R. Edward Hogan, MD, Department of Neurology, Saint Louis University, St Louis, Missouri; William R. Garnett, PharmD, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia; and Vijay M. Thadani, MD, for the Carbatrol Study Group, Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
Background: An earlier 6-month, multicenter, open-label study in patients with complex partial seizures found that a switch from multiple daily doses of conventional carbamazepine (CBZ) to twice-daily CBZ extended-release capsules (CBZ-ERC) was well tolerated, with maintenance of seizure control over the study period and significant improvements in quality of life (P<.001).
Objective: The goal of the present study was to assess the tolerability and effects on quality of life of twice-daily CBZ-ERC over the longer term in patients with seizure disorders.
Methods: This was a multicenter, open-label assessment of the long-term (12-36 months) tolerability and quality-of-life effects of twice-daily CBZ-ERC given at a daily dose equivalent to the daily dose of CBZ taken before study entry. The regimen could be adjusted as clinically indicated up to a daily dose of 1600 mg. Patients could receive up to 2 other antiepileptic drugs during the study.
Results: One hundred eighteen patients were enrolled. In patients completing >12 months of study therapy, a significant decrease in the highest mean 2-day frequency of generalized tonic-clonic seizures was observed over the first 12 months (P = .005). The significant improvements in quality of life achieved in the earlier study were maintained during the present study. Of 37 patients who were discontinued from the study, 9 met criteria mandating withdrawal from the study due to exacerbation of seizures. Three patients were discontinued from the study for adverse events judged to be unrelated to the study drug. Low incidences of rash (3.4%) and weight gain (0.8%) were reported.
Conclusions: In this population of adults with seizure disorders, CBZ-ERC twice daily was well tolerated during 12 to 36 months of open-label treatment, with no increase in seizure frequency or decrease in quality of life.
William R. Garnett, Departments of Pharmacy and Neurology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia, USA; Angus M. McLean, BioPharm Global Inc, Gaithersburg, Maryland, USA; Yuxin Zhang, Susan Clausen, and Simon J. Tulloch, Shire Pharmaceutical Development, Rockville, Maryland, USA
Objective: Carbamazepine (CBZ) effectively treats simple, complex, and secondarily generalized partial seizures. Computer simulations were carried out to investigate the effect of missing or delaying doses of carbamazepine extended-release capsules (CBZ-ERC) on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to therapeutic levels.
Patients and methods: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400-mg fasting dose of CBZ-ERC. The model was used to simulate plasma CBZ concentrations following multiple doses given every 12 h to hypothetical long-term CBZ-treated patients, with the CBZ elimination half-life set to 13.7 h to account for enzymatic autoinduction. The model was then used to simulate plasma CBZ concentrations when a dose is taken 3, 6, or 9 h late, or when two doses are taken at one time.
Results: Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4 ?g/mL only to 4 ?g/mL after 24 h without medication, and only to 2.5 ?g/mL after 36 h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9 ?g/mL, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3 h before taking the next scheduled dose, will not lead to harmful spikes in plasma concentrations of CBZ.
Conclusions: The simulations suggest that taking a missed dose of CBZ-ERC as soon as remembered, up to two doses at one time, may be the best strategy to return plasma CBZ concentrations to steady-state levels. Since the model used in this study is a simplified model of a highly complex situation, caution should be used when relating these results to clinical practice until trials are conducted in patients.
Miller AD, Krauss GL, and Hamzeh FM, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Objectives: Tolerability of 'narrow therapeutic ratio' (NTR) antiepileptic drugs may improve with uniform drug delivery. We determined whether conversion from immediate-release carbamazepine (IR-CBZ) to extended-release carbamazepine (ER-CBZ) decreased the incidence of CNS side-effects associated with drug concentration oscillations.
Methods: We compared CNS side effects and seizure frequency for patients with partial-onset seizures (n = 61) treated with IR-CBZ for >1 year with conversion to ER-CBZ for >1 year. We compared tolerability findings with absorption variability of the formulations.
Results: Incidence of CNS side-effects decreased from 49% during IR-CBZ treatment to 20% following conversion to ER-CBZ. Patients also had improved tolerability of high doses (>1200 mg/day) during ER-CBZ treatment. Pharmacokinetic analysis showed absorption and drug concentration were much more variable for the immediate-release formulation.
Conclusions: This study suggests that ER-CBZ formulations, with smoother drug delivery and less variable absorption, provide improved CNS tolerability compared with immediate-release formulations.
William R. Garnett, Departments of Pharmacy and Neurology, Virginia Commonwealth
University, Medical College of Virginia, Richmond, Virginia, USA; Thomas D. Gilbert, MS, PharMetrics, Inc., Watertown, Massachusetts, USA; and Paul O’Connor, Rph, MBA, Boston Market Strategies, Inc., Lynnfield, Massachusetts, USA
Background: Although generic formulations of immediate-release carbamazepine (IR-CBZ) are available, extended-release delivery systems may offer important advantages, including the convenience of less-frequent administration and smaller peak-to-trough serum carbamazepine (CBZ) fluctuations.
Objective: The aim of this study was to compare the patterns of pharmacotherapy, rates of adverse events, and the utilization costs among patients treated with the utilization costs among patients treated with the available CBZ formulations (ie, generic and branded IR-CBZ, and extended-release CBZ (ER-CBZ) capsules [Carbatrol®, Shire US Inc., Wayne, Pennsylvania] and tablets [Tegretol®-XR, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey]).
Methods: Data were retrieved from the PharMetrics patient-centric database (which contains integrated claims data for almost 36 million unique patients from 61 US health plans) for patients who were diagnosed with epilepsy and initiated CBZ between July 1999 and June 2001. Patient demographic and clinical characteristics, adverse events, discontinuations, CBZ therapy switches, and utilization and costs for related care subsequent to treatment initiation were recorded. Annual rates of adverse effects and discontinuations were calculated, and the risks of these events were compared across treatment groups.
Results: Data were gathered for 1737 patients. The branded CBZ group was demographically and clinically different than the other groups (ie, migraine and cerebral palsy prevalence) and therefore was excluded from event-risk analyses. Results of the proportional hazards regression analysis indicated that Tegretol®-XR patients were more likely to experience common central nervous system (CNS)-related adverse events relative to Carbatrol® (hazard ratio, 1.67; P = 0.043). A lower percentage of subjects switched off ER-CBZ relative to IR-CBZ (Carbatrol®, 5.2%; Tegretol®-XR, 5.7%; generic IR-CBZ, 13.0%; branded IR-CBZ, 16.7%). Differences in mean payments for epilepsy-related health care services at 1 year among Carbatrol®, Tegretol®-XR, and branded or generic CBZ did not reach statistical significance.
Conclusions: Among the available CBZ formulations, Carbatrol was associated with a lower incidence of common CNS adverse events. ER-CBZ formulations were also associated with reduced likelihood of therapy discontinuation or switching CBZ medications, relative to patients taking generic IR-CBZ, in this retrospective data analysis.
DM Ficker, MD, Department of Neurology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA; M Privitera, MD, Department of Neurology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA; G Krauss, MD, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; A Kanner, MD, Rush Epilepsy Center and Department of Neurological Sciences, Rush Medical College, Chicago, Illinois, USA; JL Moore, MD, Department of Neurology and College of Pharmacy, The Ohio State University, Columbus, Ohio, USA; and T Glauser, MD, Department of Neurology, Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
Abstract: The authors conducted a 3-month, prospective, open-label study assessing the effects of switching from immediate-release carbamazepine formulations to an equal total daily dose of carbamazepine extended-release capsules (CBZ-ERC) in adolescents and adults with epilepsy. Using validated, epilepsy-specific measures the authors found that switching to CBZ-ERC significantly improved patients' adverse events and quality-of-life measures. Switching to CBZ-ERC also improved seizure control.
Alaa Ahmad, Department of Pharmaceutics, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia, USA; and William R. Garnett, Department of Pharmacy and Neurology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia, USA
Carbamazepine (CBZ) is currently one of the most frequently prescribed first-line drugs for the treatment of partial and generalised tonic-clonic seizures in both adults and children. Conventional immediate-release carbamazepine (IR-CBZ) has been the standard to which new antiepileptic drugs (AEDs) have been compared. However, the use of IR-CBZ formulations has been hampered by tolerability and adherence issues. IR-CBZ has been associated with daily fluctuations in plasma CBZ concentrations, and several studies have reported a correlation between peak concentrations of CBZ and central nervous system and cognitive adverse effects. In order to avoid significant peak- to-trough plasma fluctuations, IR-CBZ must be administered according to a strict three- or four- times-daily regimen.
Extended-release formulations of CBZ, such as beaded CBZ extended-release capsules (CBZ-ERC) [Carbatrol®; Shire, Wayne, PA, USA], were therefore developed with the goal of decreasing both dosing frequency and plasma fluctuations associated with IR formulations. In adult patients, fewer cognitive adverse effects of CBZ were observed when fluctuations in plasma concentration were smoothed by slow-release absorption. Clinical studies of CBZ-ERC in patients with epilepsy have reported decreased adverse effects and improved patient-perceived quality of life. Pharmacokinetic modeling studies suggest that the improved tolerability of CBZ-ERC relative to IR-CBZ is associated with smaller and less variable daily fluctuations in CBZ concentrations.
Oxcarbazepine (OXC) is a 10-keto analog of CBZ. Although chemically related to CBZ, OXC has a completely different metabolic profile. After administration in humans, OXC is rapidly reduced by cytosolic arylketonic reductase into its active metabolite, 10,11-dihydro-10-hydroxycarbazepine (monohydroxy derivative [MHD]), whereas CBZ is metabolised by cytochrome P450 3A4 (CYP3A4) to CBZ-10,11-epoxide. Studies have suggested that OXC provides similar efficacy to IR-CBZ, but is better tolerated and associated with fewer serious events as well as fewer drug-drug interactions than IR-CBZ.
Although optimal ranges for plasma concentrations of CBZ and MHD have not been precisely defined, reports have estimated plasma therapeutic ranges for both of these compounds (4–12 mg/L and 15–35 mg/L, respectively), and maintaining plasma drug concentrations within these values may be important for preventing breakthrough seizures and toxicity. Plasma drug concentrations can be affected by patient adherence and drug-drug interactions. Typically, an inverse relationship is seen in dosing frequency versus degree of adherence. Since CBZ-ERC and OXC are administered twice daily, adherence rates are usually high.
To date, no clinical study has directly compared OXC with CBZ-ERC. Here we compare the practical steady-state plasma CBZ and MHD fluctuations using pharmacokinetic modeling of CBZ-ERC and OXC, respectively, given as monotherapy under various strict and practical dosing conditions.
Methods: Pharmacokinetic modeling was performed using published kinetic data for CBZ-ERC (400 mg twice daily) and MHD (OXC 600 mg twice daily [target dosing schedule for patients not receiving other AEDs at the time of OXC initiation] and 1200 mg twice daily [target dosing schedule for patients being switched from other AEDs to OXC monotherapy]) in adults (table I). The model was used to simulate plasma drug concentrations following multiple doses given every 12 hours to hypothetical long-term CBZ- or OXC-treated patients. The simulations were carried out using a WinNonlin® program (Pharsight Corp., Mountain View, CA, USA) and 1-compartment models with first-order absorption and elimination and no lag time. Autoinduction properties for CBZ were accounted for in the simulations. The models were then used to simulate steady-state plasma drug concentrations during twice-daily dosing (both compounds), strict (Q8h) three-times-daily dosing (OXC), and practical three-times-daily dosing (OXC; breakfast [7am], dinner [12pm], and before bed [10pm] on each day of treatment).
Results: Simulated steady-state plasma concentrations of CBZ (following treatment with CBZ-ERC 400 mg twice daily) and MHD (following treatment with OXC 600 mg and 1200 mg twice daily and 400 mg and 800 mg three times daily [strict and practical dosing schedules]) are shown in table II.
Twice-Daily Dosing Comparison
During twice-daily dosing, CBZ-ERC concentrations fluctuated between 6.4 and 7.3 mg/L, or 6.6% up or down from the mean. The concentrations of OXC fluctuated between 14.9 and 20.9 mg/L for 600 mg twice daily, and between 29.8 and 41.8 mg/L for 1200 mg twice daily (both 16.8% from the mean).
Strict Three-Times-Daily Dosing Comparison
In the simulation of strict three-times-daily dosing (Q8h), the levels of OXC fluctuated between 16.5 and 19.6 mg/L for 400 mg Q8h and between 33.1 and 39.3 mg/L for 800 mg Q8h. This was a substantially smaller fluctuation than for the simulated twice-daily dosing (8.6% vs 16.8%).
Practical Three-Times-Daily Dosing Comparison
During practical three-times-daily dosing, OXC concentrations fluctuated between 15.5 and 21.2 mg/L for 400 mg three times daily (15.5%), and between 31.0 and 42.4 mg/L for 800 mg three times daily (15.5%), which were similar to the levels of fluctuation seen in the OXC twice-daily simulations.
Discussion: Our findings from mathematical simulations suggest that greater fluctuations in plasma drug concentration are associated with OXC (similar profiles to IR-CBZ) in comparison to CBZ-ERC when each is given as monotherapy using a twice-daily dosing schedule. Furthermore, the predicted fluctuations seen using practical three-times-daily dosing of OXC are similar to those obtained when OXC is on a twice-daily basis. Thus, for the average patient, in order to achieve minimal fluctuations comparable to CBZ-ERC formulations, OXC may need to be administered according to a strict three-times-daily regimen. Diurnal fluctuations of MHD concentration have been observed in studies. Kramer has shown increased adverse events in patients who were on OXC twice daily compared with those on OXC four times daily. Since increases in number of medication doses have been associated with decreases in patient adherence, the advantages for decreasing drug level fluctuations with OXC would need to be balanced against the potential for decreased adherence because of the three-times-daily regimen. Further clinical studies are warranted to validate the conclusions of the mathematical simulations presented here.
It should be noted that, despite its apparent benefit with respect to fluctuations in plasma concentrations, CBZ is capable of inducing its own metabolism, and this feature may lead to difficulties with treatment dosing. Furthermore, CBZ is converted to its active metabolite by CYP3A4, and as a result, interactions with CYP3A4 inducers and inhibitors are possible. Both CBZ and OXC are capable of inducing hepatic enzymes that can metabolise concomitantly administered medications.
Fluctuations in drug concentrations can result in an altered response with any drug. The greater the fluctuation the greater the potential for alterations between toxicity and lack of response. While it has been suggested that oxcarbazepine is better tolerated than CBZ, this was determined using immediate-release CBZ administered three times a day. A regimen of immediate-release CBZ given three times a day will result in higher peaks that are associated with adverse events and lower troughs that are associated with breakthrough seizures. An advantage of the sustained-release dosage form is that it lowers the peaks and raises the trough values of CBZ. It does appear that there are threshold values for individual patients that result in toxicity and loss of response.
Therapeutic ranges have been suggested for some drugs. In fact, these ranges would be more appropriately called 'target ranges' because a true therapeutic range is one where the patient has the desired response without adverse events. When the population 'target ranges' are used, some patients will have adverse events in the 'therapeutic range', some will respond satisfactorily with concentrations below the 'therapeutic range', and some will require concentrations above the 'therapeutic range' to achieve the desired clinical response. The true 'therapeutic range' is best determined for a given patient. The suggested 'therapeutic range' for CBZ is 4–12 µg/mL and the 'target range' for MHD is 12–30 µg/mL.
Given individual threshold values for adverse events and loss of response for a given patient, it is difficult to conclude that fluctuations would be less problematic for one drug than the other.