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Keywords:

  • Epilepsy;
  • Anticonvulsants;
  • Pharmacokinetics;
  • Medication adherence;
  • Extended-release preparations

Summary

  1. Top of page
  2. Summary
  3. Pharmacokinetic Considerations for Antiepileptic Drugs
  4. Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs
  5. Summary
  6. Acknowledgments
  7. Disclosure
  8. References

Many antiepileptic drugs (AEDs) have short half-lives with large fluctuations in peak-to-trough plasma concentrations. Consequences of these pharmacokinetic (PK) properties may include adverse events (AEs) and breakthrough seizures, potentially leading to poor adherence. To address these challenges, newer formulations of these AEDs have been developed using unique extended-release (ER) technologies. These technologies extend the dosing interval such that dosing frequency can be minimized, which may improve patient adherence. Available ER formulations have the potential to minimize the spikes in maximum plasma concentrations (Cmax) at steady-state that often contribute to AEs during treatment with immediate-release (IR) products. In so doing, tolerability advantages may lead to increased AED effectiveness by improving adherence and allowing higher doses if clinically indicated. Direct PK comparison studies of IR and ER formulations (e.g., carbamazepine, divalproate sodium, lamotrigine, oxcarbazepine, levetiracetam, and phenytoin) have found that dose-normalized ER formulations may or may not be bioequivalent to their IR counterparts, but most ER formulations have a lower fluctuation index ([Cmax–Cmin]/Cavg) compared with the IR versions. This results in flatter concentration-time plots. Not all ER preparations improve the various PK parameters to the same extent, and PK nuances may impact the effectiveness, tolerability, and adherence rates of various ER formulations.

Epilepsy is a disabling neurologic condition characterized by recurrent, unprovoked seizures that may be accompanied by a constellation of neurologic conditions and comorbidities (Hauser & Kurland, 1975; Hauser et al., 1993). Epilepsy is a persistent condition with associated consequences beyond that of the seizure (World Health Organization, 2006). Optimal pharmacologic treatment requires that stable and appropriate concentrations of antiepileptic drugs (AEDs) be maintained over extended periods of time.

Epilepsy is a common disorder, with approximately 50 million people diagnosed worldwide (World Health Organization, 2009). The annual incidence of epilepsy in developing countries (68.7 per 100,000) is higher than that of industrialized countries (47.4 per 100,000) (Kotsopoulos et al., 2002), with age, gender, race, or socioeconomic status influencing the incidence (Banerjee et al., 2009). Epilepsy is associated with an increased risk of mortality at a rate almost twice that found in an age-matched general population (standardized mortality ratio 1.9; 95% confidence interval [CI] 1.6–2.2; p < 0.001) (Lhatoo et al., 2001).

The overarching goal in epilepsy treatment is complete long-term seizure control with no or tolerable side effects. However, suboptimal adherence, which is common among individuals treated for epilepsy (Leppik, 1988), contributes to the challenge of achieving this goal (Manjunath et al., 2009). A retrospective analysis of an insurance claims database of >40 million patients showed that approximately 40% of patients using AEDs did not adhere to the prescribed drug regimen (Davis et al., 2005). The rate of nonadherence, defined as a medication possession ratio of <80%, ranged from 32–53% depending on AED and increased with age. Another study using this same database observed declines in adherence from the time of initiation of the first AED regimen through 12 months of follow-up, with adherence dropping to <50% (Manjunath et al., 2009). A retrospective analysis of a Medicaid claims database from three states (New Jersey, Iowa, and Florida) examined quarterly rates of mortality and found a threefold increase among patients with epilepsy during nonadherent quarters compared with quarters in which patients were adherent to treatment (hazard ratio 3.32; 95% CI 3.11–3.54) (Faught et al., 2008). Incidence risk ratios were also significantly increased for motor vehicle injuries (108%), hospitalizations (86%), emergency department visits (50%), and fractures (21%) when nonadherent versus adherent quarters were compared (Faught et al., 2008). This increased morbidity significantly increased health care costs (Faught et al., 2009).

Reducing AED dosing frequency is one way to enhance patient adherence. In a prospective, randomized study of clarithromycin administered once or twice daily for 7 days for acute bacterial exacerbation of chronic bronchitis, Kardas (2007) found significantly better compliance with once-daily compared with twice-daily treatment (93.7% vs. 81.3%, respectively; p < 0.0001). Likewise, a meta-analysis of 11 randomized controlled trials (N = 3,029) that examined adherence to once- versus twice-daily antiretroviral therapy also showed that the once-daily regimen resulted in significantly better adherence (+2.9%; 95% CI 1.0–4.8%; p < 0.003) (Parienti et al., 2009). In a review examining medication adherence rates across various chronic diseases from studies using medication event monitoring systems (MEMS; Aprex Corporation, Fremont, CA, U.S.A.), adherence rates with once-daily dosing of antihypertensive medications were 49–94%, whereas rates with twice-daily dosing were 5–82% (Saini et al., 2009). In this same study, patients with stable angina had adherence rates of 84–97% with once-daily regimens versus 59–88% with twice-daily regimens, and patients with type 2 diabetes mellitus had rates of 79–94% with once-daily oral hypoglycemic regimens versus 38–67% with twice- or thrice-daily regimens (Saini et al., 2009). The same relationship was observed in a small prospective study in epilepsy (N = 26), also using MEMS, in which adherence rates were shown to decrease from 87% to 39% when dosing frequency was increased from once daily to four times daily (Cramer et al., 1989). This comparison noted statistically significant differences in adherence between once-daily and four times daily treatment (p < 0.01) and for twice- and thrice-daily administration compared with four times daily regimens (p < 0.05), but not for once- versus twice-daily treatment.

Several, but not all broad-spectrum AEDs are now available in formulations modified to allow once-daily dosing. These extended-release (ER) formulations leverage the efficacy of the immediate-release (IR) compound while attempting to improve other parameters such as tolerability and convenience. Inherent characteristics of the original molecule (e.g., bioavailability, solubility, permeability), along with the wide variety of ER technologies that modulate these characteristics, result in great variability in the extent to which available ER formulations improve the pharmacokinetics (PK) and pharmacodynamics (PD) of an agent. This review describes, compares, and contrasts the PK and PD differences of IR AEDs and their respective U.S. Food and Drug Administration (FDA)–approved ER formulations.

Pharmacokinetic Considerations for Antiepileptic Drugs

  1. Top of page
  2. Summary
  3. Pharmacokinetic Considerations for Antiepileptic Drugs
  4. Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs
  5. Summary
  6. Acknowledgments
  7. Disclosure
  8. References

IR AEDs may be associated with wide ranges of peak-to-trough plasma concentrations. Figure 1 simulates the individual PK profile of IR versus ER forms of the same medication (Pellock et al., 2004). In this illustration, twice-daily administration of an IR AED results in larger variations in AED concentrations, which may lead to clinical consequences. After dose administration, the achievement of peak concentrations that surpass the minimum toxic concentration can result in dose-limiting adverse events (AEs). End-of-dose trough drug levels that fall below the minimum effective concentration may result in breakthrough seizures. In clinical practice, the goal is to maintain AED concentrations within a target range with minimal fluctuation, thereby optimizing the benefit-to-risk ratio. Peak-to-trough variations found with IR AEDs can be minimized by two approaches: (1) increase the dosing frequency of the IR formulation to lower the individual doses and lower the Cmax while raising the Cmin; or (2) reformulate the AED treatment in a once-daily ER preparation to minimize peak-to-trough drug concentration differences. The former strategy may adversely affect patient adherence while the latter may result in more convenience for the patient, and hence positively affect adherence.

image

Figure 1.   Simulated pharmacokinetic comparison of formulations of the same drug to compare immediate- and extended-release properties. tid, thrice daily; qd, once daily. Reproduced with permission from Pellock et al. (2004).

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The magnitude of the rise and fall of drug level in plasma relative to the average plasma concentration—[Cmax–Cmin]/Cavg (i.e., the fluctuation index)—is of particular interest when comparing AEDs that have varying release properties. The lower the fluctuation index, the more likely the Cmax is blunted, thus minimizing concentration-dependent AEs and potentially allowing for uptitration to higher AED doses if needed for efficacy (Reed et al., 2006). A fluctuation index of 0 indicates no peaks and troughs, as would be observed with a continuous intravenous infusion at steady state. For ER compounds, the fluctuation index is expected to be smaller than it is for IR compounds. The area under the concentration versus time curve at steady state (AUCss) is a measure of the plasma concentration throughout the dosing interval and is proportional to the dose and inversely related to clearance of drug (Bialer, 2007). Average plasma concentration (Cavg) is defined as the AUCss for the dosing interval, divided by the dosing interval (time). An ideal AED would have minimal fluctuation and maintain steady serum concentrations over the dosing interval (Werz, 2008).

The dosing schedule for many medications is often based on the drug’s plasma elimination half-life. Some AEDs have relatively short half-lives, which necessitates delivery of multiple daily doses to maintain plasma concentrations within the narrow therapeutic window. Despite having longer half-lives, some IR AEDs (i.e., lamotrigine and topiramate) continue to be administered twice daily (Bialer, 2007); furthermore, some ER AEDs intended for once-daily dosing (i.e., valproic acid and carbamazepine) continue to be dosed more frequently than intended. The rationale for these more frequent daily doses may include a desire to titrate the drug slowly, to minimize the potential for spikes in plasma drug concentrations often associated with AEs, or to match the dosing regimen of other concomitantly prescribed AEDs (Reed et al., 2006). Another reason for more frequent dosing might be to decrease the theoretical risk of a breakthrough seizure, which may be more likely when doses of currently available once-daily formulations are missed. However, this potential risk must take the half-life of the formulation into account; missing one dose of a formulation with a half-life of 8 h administered thrice daily can have equally negative consequences as missing one dose of a formulation with a half-life of 24 h administered once daily. The improved adherence noted with once-daily versus thrice-daily AED regimens suggests an overall advantage of once-daily treatments in epilepsy.

Various innovative drug delivery technologies (e.g., Microtrol technology, OROS, DiffCore, hydrophilic matrix) have been developed to minimize the fluctuations in plasma drug levels seen with IR products (Table 1) (Reed et al., 2010). Medications used to treat a range of disorders have been prepared using these technologies, and the resulting improvements in PK profiles have increased patient adherence through simplified dosing schedules (Saini et al., 2009) and have enabled dose increases in an effort to achieve greater efficacy (Miller et al., 2004; Smith et al., 2004).

Table 1.    Food and Drug Administration–approved extended-release antiepileptic drugs
Active ingredientBrand nameManufacturerTechnology
  1. CR, controlled-release; ER, XR, extended-release; IR, immediate-release; OROS, osmotic release delivery system.

  2. Adapted with permission from Reed et al. (2010).

CarbamazepineCarbatrolShire (Wayne, PA, U.S.A.)Fixed ratio of 3 bead types: 25% IR, 35% enteric coated, 40% ER (Microtrol)
CarbamazepineTegretol-CR DivitabsNovartis (Basel, Switzerland)Crystalline matrix
CarbamazepineTegretol-XRNovartisOROS
OxcarbazepineApydan extentDesitin Arzneimittel GmbH (Hamburg, Germany)Unknown
Divalproex sodiumDepakote ERAbbott (Abbott Park, IL, U.S.A.)Hydrophilic matrix technology
Divalproex sodiumDepakote DRAbbottEnteric-coated
LamotrigineLamictal XRGlaxoSmithKline (Research Triangle Park, NC, U.S.A.)Modified-release eroding matrix (Diffcore)
LevetiracetamKeppra XRUCB (Brussels, Belgium)Film-coated tablet
PhenytoinDilantin, Dilantin-125, Phenytek, Prompt, Dilantin Kapseals, Di-PhenVariousVarious

Bioequivalence standards for extended-release formulations

Ideally, an ER formulation should be bioequivalent to the corresponding IR form of the medication when given as directed. Such bioequivalence has advantages, especially in patients who wish to be switched to an ER product. The FDA accepts bioequivalence between two drug products if the 90% CIs around the ratio of geometric least squares means of the plasma drug concentration–time curve (AUC) and the values of the maximum plasma drug concentrations (Cmax) are contained within the 0.80–1.25 bioequivalence limits (Center for Drug Evaluation and Research, 2003).

Although bioequivalence of a newly formulated ER product to the original IR product is ideal, it is not a prerequisite for FDA approval. Indeed, there have been discussions at the FDA regarding modified-release products regarding whether standard bioequivalence measures are optimal, as significant deviations in concentration profiles in the absorption phase have been observed even when an ER drug has met the traditional criteria for bioequivalence to an IR counterpart (Endrenyi & Tothfalusi, 2010). A more robust measure of bioequivalence may be the determination of partial AUC (and associated 90% CIs), especially for modified-release products. Partial AUCs indicate systemic exposures to the drug calculated to any given sampling time point and represent a particularly useful PK parameter for drugs with a low fluctuation index, such as ER formulations, because partial AUCs can identify small changes in drug exposure throughout the dosing interval. When segregated by specific time points, the partial AUC should approximate Cavg and be maintained throughout the day. This measure is gaining momentum as an additional measure of therapeutic equivalence (as is the case with Ambien CR*** [Sanofi US, Bridgewater, NJ, U.S.A.]) and may serve as an indicator of absorption rates, sometimes correlating better with drug toxicity (Tothfalusi et al., 2008).

Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs

  1. Top of page
  2. Summary
  3. Pharmacokinetic Considerations for Antiepileptic Drugs
  4. Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs
  5. Summary
  6. Acknowledgments
  7. Disclosure
  8. References

We conducted a review of published PK studies that compared the bioequivalence of IR and ER formulations (Table 2) to examine PK differences between formulations and how such differences may translate to potential advantages for ER formulations. The fluctuation index for almost all ER formulations was <0.50, indicating that the ER technologies effectively extended the dosing interval with a reduced risk of excessive plasma level fluctuation. The notable exception to this finding is ER levetiracetam. As would be expected among bioequivalent products, the AUC from time 0 to the last measurable concentration (AUC0-τ) did not significantly differ between the IR and ER formulations.

Table 2.   Mean pharmacokinetic comparisons of immediate-release and extended-release formulations of the same molecule
Antiepileptic DrugReferencesDesignComparatorsDosingCmax (SD) (μg/ml)Cmin (SD) (μg/ml)AUC0-τ (SD) (μg/ml/h)Tmax (SD) (h)Fla (SD)
  1. aFluctuation index = ([Cmax–Cmin]/Cavg).

  2. bp < 0.05 versus IR formulation.

  3. cAUC0-24.

  4. dFor Tompson et al., neutral concomitant AEDs included oxcarbazepine, levetiracetam, gabapentin, topiramate, zonisamide, and tiagabine; inducers included carbamazepine, phenytoin, phenobarbital, and primidone; inhibitors included valproic acid. Subjects taking concomitant valproic acid could not be on an additional AED that was an inducer in this study.

  5. ePeak-to-trough fluctuation.

  6. AED, antiepileptic drug; AUC, area under the concentration time curve; b.i.d., twice daily; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration; CO, crossover; DB, double-blind; ER, extended-release; FI, fluctuation index; IR, immediate-release; NR, not reported; MD, multiple dose; OL, open-label; q.d., once daily; q.i.d., four times daily; R, randomized; SD, standard deviation; T, titrated; Tmax, time to maximum plasma concentration; t.i.d., three times daily.

Carbamazepine Canger et al. (1990) CO, DBTegretol IRTitrated13.8 (2.8)b 9.3 (2.3)115.8 (23.4)NR0.31 (0.1)b
Tegretol CRTitrated12.2 (2.9) 9.2 (2.3)107.1 (25.1)NR0.26 (0.1)
Garnett et al. (1998) CO, DB, RCarbatrol800, 1,200, or 1,600 mg divided b.i.d.11.2 7.5221.81NR0.47
Tegretol IR800, 1,200, or 1,600 mg divided q.i.d.11.7 8.3235.8NR0.49
Divalproate sodium Dutta et al. (2002) CO, MD, OL, R, TDepakote ER1,000 mg q.d.96.0 (18.5)b65.4 (17.5)1,970 (402) 7.7 (5.3)0.39 (0.15)b
Depakote DR875 mg b.i.d.112 (18.0)59.1 (12.0)1,920 (355) 4.0 (1.5)0.67 (0.16)
Depakote® ER1,500 mg q.d.116 (17.1)b82.2 (19.1)b2,420 (397) 6.2 (4.1)0.34 (0.15)b
Depakote DR1,250 mg b.i.d.127 (19.3)66.4 (14.0)2,200 (345) 4.5 (2.7)0.67 (0.17)
Reed et al. (2006) CO, MD, OL, RDepakote ERAdjusted q.d.71.4 (17.5)b39.5 (15.4)1,366 (376)c10.3 (5.8)0.59 (0.27)
Depakote ERAdjusted b.i.d.71.7 (17.7)b45.6 (14.1)1,418 (382)c 7.0 (5.3)0.46 (0.16)
DivalproexAdjusted q.i.d.82.8 (21.8)41.0 (14.3)1,440 (384)c 8.8 (8.0)0.71 (0.20)
Lamotrigine Tompson et al. (2008)d MD, OLLamictal XR (monotherapy or with other concomitant AEDs)Adjusted q.d. (dose normalized) Neutral Induced Inhibited 6.83  4.77  7.77 4.87  2.10  6.32138  79 1676 (0–24) 4 (0–24) 11 (0–24)0.341 0.817 0.209
Lamictal (IR) (monotherapy or with other concomitant AEDs)Adjusted b.i.d. (dose normalized) Neutral Induced Inhibited 7.82  6.71 10.2 4.57  2.66  7.44142 100 208 1.5 (0.5–3.02)  1.01 (0.5–2.98)  1.0 (0.5–6.13)0.545 0.986 0.318
Oxcarbazepine Steinhoff (2009) CO, OL, RApydan extent300 mg b.i.d. 9.7 (1.9) 6.6 (1.3)196 (35)NR0.39 (0.08)
Oxcarbazepine IR300 mg b.i.d.10 (1.4) 6.0 (1.2)194 (30)NR0.54 (0.09)
Levetiracetam Rouits et al. (2009) CO, OL, RKeppra XR1,000 mg q.d.21.3 (14.2) 5.9 (17.2)309 (13.3)4 (2–6)1.19e
Keppra500 mg b.i.d.25.6 (18.6) 8.0 (21.9)327 (15.9) 0.75 (0.25–2)1.27e

Analysis of specific AEDs

Carbamazepine

IR carbamazepine has been used for decades, but 2.5-fold fluctuations in peak-trough concentrations continue to be noted (Jensen et al., 1990). Two ER carbamazepine formulations (Carbatrol [Shire, Wayne, PA, U.S.A.] and Tegretol-CR [Ciba-Geigy S.p.A., Origgio, Varese, Italy]) were evaluated in PK studies that compared these formulations with the original IR formulation (Table 2). In one study (Canger et al., 1990), ER carbamazepine produced a significantly lower fluctuation (p < 0.015) in serum carbamazepine levels than IR carbamazepine, and this was felt to be a result of a significantly lower Cmax with the ER formulation (p < 0.01). This fluctuation difference was associated with significantly fewer AEs globally and fewer intermittent AEs with ER carbamazepine (p < 0.001 for both). In addition, monthly seizure frequencies were significantly reduced during treatment with ER carbamazepine (p = 0.013), although the study was not designed to evaluate efficacy (Canger et al., 1990). In another study evaluating the bioequivalence of IR carbamazepine administered four times daily to an ER carbamazepine administered twice daily (Carbatrol), the formulations were bioequivalent (Garnett et al., 1998). No fluctuation differences were noted for carbamazepine or the 10, 11 epoxide metabolite levels with either formulation, and no differences in average seizure frequency were noted between IR and ER carbamazepine. The only treatment-emergent AE noted during the trial was somnolence in a patient receiving IR carbamazepine (Garnett et al., 1998).

A range of technologies have been applied to formulating carbamazepine for purposes of producing ER characteristics (Table 1). The two branded ER carbamazepine products, Carbatrol and Tegretol-XR, use different technologies. Carbatrol is formulated using Microtrol technology and is composed of a mixture of IR, ER, and enteric-release beads within a capsule. The capsule can be swallowed whole or can be opened and sprinkled on food, a feature of particular benefit to patients who have difficulty swallowing (Stevens et al., 1998). Tegretol-XR is formulated using the OROS technology, which depends on gastric absorption of osmotically drawn water, forcing carbamazepine out of the tablet with hydrostatic pressure (Tegretol OROS Study Group, 1995).

The two-branded ER formulations of carbamazepine noted above, administered twice daily, were compared in a small head-to-head crossover study and, although both formulations are bioequivalent to IR carbamazepine administered four times daily, some PK differences were noted (Stevens et al., 1998). For carbamazepine, the coefficient of variability for AUC0-τ was 20% for Tegretol-XR and 12% for Carbatrol, suggesting that the latter product is more predictably delivered. Peak-to-trough blood levels were low for each formulation (28–40%). The fluctuation index was higher for Carbatrol (0.67) than Tegretol-XR (0.50) for carbamazepine, but the carbamazepine fluctuation index for the epoxide metabolite was higher for Tegretol-XR (0.56) than for Carbatrol (0.28); the clinical significance of this finding in light of the bioequivalence of the two ER products is unclear (Stevens et al., 1998).

Divalproex sodium

PK analyses comparing a twice-daily delayed-release (DR) divalproex formulation to a once-daily ER formulation had similar findings to those observed in the carbamazepine studies. Given that the ER formulation is not bioequivalent to the traditional DR formulation of divalproex sodium (Depakote ER PI, 2010), two comparisons of bioequivalence were performed using ER versus IR doses that were higher by 14% (1,000 mg ER vs. 875 mg DR) and 20% (1,500 mg ER vs. 1,250 mg DR) (Dutta et al., 2002). Results showed equivalent exposures were attained in the lower dose comparison, whereas Cmax and the degree of fluctuation were significantly reduced (p < 0.05 for each) with the ER formulation. In the higher dose comparison, the ER formulation resulted in significantly higher exposure and Cmin (p < 0.05 for each), whereas Cmax and the degree of fluctuation were significantly reduced (p < 0.05 for each) versus that found with IR dosing. Clinically, these findings may translate to fewer AEs and a lower likelihood of breakthrough seizures with once-daily divalproex sodium ER treatment.

The pharmacokinetics of conventional IR divalproex, dosed four times daily, was compared with that of ER divalproex dosed once or twice daily. The ER divalproex daily and twice-daily regimens had essentially flat concentration versus time profiles and had significantly lower mean fluctuation indices (16.9% [p = 0.024] and 35.2% [p < 0.001], respectively) than the IR formulation (Reed et al., 2006). As would be expected, Cmax was blunted in both ER regimens compared with the IR regimen; Cmin was maintained and no statistically significant differences were observed between ER divalproex (either regimen) and IR divalproex given every 6 h (Reed et al., 2006). For the ER divalproex once-daily regimen, the fluctuation index was larger (0.59) than that of the twice-daily regimen (0.46), but as no safety or tolerability data were reported, it is unknown if these differences had clinical relevance. A pooled analysis of nine open-label studies comparing the efficacy and safety of ER divalproex versus IR divalproex in epileptic and psychiatric patients has been reported (Smith et al., 2004). In two of five epilepsy trials reporting comparative seizure rates, ER divalproex was associated with fewer seizures (19%) versus those found during treatment with DR divalproex (32%; p = 0.02). In two of four psychiatric studies reporting efficacy, 90% of patients showed either no change or some improvement; 19 of 23 patients who showed a change in clinical status were improved (p = 0.003) following conversion to ER divalproex. From a tolerability standpoint, ER divalproex was associated with a significant improvement in tremor, weight gain, and gastrointestinal complaints after the switch (p < 0.001 for each) (Smith et al., 2004).

Phenytoin

At least two once-daily ER formulations of phenytoin (Dilantin Kapseals [Pfizer, New York, NY, U.S.A.] and Phenytek [Mylan, Morgantown, WV, U.S.A.]) have been developed. No direct PK comparisons between these ER formulations and the original IR formulation could be located in the published literature. One bioequivalence analysis compared the PK profile of 100 mg ER phenytoin dosed three times daily with 300 mg ER phenytoin dosed once daily and observed no statistical differences between Cmax, Cmin, or AUC at steady state; 90% CIs were within standard bioequivalence limits (Randinitis et al., 1990). Fluctuation indices for the two formulations were not reported.

Levetiracetam

In an analysis of levetiracetam IR and ER formulations, bioavailability was found to be similar in healthy volunteers (Rouits et al., 2009). In this comparison, Cmin was lower with the ER formulation (5.9 μg/ml) than with the IR formulation (8.0 μg/ml) and Cmax was lower with the ER formulation (21.3 μg/ml) than with the IR formulation (25.6 μg/ml; 90% CI 69.7–77.6). Although the 90% CIs for AUC0-24 at steady state were within the 80–125% bioequivalence limits, this was not the case for either Cmin or Cmax. Healthy subjects taking ER levetiracetam reported a lower rate of asthenia (n = 10, 42%) than with IR levetiracetam (n = 14, 58%); however, other reported AEs did not differ in incidence by more than one patient each between the two treatments (Rouits et al., 2009).

Lamotrigine

Lamotrigine is metabolized via glucuronidation; the hepatic enzyme UGT1A4 is principally responsible for the process (Rowland et al., 2006). As such, its clearance can be affected by other agents that either induce or inhibit this enzyme. Phenytoin and carbamazepine are known inducers of UGT1A4, whereas valproic acid is a known inhibitor. When lamotrigine is administered in combination with enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, or primidone), a twofold increase in steady-state clearance (Lamictal XR [PI], 2011) and an approximate 40% reduction in half-life (from 24 to 14 h) is noted (Jawad et al., 1987). Valproic acid is a known inhibitor of glucuronidation, causing a 21% decrease in steady-state clearance, increasing lamotrigine elimination half-life and AUC (Yuen et al., 1992). Therefore, dose adjustment is often necessary in patients who require polypharmacy.

In a PK study comparing ER lamotrigine with IR lamotrigine in patients who were neutral, induced, or inhibited according to their concomitant medication regimen, the use of ER lamotrigine slowed the rate of absorption (indicated by longer time to maximum plasma concentration) and decreased mean fluctuation indices 17–37% versus that found with IR lamotrigine (Tompson et al., 2008). This study enrolled individuals taking a wide range of lamotrigine dosages (as would be seen in a true clinical setting), and large interpatient variabilities were noted for Cmax and AUC0-24. When dose-normalized Cmax was analyzed at steady-state, Cmax was 29%, 12%, and 11% lower with ER lamotrigine in the induced, inhibited, and neutral groups, respectively, compared with IR lamotrigine. This is as expected because of slower absorption with the ER formulation. Trough concentrations were similar between the two formulations. Most patients (24/35; 69%) preferred the once-daily ER regimen (Tompson et al., 2008).

Oxcarbazepine

An ER oxcarbazepine formulation (Apydan extent [Desitin Pharma, Hamburg, Germany]) was approved in Germany in January 2008. Although originally intended for once-daily use, this medication did not prove superior in efficacy or tolerability in this administration schedule compared with a twice-daily IR oxcarbazepine schedule in a phase 3 clinical trial (Bialer et al., 2007); the drug’s subsequent labeling in Germany was for twice-daily administration (Steinhoff, 2009). A multiple-dose PK comparison of IR oxcarbazepine versus Apydan, both given twice daily, was notable for a 44% reduction in oxcarbazepine Cmax with Apydan; however, the Cmax and AUC for the monohydroxy derivative (MHD) between the two formulations were nearly identical (Steinhoff, 2009). The pharmacologic activity of oxcarbazepine is exerted primarily through the active metabolite, MHD; unchanged oxcarbazepine represents only 2% of the dose, whereas ∼70% of the dose is present as MHD (Trileptal [PI], 2011). Peak-to-trough fluctuations for oxcarbazepine and the MHD were reduced by 36% and 28%, respectively, with Apydan compared with the IR preparation (Steinhoff, 2009).

Tolerability of immediate- and extended-release antiepileptic drugs

Few studies have directly compared the tolerability profiles of IR and ER AEDs, but secondary comparisons are available from clinical, conversion, and PK studies. A clinically significant improvement in tolerability is an important parameter in determining the success of an ER formulation, usually reflecting a slowed absorption rate and blunted Cmax. In a review of several IR lamotrigine and ER lamotrigine studies, ER lamotrigine–treated patients reported fewer AEs, especially dizziness, diplopia, ataxia, and nausea (Blaszczyk & Czuczwar, 2010). In another study comparing the PK parameters of IR carbamazepine and CR carbamazepine, significantly fewer patients reported AEs (n = 26, IR carbamazepine vs. n = 6, CR carbamazepine; p < 0.001) and significantly more patients rated tolerability as “good or very good” (n = 27, IR carbamazepine vs. n = 47, CR carbamazepine; p < 0.001) with the CR versus IR carbamazepine formulation (Canger et al., 1990). These improvements allowed patients in the CR carbamazepine group to use higher doses of carbamazepine.

Safety was assessed in a small group of difficult-to-treat patients with epilepsy who were switched from IR oxcarbazepine to ER oxcarbazepine (Steinhoff & Wendling, 2009). Fasting serum MHD levels, adverse event profile (AEP) scores, and Quality of Life in Epilepsy-10 (QOLIE-10) scores were obtained on study day 1 while patients were receiving IR oxcarbazepine. The AEP was used to assess 10 possible AEs associated with AED therapy (each rated on a scale of 0 [no AE] to 6 [most severe quantity of AEs]). Lower QOLIE-10 scores indicate better quality of life. On study day 2, patients were switched abruptly to ER oxcarbazepine. Five days after the switch, serum MHD levels, AEP scores, and QOLIE-10 scores were assessed again and compared with values measured while patients were receiving IR oxcarbazepine. The AEP scores were significantly lower with ER oxcarbazepine than with IR oxcarbazepine (23.6 ± 16.7 vs. 44.3 ± 19.3, respectively; p < 0.001). Nearly every patient (26/27; 96%) reported an improved AEP score with ER oxcarbazepine. Significant improvements in quality-of-life measures were also noted for ER versus IR oxcarbazepine (p < 0.001) and occurred without a decrease in serum concentrations of MHD. Indeed, MHD levels were significantly elevated in 22 of 27 (81%; p < 0.001) patients treated with ER oxcarbazepine compared with IR oxcarbazepine. Of interest, 85% (23/27) of patients reported improved quality of life (Steinhoff & Wendling, 2009).

One study evaluated the tolerability of patients switched from IR carbamazepine to ER carbamazepine (Miller et al., 2004). Treatment with the ER formulation resulted in significant reductions in central nervous system (CNS) AEs (from 49% to 20%; p < 0.001) such as sedation, diplopia, confusion, ataxia, dizziness, and poor coordination, and 80% of patients who previously reported CNS AEs with the IR formulation reported no CNS AEs with the ER formulation. In addition, patients were able to tolerate higher doses of carbamazepine with the ER formulation. This may have been due to a lower and less variable absorption constant (mean 0.08; range 0.07–0.10) observed during the ER phase. The standard deviation for the absorption constant of the ER formulation was fivefold less than the IR formulation, indicating a large reduction in variability (mean 0.44; range 0.27–0.58) noted in PK studies of the IR formulation (Miller et al., 2004). These findings are consistent with a recent Cochrane Database review of 10 carbamazepine studies that concluded that the ER formulation of carbamazepine may reduce the incidence of AEs relative to the IR formulation (Powell et al., 2010).

Summary

  1. Top of page
  2. Summary
  3. Pharmacokinetic Considerations for Antiepileptic Drugs
  4. Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs
  5. Summary
  6. Acknowledgments
  7. Disclosure
  8. References

The advent of novel ER technologies has enabled AEDs with traditionally variable PK profiles to be more predictable and consistent. However, technologic platforms differ in the extent to which they improve the PK parameters of an IR medication. In general, ER formulations reduce peak-to-trough fluctuation, which is an advantage in terms of tolerability. Improved AE profiles may permit the administration of higher doses in patients who require them. As with the original IR AED preparations, detailed knowledge of an ER formulation’s PK profile can be crucial to provide the best possible care to patients with epilepsy. Ideally, this will lead to improved adherence and improved overall outcomes.

Acknowledgments

  1. Top of page
  2. Summary
  3. Pharmacokinetic Considerations for Antiepileptic Drugs
  4. Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs
  5. Summary
  6. Acknowledgments
  7. Disclosure
  8. References

The authors thank John H. Simmons, M.D., of Peloton Advantage for editorial and medical writing support, which was funded by Supernus Pharmaceuticals.

Disclosure

  1. Top of page
  2. Summary
  3. Pharmacokinetic Considerations for Antiepileptic Drugs
  4. Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs
  5. Summary
  6. Acknowledgments
  7. Disclosure
  8. References

We acknowledge that: (1) both coauthors have been substantively involved in the preparation of the manuscript; (2) no undisclosed groups or persons have had a primary role in the manuscript preparation (i.e., there are no “ghost writers”); and (3) both coauthors have seen and approved the submitted version of the paper and accept responsibility for its content. Dr. Leppik has no financial disclosures relevant to this manuscript to report. Dr. Hovinga has no financial disclosures to report. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Pharmacokinetic Considerations for Antiepileptic Drugs
  4. Pharmacokinetic Comparison of Extended-Release Antiepileptic Drugs
  5. Summary
  6. Acknowledgments
  7. Disclosure
  8. References