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Oxcarbazepine extendedrelease formulation in epilepsy Expert Rev. Clin. Pharmacol. 2(2), 155–162 (2009)
Bernhard J Steinhoff Epilepsiezentrum Kork, Landstr. 1, D-77694 Kehl-Kork, Germany Tel.: +49 785 184 2250 Fax: +49 785 184 2555 [email protected]
Oxcarbazepine (OXC) is a 10-keto-analogue of carbamazepine, which was developed and labeled as a follow-up antiepileptic drug, that was intended to overcome some of the pharmacological drawbacks of carbamazepine with similar efficacy. The main advantage is the nonoxidative metabolic pathway that allows a lower enzyme-induction profile and fewer drug interactions. OXC is rapidly and extensively reduced by cytosolic hepatic enzymes to its monohydroxylated derivative (MHD), thus OXC may be regarded as a prodrug with MHD representing the active antiepileptic agent. The immediate-release (IR) formulation of OXC (Trileptal®, Timox®) has an almost complete bioavailibilty. It is rapidly absorbed and reaches peak concentrations after 1–3 h. MHD peak concentrations are measured within 4–12 h. Elimination half-life in healthy subjects is 1–5 h for OXC and 7–20 h for MHD. The OXC plasma concentration peak may have been responsible for side effects, such as dizziness, vertigo, coordination problems or blurred vision, which appeared more often with this formulation in individual cases than with the formulation available prior to 2000, or with another formulation that has been distributed in Scandinavian countries. Both possibilities offer a profile approaching the characteristics of an extended-release (ER) formulation. ER OXC was labeled in Germany in 2008 (Apydan® extent, Desitin Arzneimittel GmbH, Hamburg, Germany). Under steady-state conditions, Phase I studies show bioequivalence between IR and ER OXC. With ER OXC, OXC plasma peak concentrations and both OXC and MHD peak–trough fluctuations are markedly reduced. In clinical trials, comparisons between IR OXC twice daily versus ER OXC once daily failed to show significant differences; efficacy tended to be better with IR OXC, whereas OXC ER showed insignificant tolerability advantages. Another study is currently ongoing to compare the tolerability of both formulations under twice-daily administration conditions in patients with difficult-to-treat epilepsies who require a dosage increase of OXC and who are randomized to IR or ER OXC. Keywords : efficiency • epilepsy • extended release • immediate release • oxcarbazepine • tolerability
Oxcarbazepine (OXC; 10,11-dihydro-10-oxo5H-dibenz[b,f ]azepine-5-carboxamide) is a 10-keto-analogue of carbamazepine (CBZ) that was developed as a follow-up antiepileptic drug (AED) in order to overcome some of the pharmacological drawbacks of CBZ but still have comparable efficacy [1] . Compared with CBZ, the main advantage of OXC is the nonoxidative pathway that leads to a lower enzyme-induction potential and fewer and less extensive drug interactions [2–5] . Oxcarbazepine is rapidly and extensively reduced by cytosolic hepatic enzymes to the monohydroxylated derivative 10,11-dihydro-10hydro-carbamazepine (MHD) (Figure 1) [5,6] . This step is mediated by cytosolic arylketone reductases [6] . Owing to the rapid and almost complete presystemic first-pass conversion to MHD [5] , OXC may be regarded as a prodrug with MHD www.expert-reviews.com
10.1586/17512433.2.2.155
representing the active metabolite of OXC and, thus, the essential antiepileptic agent. The conversion to MHD is stereoselective and results approximately in a 1:4 ratio between the (R-) and the (S+) enantiomeres [7–9] . OXC and MHD exhibit linear phamacokinetics [10] . Protein binding is 60% for OXC and 40% for MHD [11] . OXC is excreted mainly by the kidneys [5,7] . The fecal excretion rate is below 5% [7] . Oxcarbazepine and MHD have been shown to block voltage-sensitive sodium channels [12] . Contrary to CBZ, they do not block sodium currents directly but block them based on voltage- and use-dependent limitations of action potential firing [13,14] . In addition, MHD reduced glutamatergic synaptic transmission and high-voltage-activated N-type calcium channels [14–16] . Similar to CBZ, MHD was reported to increase hyperpolarizing potassium
© 2009 Expert Reviews Ltd
ISSN 1751-2433
155
Drug Profile
A
Steinhoff
B
O
HO
N O
N NH2
O
NH2
Figure 1. (A) Oxcarbazepine and (B) its monohydroxylated derivative.
currents and to have NMDA-blocking capabilities, whereas no effects were demonstrated concerning serotonin, GABA receptors and acetylcholine receptors [13] . Monohydroxylated derivative inhibits the cytochrome P450 (CYP)2C19 in vitro [17] . It is a weak inducer of uridine diphosphate (UDP)-glucuronyltransferase (UDPGT) but is reported not to have a relevant effect on drugs or substances that are mainly eliminated by conjugation through UDPGT enzymes [6] . Strong enzyme inducers, such as carbamazepine, phenytoin (PHT) or phenobarbital, may reduce MHD levels by 30–40% [6] . OXC may increase the concentrations of PHT: at doses above 1200 mg, a 40% increase of PHT and a 15% increase of phenobarbital have been described [6] . OXC may decrease the concentrations of lamotrigine and topiramate [7] . Since the concentrations of ethynilestradiol and levonorgestrel may be lowered, the reliability of hormonal contraception is weakened under OXC intake [6,7] . The immediate-release (IR) formulation of OXC (Trileptal®, Timox®) has an almost complete bioavailibilty of 95% [6,7] . It is absorbed rapidly and reaches peak concentrations (Cmax) after 1–3 h. MHD peak concentrations occur within 4–12 h [7] . Elimination half-life in healthy subjects is 1–5 h for OXC and 7–20 h for MHD [7] . This formulation was labeled and distributed worldwide in the year 2000 as adjunctive therapy or monotherapy for patients with localization-related epilepsies with partial seizures with and without secondary generalization in adults and children [6] . This was after various controlled trials had demonstrated a similar efficacy compared with classical AEDs, such as CBZ, PHT or valproate (VPA), in monotherapy or as an add-on AED compared with other effective AEDs or with placebo in both adults and pediatric studies [18–27] . In newly diagnosed patients with focal seizures with and without secondary generalization, approximately 50–60% became seizure-free with OXC monotherapy [22,23,26] . OXC as an add-on AED has a dose-dependent effect: a reduction of the seizure frequency of all seizures by at least 50% was achieved in 27% with OXC 600 mg, in 42% with OXC 1200 mg and in 50% with OXC 2400 mg. The effect on secondary generalized tonic–clonic seizures (GTCS) was particularly convincing: the reduction rate of GTCS was 71% with OXC 600 mg, 86% with OXC 1200 mg and 94% with OXC 2400 mg. However, this dose-dependent effect was partially compensated by higher discontinuation rates due to side effects with increasing dosages, 156
which were 36% with OXC 1200 mg and 67% with add-on OXC 2400 mg [25] . The recommended dosage for monotherapy is 600–1200 mg/day. In difficult-to-treat patients, higher dosages may be necessary [28] . OXC has been further investigated and advocated in other indications, such as trigeminal neuralgia, neuropathic pain, borderline personality and affective disorders [1,16,29–32] . The most frequent adverse effects (
Oxcarbazepine extendedrelease formulation in epilepsy Expert Rev. Clin. Pharmacol. 2(2), 155–162 (2009)
Bernhard J Steinhoff Epilepsiezentrum Kork, Landstr. 1, D-77694 Kehl-Kork, Germany Tel.: +49 785 184 2250 Fax: +49 785 184 2555 [email protected]
Oxcarbazepine (OXC) is a 10-keto-analogue of carbamazepine, which was developed and labeled as a follow-up antiepileptic drug, that was intended to overcome some of the pharmacological drawbacks of carbamazepine with similar efficacy. The main advantage is the nonoxidative metabolic pathway that allows a lower enzyme-induction profile and fewer drug interactions. OXC is rapidly and extensively reduced by cytosolic hepatic enzymes to its monohydroxylated derivative (MHD), thus OXC may be regarded as a prodrug with MHD representing the active antiepileptic agent. The immediate-release (IR) formulation of OXC (Trileptal®, Timox®) has an almost complete bioavailibilty. It is rapidly absorbed and reaches peak concentrations after 1–3 h. MHD peak concentrations are measured within 4–12 h. Elimination half-life in healthy subjects is 1–5 h for OXC and 7–20 h for MHD. The OXC plasma concentration peak may have been responsible for side effects, such as dizziness, vertigo, coordination problems or blurred vision, which appeared more often with this formulation in individual cases than with the formulation available prior to 2000, or with another formulation that has been distributed in Scandinavian countries. Both possibilities offer a profile approaching the characteristics of an extended-release (ER) formulation. ER OXC was labeled in Germany in 2008 (Apydan® extent, Desitin Arzneimittel GmbH, Hamburg, Germany). Under steady-state conditions, Phase I studies show bioequivalence between IR and ER OXC. With ER OXC, OXC plasma peak concentrations and both OXC and MHD peak–trough fluctuations are markedly reduced. In clinical trials, comparisons between IR OXC twice daily versus ER OXC once daily failed to show significant differences; efficacy tended to be better with IR OXC, whereas OXC ER showed insignificant tolerability advantages. Another study is currently ongoing to compare the tolerability of both formulations under twice-daily administration conditions in patients with difficult-to-treat epilepsies who require a dosage increase of OXC and who are randomized to IR or ER OXC. Keywords : efficiency • epilepsy • extended release • immediate release • oxcarbazepine • tolerability
Oxcarbazepine (OXC; 10,11-dihydro-10-oxo5H-dibenz[b,f ]azepine-5-carboxamide) is a 10-keto-analogue of carbamazepine (CBZ) that was developed as a follow-up antiepileptic drug (AED) in order to overcome some of the pharmacological drawbacks of CBZ but still have comparable efficacy [1] . Compared with CBZ, the main advantage of OXC is the nonoxidative pathway that leads to a lower enzyme-induction potential and fewer and less extensive drug interactions [2–5] . Oxcarbazepine is rapidly and extensively reduced by cytosolic hepatic enzymes to the monohydroxylated derivative 10,11-dihydro-10hydro-carbamazepine (MHD) (Figure 1) [5,6] . This step is mediated by cytosolic arylketone reductases [6] . Owing to the rapid and almost complete presystemic first-pass conversion to MHD [5] , OXC may be regarded as a prodrug with MHD www.expert-reviews.com
10.1586/17512433.2.2.155
representing the active metabolite of OXC and, thus, the essential antiepileptic agent. The conversion to MHD is stereoselective and results approximately in a 1:4 ratio between the (R-) and the (S+) enantiomeres [7–9] . OXC and MHD exhibit linear phamacokinetics [10] . Protein binding is 60% for OXC and 40% for MHD [11] . OXC is excreted mainly by the kidneys [5,7] . The fecal excretion rate is below 5% [7] . Oxcarbazepine and MHD have been shown to block voltage-sensitive sodium channels [12] . Contrary to CBZ, they do not block sodium currents directly but block them based on voltage- and use-dependent limitations of action potential firing [13,14] . In addition, MHD reduced glutamatergic synaptic transmission and high-voltage-activated N-type calcium channels [14–16] . Similar to CBZ, MHD was reported to increase hyperpolarizing potassium
© 2009 Expert Reviews Ltd
ISSN 1751-2433
155
Drug Profile
A
Steinhoff
B
O
HO
N O
N NH2
O
NH2
Figure 1. (A) Oxcarbazepine and (B) its monohydroxylated derivative.
currents and to have NMDA-blocking capabilities, whereas no effects were demonstrated concerning serotonin, GABA receptors and acetylcholine receptors [13] . Monohydroxylated derivative inhibits the cytochrome P450 (CYP)2C19 in vitro [17] . It is a weak inducer of uridine diphosphate (UDP)-glucuronyltransferase (UDPGT) but is reported not to have a relevant effect on drugs or substances that are mainly eliminated by conjugation through UDPGT enzymes [6] . Strong enzyme inducers, such as carbamazepine, phenytoin (PHT) or phenobarbital, may reduce MHD levels by 30–40% [6] . OXC may increase the concentrations of PHT: at doses above 1200 mg, a 40% increase of PHT and a 15% increase of phenobarbital have been described [6] . OXC may decrease the concentrations of lamotrigine and topiramate [7] . Since the concentrations of ethynilestradiol and levonorgestrel may be lowered, the reliability of hormonal contraception is weakened under OXC intake [6,7] . The immediate-release (IR) formulation of OXC (Trileptal®, Timox®) has an almost complete bioavailibilty of 95% [6,7] . It is absorbed rapidly and reaches peak concentrations (Cmax) after 1–3 h. MHD peak concentrations occur within 4–12 h [7] . Elimination half-life in healthy subjects is 1–5 h for OXC and 7–20 h for MHD [7] . This formulation was labeled and distributed worldwide in the year 2000 as adjunctive therapy or monotherapy for patients with localization-related epilepsies with partial seizures with and without secondary generalization in adults and children [6] . This was after various controlled trials had demonstrated a similar efficacy compared with classical AEDs, such as CBZ, PHT or valproate (VPA), in monotherapy or as an add-on AED compared with other effective AEDs or with placebo in both adults and pediatric studies [18–27] . In newly diagnosed patients with focal seizures with and without secondary generalization, approximately 50–60% became seizure-free with OXC monotherapy [22,23,26] . OXC as an add-on AED has a dose-dependent effect: a reduction of the seizure frequency of all seizures by at least 50% was achieved in 27% with OXC 600 mg, in 42% with OXC 1200 mg and in 50% with OXC 2400 mg. The effect on secondary generalized tonic–clonic seizures (GTCS) was particularly convincing: the reduction rate of GTCS was 71% with OXC 600 mg, 86% with OXC 1200 mg and 94% with OXC 2400 mg. However, this dose-dependent effect was partially compensated by higher discontinuation rates due to side effects with increasing dosages, 156
which were 36% with OXC 1200 mg and 67% with add-on OXC 2400 mg [25] . The recommended dosage for monotherapy is 600–1200 mg/day. In difficult-to-treat patients, higher dosages may be necessary [28] . OXC has been further investigated and advocated in other indications, such as trigeminal neuralgia, neuropathic pain, borderline personality and affective disorders [1,16,29–32] . The most frequent adverse effects (
