nausea and vomiting, which will alter the contact time of the drug with the GI mucosa, and thus may decrease its absorption. Another example is patients in volume overload states (cirrhosis and heart failure) with concomitant GI tract edema. There is a possibility of decreased drug absorption leading to decreased bioavailability.
The loading dose of a drug is determined using the volume of distribution. Loading dose relates to the amount of a drug available in the body versus its plasma concentration, and these are used to decrease the time to steady state. The loading dose is independent of renal clearance, and hence usually does not require modification in renal impairment. Another aspect altered in CKD patients is drug protein binding. A bound drug is generally not available to exert a pharmacological effect, and some drugs bind extensively to plasma proteins. Patients with CKD and nephrotic syndrome are in a hypoalbuminemic state and total drug binding will be decreased, resulting in a larger amount of free drug (for a given total concentration) available to exert a clinical effect. Uremic molecules and other organic waste products that accumulate in renal failure have the ability to bind plasma proteins and displace drugs from their binding sites. They also downregulate the expression of many cytochrome P450 enzyme activities, resulting in slower liver metabolism, longer drug half-life and an increased risk of drug toxicity.[5–8]
Pharmacological management of the patient with CKD is difficult and at times imprecise. Therefore, accurate estimation of renal function, clinical judgment and therapeutic drug level monitoring (when available) must be applied. As a general recommendation for patients with severe acute kidney injury, dosing should be based on an estimated GFR of <10 ml/min.
Replacement Therapy & Dialysis
In addition to the dose adjustments necessary in patients with acute kidney injury and CKD, differences have to be considered in patients with ESRD on renal replacement therapy, as now the clearance of the drug by hemodialysis has to be considered. Different modalities exist, including intermittent hemodialysis (3–4 h sessions 3–4 times a week), peritoneal dialysis, home daily/nightly hemodialysis, and continuous renal replacement therapy in the acutely ill patient. Physiochemical properties of a drug affect its removal. As molecular size decreases and water solubility increases, drug removal increases. As protein binding increases and volume of distribution increases, a drug becomes less readily dialyzed, as only a small portion of the total amount of drug in the body circulates in the vascular space, with a much larger portion out of reach of dialytic removal.
Hemodialysis
Hemodialysis (HD)-related factors, including membrane type, surface area, blood flow rates and dialysis frequency/duration also alter the drugs clearance. Furthermore, with the advent of dialysis membranes with larger surface areas and high-flux properties (larger pore size) more drugs can be dialyzed than those reported in the past (as studies were carried out with low-efficiency dialyzers). An example is phenytoin, where reports of postdialysis seizures were related to decreased phenytoin levels after HD with high-efficiency dialyzers. In general, drugs that are known to be significantly cleared by hemodialysis should be admnistered after dialysis, in the case of AEDs the purpose is to prevent post-HD seizures.
Peritoneal Dialysis
Peritoneal dialysis is another modality of renal replacement therapy, in which the peritoneal membrane is used as the dialyzing membrane. This membrane is much less effective compared with hemodialysis in regards to drug clearance. However, increased drug dialyzability may occur in the setting of peritoneal dialysis-associated peritonitis, as a significant amount of the drug binds to proteins and can be removed in peritoneal effluents.
Home Hemodialysis/Nocturnal Hemodialysis
These techniques consist of either short daily treatments or long nightly treatments, both at home. Short daily dialysis treatments run for 2–3 h, 5–6 times per week. Nocturnal HD is carried out while the patient sleeps, consist of longer hours of treatment and is carried out 3–6 nights per week. Schedules are tailored to fit each patient’s needs. At this point, there are insufficient data on this relatively recent modality. Overall, the same concept as in HD applies, except that home/nocturnal dialysis can entail a longer time on dialysis. Similar supplemental strategies as those used in HD patients can be used.
Continuous Renal Replacement Therapy
Continuous renal replacement therapy is the dialysis modality usually used in the hemodynamically unstable acutely ill patient. The drug clearance will differ when compared with hemodialysis as there is continuous ultrafiltration of plasma water and larger quantities of drug can be removed. Membranes used in continuous renal replacement therapy are usually of larger pore size, and this allows larger molecules to be filtered, which can increase drug clearance.
Individual Antiepileptic Drugs
Vigabatrin
Vigabatrin is indicated as monotherapy for children with infantile spasms and as adjunct therapy for adults with refractory complex partial seizures. Vigabatrin is a racemic mixture of two enantiomers, S(+) and R(-), with the S(+) being the active compound. Vigabatrin’s antiseizure effect is believed to be the result of its action as an irreversible suicide inhibitor of γ-aminobutyric acid transaminase (GABA-T). This action results in increased levels of GABA in the CNS.[9]
Following oral administration, vigabatrin is essentially completely absorbed and peak plasma concentrations are reached within 2 h. The plasma elimination half-life is approximately 5–8 h in young adults and 12–13 h in the elderly. Vigabatrin is not plasma protein bound. Due to its irreversible inhibition of GABA-T, the clinical effects of vigabatrin may outlast drug half-life, and is determined by the time required to synthesize new enzyme. Therapeutic and toxic levels of vigabatrin have not been established.
Vigabatrin is eliminated renally, with minimal metabolic transformation. After an oral dose, 70% is excreted in the urine unchanged.[10] In renal impairment, elimination is prolonged and the rate of renal clearance is directly related to creatinine clearance. In patients with mild renal impairment (creatinine clearance 50–80 ml/min), the dose should be decreased by 25%, in patients with moderate renal impairment (creatinine clearance 30–50 ml/min), the dose should be decreased by 50%, and in patients with severe renal impairment (creatinine clearance 10–30 ml/min), the dose should be decreased by 75%.[9]
The effect of dialysis on vigabatrin clearance has not been adequately studied. However, both the S(+) and the R(-) enantiomers of vigabatrin can be recovered in dialysate after hemodialysis, and have been reported to have a similar dialysis clearance. It has been reported that up to 60% of vigabatrin can be removed from the blood pool after hemodialysis, and thus a replacement dose should be considered after each dialysis session in order to maintain therapeutic efficacy.[9] Knowing that vigabatrin is not protein bound, and that up to 60% of the drug can be removed by hemodialysis, a safe approach would be to supplement approximately half of the dose after hemodialysis. If given daily, then administer the dose after the dialysis session on these days instead of adding a supplemental dose.
Rufinamide
Rufinamide is an orphan drug indicated for adjunctive treatment of partial seizures and drop attacks associated with Lennox–Gastaut syndrome in patients 4 years of age and older. The mechanism by which rufinamide exerts its antiepileptic effect is unknown, but it is suggested that the principal mechanism of action of rufinamide is via voltage-dependant sodium channel blockade, causing prolongation of the inactive state.
Following oral administration, approximately 85% of the dose is absorbed. Food can increase the absorption of rufinamide by 34%. Rufinamide peak plasma concentrations occur between 4 and 6 h, and the plasma half-life of rufinamide is approximately 6–10 h. Rufinamide is 34% plasma protein bound, predominantly to albumin.
Rufinamide is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Renal excretion is the predominant route of elimination. Since rufinamide pharmacokinetics are not affected by severe renal impairment, patients with a creatinine clearance less than 30 ml/min do not require dosage adjustments. Hemodialysis may reduce plasma concentrations by approximately 30%. Area under the curve is decreased by 29% and Cmax by 16%.[8] Accordingly, adjusting the dose during the dialysis process should be considered. A sensible approach would be to give a 30% supplemental dose after HD. Because of possible redistribution, an even safer approach may be to give a lower amount (~20%) and titrate up if post-HD seizures occur.[11]
Lacosamide
Lacosamide is indicated as adjunctive therapy in the treatment of adults with partial onset seizures. Lacosamide is a functionalized amino acid with a novel mechanism of action. Its antiepileptic activity is thought to be exerted via slow inactivation of voltage-gated sodium channels.[12]
Lacosamide is completely absorbed after oral administration and has 100% bioavailability. Peak plasma concentrations are reached within 1–4 h, and the elimination half-life is approximately 13 h. Lacosamide is less than 15% plasma protein bound. Lacosamide and its major inactive metabolite are eliminated from the systemic circulation primarily by renal excretion.
Plasma concentration of lacosamide is increased approximately 25% in patients with mild and moderate renal impairment, and 60% in severely renally impaired patients compared with subjects with normal renal function (creatinine clearance >80 ml/min). In patients with mild or moderate renal impairment, no dose adjustment is considered to be necessary. A maximum dose of 300 mg/day should not be exceeded in patients with severe renal impairment or in patients with ESRD.
Hemodialysis can effectively remove lacosamide from plasma. After a 4-h hemodialysis treatment, lacosamide plasma concentration is decreased by approximately 50%. A supplemental dose of up to 50% following hemodialysis should be considered.[13]
Pregabalin
Pregabalin is indicated for the treatment of partial onset seizures in adults. Pregabalin has a similar structure and site of action to gabapentin. Both drugs exert their anticonvulsant effect at the α2δ protein, an auxiliary subunit of voltage-gated calcium channels. By binding to α2δ subunits, pregabalin reduces the synaptic release of several neurotransmitters, thereby reducing neuronal excitability. Pregabalin also increases neuronal GABA levels by producing a dose-dependent increase in glutamic acid decarboxylase activity.
Pregabalin is rapidly absorbed after oral administration and peak plasma concentrations are reached within 1.5 h of administration. Pregabalin does not bind to plasma proteins. Pregabalin is eliminated primarily by renal excretion as an unchanged drug and has an elimination half-life of approximately 6 h.[14]
For patients with renal failure, the pregabalin daily dose should be adjusted based on creatinine clearance. The maximum recommended dose for patients with a creatinine clearance greater than 60 ml/min is 600 mg/day. If the creatinine clearance is between 30 and 60 ml/min, the maximum recommended dose decreases to 300 mg/day in two to three divided doses. When the creatinine clearance is between 15 and 30 ml/min, the maximum recommended dose is 150 mg daily in one to two divided doses. A maximum of a single daily dose of 75 mg per day is recommended when the creatinine clearance is less than 15 ml/min.
A supplemental dose should be administered immediately following each hemodialysis treatment. Patients on 25 mg daily should take one supplemental dose of 25 or 50 mg. Patients on 25–50 mg daily should take one supplemental dose of 50 or 75 mg. Patients on 50–75 mg daily should take one supplemental dose of 75 or 100 mg. Patients on 75 mg daily should take one supplemental dose of 100 or 150 mg.[15]
Ezogabine (Retigabine)
Ezogabine is indicated for the treatment of partial seizures in adults. Ezogabine, also known as retigabine, is the first neuronal potassium channel opener developed for the treatment of epilepsy. The exact mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine stabilizes neuronal KCNQ channels in the open position, increasing the stabilizing membrane current and preventing bursts of action potentials during the sustained depolarizations associated with seizures. In vitro studies suggest that ezogabine may also exert antiepileptic effects through augmentation of GABA-mediated currents.[16]
After oral administration, approximately 60% of the dose is bioavailable. Ezogabine is extensively metabolized by hepatic hydrolysis, acetylation and glucuronidation. The pharmacokinetic profile is linear, reaching peak plasma concentrations in 1–2 h. The half-life of ezogabine ranges from 6–10 h. It is approximately 80% protein bound. Elimination of the parent compound and its metabolites is primarily renal.[16]
A single dose study shows that ezogabine exposure is increased and plasma and renal clearance are decreased as severity of renal impairment increases. Relative to healthy subjects, ezogabine exposure is increased approximately 30% with mild impairment, and almost 100% with moderate or severe impairment and in individuals requiring dialysis. In addition, half-life may be as long as 23 h in patients requiring dialysis.[17]
It is recommended that for patients with moderate to end-stage renal impairment, treatment should be initiated at 50 mg three times daily, increasing at weekly intervals by no more than 50 mg three times daily, to a maximum of 200 mg three times daily.[18] The effect of hemodialysis on ezogabine clearance has not been adequately established, but taking into account that it is highly protein bound, clearance by dialysis should be low. Dosing after dialysis is probably not needed.
Eslicarbazepine
Eslicarbazepine acetate is a prodrug that is activated to eslicarbazepine, an active metabolite of oxcarbazepine. Eslicarbazepine acetate stabilizes the inactive state of voltage-gated sodium channels preventing their return to the activated state and sustained repetitive neuronal firing. This is the same mechanism of action as carbamazepine. The main distinction between eslicarbazepine acetate and carbamazepine is the lack of a toxic epoxide. Eslicarbazepine acetate is currently being developed as adjunctive treatment for partial onset seizures, with the aim of improving the efficacy and tolerability profiles of oxcarbazepine and carbamazepine.[19]
Following oral administration, eslicarbazepine acetate is rapidly absorbed and undergoes extensive first pass hydrolysis to its major active metabolite, eslicarbazepine. The two minor active metabolites are (R)-licarbazepine and oxcarbazepine. Eslicarbazepine is approximately 60% orally bioavailable, and reaches peak plasma concentrations in 2–3 h.[20] A thorough analysis shows the pharmacokinetics of eslicarbazepine to be linear and dose proportional. Eslicarbazepine has a half-life of 12–20 h, while that of oxcarbazepine and (R)-licarbazepine is 12–14 h and >24 h, respectively.[21] Eslicarbazepine is approximately 30% protein bound. Eslicarbazepine acetate and its metabolites are mainly excreted in the urine unchanged. Renal clearance of eslicarbazepine is lower than GFR in healthy subjects. This suggests that renal tubular reabsorption occurs.[22]
An open-label, parallel group study that evaluated the effects of renal impairment and hemodialysis on the pharmacokinetics of eslicarbazepine found that renal function has a significant effect on the clearance of eslicarbazepine and its metabolites. The proportion of eslicarbazepine excreted in the urine decreases as renal function worsens. Therefore, the extent of systemic exposure 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. Treatment should be initiated with 400 mg every other day for 2 weeks, followed by 400 mg daily. The dose should not exceed 600 mg.[17]
Dialysis effectively removes eslicarbazepine metabolites from the circulation. Patients may require supplemental doses after hemodialysis. Since the correlation between the dose of eslicarbazepine acetate and the level of active metabolites is not clearly defined, administration of the usual dose after dialysis will probably maintain therapeutic plasma levels.
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]
Perampanel
Perampanel is a highly selective, noncompetitive AMPA-type glutamate receptor antagonist currently in development for the treatment of partial seizures in patients with epilepsy.
After oral administration, perampanel is nearly 100% bioavailable. Peak plasma levels are reached between 15 min and 2 h. It is 95% bound to plasma proteins, and is primarily metabolized via CYP3A4. A total of 30% of the dose is excreted in the urine, while the remaining portion is excreted in the feces.[25]
The use of perampanel in patients with altered renal function has not been studied. It is not known whether hemodialysis reduces perampanel serum concentrations and it should therefore be used with caution in patients who require hemodialysis. One could hypothesize that, since perampanel is highly protein bound and metabolized via cytochrome, it should not be removed by hemodialysis, but more studies are needed.
Clobazam
Clobazam is the first and only 1,5-benzodiazepine in clinical use as an anticonvulsant. Clobazam exerts it anticonvulsant effects via its selective affinity for the ω 2 site of the GABA-A receptor, where it has agonistic activity.
After oral administration, clobazam is rapidly and virtually completely absorbed, with plasma peak concentrations in 1–4 h. It is highly lipid soluble and 90% protein bound. Clobazam is extensively metabolized in the liver to several metabolites. The half-life of the parent compound is 18 h. N-desmethyl-clobazam, the main active metabolite, attains maximal plasma concentration after 24–72 h. Its elimination half-life is approximately 50 h.[26]
A study conducted to determine the effect of renal impairment on the pharmacokinetics of clobazam and N-desmethyl-clobazam in adult patients with impaired renal function observed no clinically meaningful relationship between pharmacokinetic parameters and renal function. Mild and moderate renal impairment did not have a clinically meaningful effect on the plasma protein binding of clobazam or N-desmethyl-clobazam compared with matched controls with normal renal function.[27] Hemodialysis has little or no effect on plasma concentrations of clobazam or its metabolites.[28] Based on these findings, dosage adjustment should not be necessary in patients with impaired renal function.
Take-home Message
The landscape of AEDs is constantly evolving, with new agents becoming available on a regular basis. For many of the newer AEDs, specific data are lacking to assist the clinician in the care patients with renal failure. Nonetheless, a good understanding of the medications and their behavior in kidney disease allows for a rational and common sense approach that can be safe and effective.
Expert Commentary
The pharmacokinetics and pharmacodynamics of drugs are affected in patients with CKD and in patients with ESRD on renal replacement therapy. Protein binding, volume of distribution and renal elimination are only some of the aspects. In addition, drug dosing in kidney disease can become even more challenging due to the high number of comorbid conditions in this patient population. Some drugs can be readily removed by the currently used dialysis techniques. The data available for hemodialysis and drug clearance cannot be extrapolated to ESRD patients on peritoneal dialysis as these membranes have different properties. A sensible approach is to administer the regular antiepileptic dose after the hemodialysis session. In situations in which this is not possible, one can give a supplemental dose after hemodialysis. To estimate the supplemental dose one has to know the percentage of reduction in plasma concentration (in drugs where levels can be measured), or the percentage of drug found in the dialysate. A supplemental dose that is slightly lower than that estimated to be removed by dialysis would be a safe approach. In an era where drug levels are not always readily available, knowledge of the pharmacokinetics and pharmacodynamics of AEDs will aid the clinician in preventing adverse effects or therapeutic failure.
In the end, shortly after a drug is made available there is always a paucity of data on its in unusual settings, such as renal disease. Such experience is acquired after the drug has been used regularly. Nonetheless, we feel that this review will offer valuable guidance.
Five-year View
In the next 5 years, there will be other new AEDs available, and their use in this difficult population will have to be discussed. Since specific data are usually limited until a drug is on the market for many years, common sense and clinical judgment are often the best tools we have to take care of patients
