US20100048538A1 - Therapeutical Uses of Eslicarbazepine - Google Patents

Therapeutical Uses of Eslicarbazepine Download PDF

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US20100048538A1
US20100048538A1 US12/522,535 US52253508A US2010048538A1 US 20100048538 A1 US20100048538 A1 US 20100048538A1 US 52253508 A US52253508 A US 52253508A US 2010048538 A1 US2010048538 A1 US 2010048538A1
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disorders
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eslicarbazepine
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Patricio Manuel Vieira Araújo Soares Da Silva
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Bial Portela and Cia SA
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Definitions

  • This invention relates to drug therapies. More particularly the invention relates to the therapeutical use of eslicarbazepine and eslicarbazepine acetate.
  • eslicarbazepine acetate means (S)-( ⁇ )-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide.
  • eslicarbazepine or S-licarbazepine means (S)-(+)-10,11-dihydro-10-hydroxy-5H dibenz/b,f/azepine-5-carboxamide.
  • Eslicarbazepine acetate (S)-( ⁇ )-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide, is a new drug currently being developed which is useful for the treatment of various conditions, such as, for example, epilepsy and affective brain disorders, as well as pain conditions and nervous function alterations in degenerative and post-ischemic diseases.
  • eslicarbazepine acetate is believed to avoid the production of certain toxic metabolites (such as, for example, epoxides) and to avoid the unnecessary production of enantiomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity (Almeida et al., 2005a; Almeida et al., 2005b; Almeida et al., 2002; Almeida et al., 2003; Almeida et al., 2004; Benes et al., 1999; Bialer et al., 2004; Soares-da-Silva, 2004).
  • toxic metabolites such as, for example, epoxides
  • eslicarbazepine acetate is almost entirely metabolized to the active metabolite eslicarbazepine (Almeida et al., 2005a; Almeida et al., 2005b).
  • the term “pharmacoresistant”, and variations thereon, will be understood to relate to a condition where the patient is not responsive to pharmaceutical treatment at all;
  • refractory will be understood to relate to a condition wherein the patient becomes progressively less responsive to their medication and, in the case of epilepsy, suffers from an increasing number of seizures; and the term “intractable”, and variations thereon, will be understood to signify difficult-to-treat or treatment(drug)-resistant and thus encompasses both pharmacoresistant and refractory conditions.
  • Resistance to pharmacological therapy is one of the major problems in the treatment of epilepsy (Löscher et al., 2004). Approximately one third of all epilepsy patients do not become seizure free, despite treatment with two or more antiepileptic drugs (AEDs) at a maximal tolerated dose. This intractability is even higher (50-70%) in patients with temporal lobe epilepsy (Kwan et al., 2000; Mohanraj et al., 2005; Schmidt et al., 2005; Stephen et al., 2006).
  • P-glycoprotein (P-gp or ABCB1 or MDR1) is the most extensively studied multidrug transporter. In fact, P-gp transports a variety of xenobiotics, including commonly used AEDs (Potschka et al., 2002; Potschka et al., 2001a; Potschka et al., 2001b; Rizzi et al., 2002; Sills et al., 2002).
  • P-glycoprotein P-gp or MDR1
  • MRP multidrug resistance protein
  • Epilepsy was the first CNS disorder for which drug resistance was associated with enhanced expression of multidrug transporters in the brain (Tishler et al., 1995).
  • the expression of multidrug transporters in the astroglial end-feet covering the blood vessels that are found in epileptogenic brain tissue might represent a ‘second barrier’ under these conditions (Abbott, 2002; Sisodiya et al., 2002).
  • AEDs which have been made lipophilic to allow them to penetrate the brain, are substrates for P-gp or MRPs in the BBB (Potschka et al., 2002; Potschka et al., 2001a; Potschka et al., 2003; Potschka et al., 2001b; Rizzi et al., 2002; Schinkel et al., 1996; Sills et al., 2002; Tishler et al., 1995).
  • the uptake of these drugs by the brain can be increased by knocking out or blocking P-gp.
  • the overexpression of these transporters in epileptogenic tissue is likely, therefore, to reduce the amount of drug that reaches the epileptic neurons. This is one plausible explanation for multidrug resistance in epilepsy (Sisodiya, 2003).
  • verapamil Because of its efficient efflux transport by P-gp at the BBB, verapamil itself does not penetrate into the brain (Kortekaas et al., 2005), so the improved seizure control observed both experimentally and clinically in response to co-administration of verapamil and AEDs is not secondary to the calcium channel-blocking effect of verapamil.
  • the promising clinical results of combined treatment with verapamil and AEDs (Summers et al., 2004)
  • Summers et al. went on to test combinations of AEDs and verapamil in other patients with drug-resistant epilepsy, again with a favourable outcome (for details see (Löscher et al., 2005a)).
  • Oxcarbazepine has been used either in monotherapy or in adjunctive therapy in patients with partial-onset seizures with or without secondary generalization (May et al., 2003; Schmidt et al., 2001; Shorvon, 2000; Tartara et al., 1993).
  • Oxcarbazepine undergoes rapid 10-keto reduction to a mixture of S-licarbazepine and R-licarbazepine the racemic mixture if which is usually referred as licarbazepine (10-hydroxy-10,11-dihydrocarbazepine, 10-OHCBZ, or MHD) (Faigle et al., 1990; Feldmann et al., 1978; Feldmann et al., 1981; Flesch et al., 1992; Schutz et al., 1986; Volosov et al., 1999).
  • licarbazepine (10-OHCBZ) was suggested not to cross the blood-brain barrier by simple diffusion, namely being a substrate of P-gp.
  • the level of expression of MDR1 was found to be inversely correlated with 10-OHCBZ concentration in the epileptic tissue (Marchi et al., 2005). It was concluded that P-gp may play a role in the resistance to oxcarbazepine by determining the attainment of insufficient concentrations of its active metabolite at neuronal targets (Marchi et al., 2005).
  • S-licarbazepine is not a substrate for P-glycoprotein (P-gp) or Multiple Resistant Proteins (MRPs). This discovery offers opportunities for the treatment of pharmacoresistant epilepsy, and other conditions.
  • P-gp P-glycoprotein
  • MRPs Multiple Resistant Proteins
  • inhibitors of P-gp or MRPs do not interfere with the brain penetration of the main active metabolite of eslicarbazepine acetate, S-licarbazepine, a discovery that offers opportunities for the treatment of pharmacoresistant epilepsy with eslicarbazepine acetate.
  • eslicarbazepine Due to the unexpected potential of eslicarbazepine, the main active metabolite of eslicarbazepine acetate, to not serve as a substrate for efflux pumps such as P-gp and MRP, and therefore not require adjunctive administration of a P-gp or MRP inhibitor these compounds are considered to offer advantages over other AEDs for the clinical management of difficult-to-treat patients afflicted with epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases.
  • eslicarbazepine or eslicarbazepine acetate in the manufacture of a medicament for treating a condition selected from epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases in circumstances where the use of a P-glycoprotein inhibitor or a Multiple Resistant Protein inhibitor would adversely affect the subject being treated.
  • the administration of the P-glycoprotein inhibitor, verapamil adversely affects subjects suffering from a heart condition.
  • the administration of eslicarbazepine or eslicarbazepine acetate to a patient suffering from a heart condition, and who is also suffering from one or more of said selected conditions mentioned above enables the selected condition or conditions to be treated effectively without the need for administering a P-glycoprotein inhibitor or a Multiple Resistant Protein inhibitor.
  • Examples of heart conditions which are adversely affected by the administration of verapamil include: Bradycardia; second and third degree atrioventricular block; heart failure; Wolff-Parkinson-White syndrome; patients using beta-blocker treatment.
  • Contra-indications for cyclosporine include but are not limited to: patients hypersensitive to cyclosporine, uncontrolled hypertension, premalignant skin lesions or current malignancies, chickenpox and herpes zoster, renal or hepatic impairment, patients suffering from any type of bacterial or viral infection.
  • Contra-indications for probenecid include but are not limited to: hypersensitivity to probenecid or colchicine, patients under 2 years of age, blood dyscrasias, uric acid kidney stones.
  • eslicarbazepine or eslicarbazepine acetate administered to a patient suffering from one of the contra-indicated conditions or falling into one of the contra-indicated categories listed above, and who is also suffering from one or more of epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases, enables this latter condition or conditions to be treated effectively without the need for administering a P-glycoprotein inhibitor or a Multiple Resistant Protein inhibitor.
  • eslicarbazepine acetate or eslicarbazepine in the manufacture of a medicament for treating a drug resistant condition selected from epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases, wherein the patient to be treated is suffering from a condition which requires administration of a drug which reacts adversely with a P-gp inhibitor or an MRP inhibitor.
  • P-glycoprotein inhibitors and Multiple Resistant Protein inhibitors include: cyclosporin, verapamil, valspodar, biricodar, probenecid, elacridar, tariquidar XR9576, zosuquidar LY335979, laniquidar R101933, ONT-093.
  • eslicarbazepine or eslicarbazepine acetate in the manufacture of a medicament for treating an intractable condition selected from epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases.
  • the intractable condition is, at least in part, caused by an overexpression of P-gp or MRP.
  • the intractable state of the condition is, at least in part, due to an overexpression of P-gp or MRP.
  • the intractable condition is a pharmacoresistant condition.
  • the intractable state of the condition is due to the patient's being resistant to treatment with a pharmaceutical which is not a substrate for P-gp or MRP.
  • the intractable condition is a pharmacoresistant condition.
  • the eslicarbazepine or eslicarbazepine acetate is administered as a monotherapy for treating said condition.
  • the eslicarbazepine or eslicarbazepine acetate is administered in the absence of a P-glycoprotein inhibitor, such as verapamil, or a Multiple Resistant Protein inhibitor, such as probenecid.
  • eslicarbazepine or eslicarbazepine acetate in combination with a second drug which reacts adversely with a P-glycoprotein inhibitor or a Multiple Resistant Protein inhibitor, in the manufacture of a medicament for treating a condition selected from epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases.
  • a condition selected from epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases.
  • the second drug may be a drug for the treatment of bradycardia; second and third degree atrioventricular block; heart failure; or Wolff-Parkinson-White syndrome; uncontrolled hypertension; premalignant skin lesions or current malignancies; chickenpox or herpes zoster; renal or hepatic impairment; any type of bacterial or viral infection; blood dyscrasias; or uric acid kidney stones.
  • the condition may be an intractable condition.
  • the intractable condition is, at least in part, caused by an overexpression of P-gp or MRP.
  • the intractable state of the condition is, at least in part, due to an overexpression of P-gp or MRP.
  • the intractable condition is a pharmacoresistant condition.
  • the intractable condition is a refractory condition.
  • the intractable state of the condition is due to the patient's being resistant to treatment with a pharmaceutical which is not a substrate for P-gp or MRP.
  • the intractable condition is a pharmacoresistant condition.
  • the intractable condition is a refractory condition.
  • the eslicarbazepine or eslicarbazepine acetate and the second drug are administered in the absence of a P-glycoprotein inhibitor, such as verapamil, or a Multiple Resistant Protein inhibitor, such as probenecid.
  • a P-glycoprotein inhibitor such as verapamil
  • a Multiple Resistant Protein inhibitor such as probenecid.
  • eslicarbazepine or eslicarbazepine acetate in combination with a drug to treat a heart condition, in the manufacture of a medicament for treating said heart condition and a further condition selected from epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases.
  • the drug for treating the heart conditions may be a drug for the treatment of bradycardia; second and third degree atrioventricular block; heart failure; or Wolff-Parkinson-White syndrome.
  • eslicarbazepine or eslicarbazepine acetate in combination with a drug to treat one or more of the following conditions: uncontrolled hypertension, premalignant skin lesions or current malignancies, chickenpox and herpes zoster, renal or hepatic impairment, any type of bacterial/viral infection, blood dyscrasias, and uric acid kidney stones, in the manufacture of a medicament for treating said condition and a further condition selected from epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases.
  • the epilepsy, central and peripheric nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, and nervous function alterations in degenerative and post-ischemic diseases may be intractable, which intractable state may be caused by overexpression of P-gp and/or MRP.
  • the intractable condition is a pharmacoresistant condition.
  • the intractable condition is a refractory condition.
  • the intractable state of the condition is due to the patient's being resistant to treatment with a pharmaceutical which is not a substrate for P-gp or MRP.
  • the intractable condition is a pharmacoresistant condition.
  • the intractable condition is a refractory condition.
  • a pharmaceutical composition comprising eslicarbazepine acetate or eslicarbazepine in combination with a drug which reacts adversely with a P-glycoprotein inhibitor or a Multiple Resistant Protein inhibitor, and a pharmaceutically acceptable carrier.
  • the drug which reacts adversely with a P-glycoprotein inhibitor or a Multiple Resistant Protein inhibitor may be a drug for the treatment of bradycardia; second and third degree atrioventricular block; heart failure; or Wolff-Parkinson-White syndrome; uncontrolled hypertension, premalignant skin lesions or current malignancies, chickenpox and herpes zoster, renal or hepatic impairment, any type of bacterial/viral infection, blood dyscrasias, and uric acid kidney stones.
  • a pharmaceutical composition comprising eslicarbazepine acetate or eslicarbazepine in combination with a drug for treating one or more of the following conditions: a heart condition, uncontrolled hypertension, premalignant skin lesions or current malignancies, chickenpox and herpes zoster, renal or hepatic impairment, any type of bacterial/viral infection, blood dyscrasias, and uric acid kidney stones, and a pharmaceutically acceptable carrier.
  • the drug for treating the heart condition may be a drug for the treatment of bradycardia; second and third degree atrioventricular block; heart failure; or Wolff-Parkinson-White syndrome.
  • the pharmaceutical composition may be formulated in any suitable manner, such as an oral dosage form, such as a tablet or capsule.
  • eslicarbazepine or eslicarbazepine acetate may be used to treat a variety of conditions which have previously proved difficult to treat with medicaments that are substrates for P-glycoprotein or Multiple Resistant Proteins.
  • treatment and variations such as ‘treat’ or ‘treating’ refer to any regime that can benefit a human or non-human animal.
  • the treatment may be in respect of an existing condition or may be prophylactic (preventative treatment). Treatment may include curative, alleviation or prophylactic effects.
  • eslicarbazepine and eslicarbazepine acetate are useful to treat patients who suffer from a relapse after treatment with one or more pharmaceutical, i.e. refractory conditions, and also those who are unresponsive to treatment with any pharmaceutical, i.e. pharmacoresistant conditions.
  • eslicarbazepine and eslicarbazepine acetate would be useful in the treatment of subjects having more than 4 seizures per week despite with treatment with one or more antiepileptic drug.
  • eslicarbazepine and eslicarbazepine acetate would be useful in the treatment of subjects suffering from a relapse after administration of one or more pharmaceutical which is a P-gp or MRP transporter substrate (e.g. carbamazepine, oxcarbazepine).
  • a pharmaceutical which is a P-gp or MRP transporter substrate (e.g. carbamazepine, oxcarbazepine).
  • eslicarbazepine and eslicarbazepine acetate would be useful in the treatment of subjects suffering from a relapse after administration of one or more analgesic which is P-gp or MRP transporter substrate (e.g. carbamazepine, oxcarbazepine).
  • analgesic which is P-gp or MRP transporter substrate (e.g. carbamazepine, oxcarbazepine).
  • the invention also encompasses methods of treating the conditions mentioned above, which involve administering a therapeutically effective amount of the active ingredient or ingredients to a subject in need thereof.
  • the subject treated in accordance with the invention is preferably a human subject.
  • Medical conditions that can be treated with either eslicarbazepine acetate or S-licarbarzepine with no need for adjunctive therapy with P-gp or MRP blockers include:
  • FIG. 1 is a graph showing the brain/plasma ratio (Cmax and AUC) for S-licarbazepine and R-licarbazepine;
  • FIG. 2 shows the effect of probenecid and verapamil on the brain plasma ratio for S-licarbazepine and R-licarbazepine
  • FIG. 3 shows the effect of verapamil and probenecid on the S-licarbazepine brain/plasma ratio after the administration eslicarbazepine acetate
  • FIG. 4 shows the effect of twice daily treatment with S-licarbazepine on acquisition of kindling
  • FIG. 5 shows the effect of twice daily treatment with R-licarbazepine on acquisition of kindling
  • FIG. 6 shows formalin paw test data for S-licarbazepine, R-licarbazepine and gabapentin.
  • mice weighing 30-35 g were maintained under controlled environmental conditions (23-24° C.) for at least 5 days before the experiment. All animals interventions were performed in accordance with the European Directive number 86/609, and the rules of the “Guide for the Care and Use of Laboratory Animals”, 7th edition, 1996, Institute for Laboratory Animal Research (ILAR), Washington, D.C. In the first series of experiments mice were given by gastric tube S-licarbazepine or R-licarbazepine (350 mg/kg). Blood and brain samples were obtained at 12 different timepoints (15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 10 h, 16 h, 24 h, 48 h and 72 h) after drug administration.
  • mice pre-treated with vehicle, verapamil (20 mg/kg) or probenecid (100 mg/kg) were given 30 min later intraperitoneally S-licarbazepine or R-licarbazepine (100 mg/kg).
  • Probenecid has been shown to inhibit both MRP1 and MRP2 (Gerk et al., 2002; Scheffer et al., 2002), but also inhibits organic anion transporters.
  • P-gp and MRP1/2 inhibitors are more selective P-gp and MRP1/2 inhibitors exist, verapamil and probenecid are widely used standard inhibitors of these multidrug transporters. After collection of blood, plasma was obtained by centrifugation.
  • Brain samples were homogenised in phosphate buffer (pH 5; 4 mL/g) followed by centrifugation and collection of the supernatant. Plasma and the tissue supernatant were stored frozen until analysis.
  • the assay of S-licarbazepine and R-licarbazepine was performed using a HPLC-UV or LC-MS method following solid phase extraction.
  • the following pharmacokinetic parameters for S-licarbazepine and R-licarbazepine were derived by non-compartmental analysis from the concentration versus time profiles: maximum observed plasma drug concentration (Cmax), time at which the Cmax occurred (tmax), area under the plasma concentration versus time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t) and AUC from time zero to infinity (AUC0- ⁇ ), elimination half-life (t1 ⁇ 2) and mean residence time (MRT).
  • the pharmacokinetic parameters were determined using WinNonlin (version 4.0).
  • Seizure severity was ranked according to a modified system of Racine (Racine, 1972): 1, mild facial clonus and eye blinking; 2, severe facial clonus, head nodding, chewing; 3, unilateral or alternating forelimb clonus; 4, bilateral forelimb clonus with rearing and falling; 5, bilateral forelimb clonus with rearing and falling; 6, tonic fore- and/or hindlimb extension.
  • the method which detects analgesic/anti-inflammatory activity, follows that described by Wheeler-Aceto et al (Wheeler-Aceto et al., 1991).
  • NMRI mice were given an intraplantar injection of 5% formalin (25 ⁇ l) into the posterior left paw. This treatment induced paw licking in control animals. The time spent licking was counted for 15 minutes, beginning 15 minutes after injection of formalin. 10 mice were studied per group. The test was performed blind.
  • S-Licarbazepine and R-licarbazepine were tested at the dose of 100 mg/kg p.o., administered 120 minutes before the test (i.e. 100 minutes before formalin), and compared with a vehicle control group in each experiment.
  • both S-licarbazepine and R-licarbazepine are rapidly absorbed after oral administration with Cmax in plasma attained at 15 min (tmax). After the administration of S-licarbazepine only S-licarbazepine is found in plasma, whereas after the administration of R-licarbazepine small amounts of S-licarbazepine were found to be detectable in plasma though the major circulating material is R-licarbazepine (Table 1).
  • the brain/plasma ratio (considering either Cmax or AUC), the S-licarbazepine brain/plasma ratio was considerably greater than the R-licarbazepine brain/plasma. This clearly indicates that there is stereoselectivity in the process of crossing the blood-brain barrier.
  • mice were pretreated with verapamil or probenecid. As shown, in FIG. 2 , verapamil and probenecid failed to affect the S-licarbazepine brain/plasma ratio. By contrast, verapamil, but not probenecid, markedly increased the R-licarbazepine brain/plasma ratio ( FIG. 2 ). This indicates that S-licarbazepine is not a substrate for both P-gp and MRP, whereas R-licarbazepine is a substrate for P-gp, but not for MRP. It is interesting to underline the fact that the R-licarbazepine brain/plasma ratio after verapamil equals that of S-licarbazepine in vehicle-treated animals ( FIG. 2 ).
  • verapamil and probenecid failed to affect the S-licarbazepine brain/plasma ratio after the administration eslicarbazepine acetate (100 mg/kg, i.p.).
  • seizure severity scores were compared between R-licarbazepine treated animals and control animals, no significant differences were determined except for one stimulation session, i.e. the stimulation in the afternoon of day 8. The number of stimulations necessary to induce a seizure with a severity score of 3, 4, 5, and 6 did not differ between treated mice and control mice ( FIG. 5 ).
  • treatment was terminated at day 12 100% of the vehicle-treated animals and all of the treated animals had reached the kindling criterion, i.e. at least one generalized seizure (score 4-6). During the course of the experiment no adverse effects were obvious in R-licarbazepine treated animals.
  • Plasma PK after S-Licarbazepine after R-Licarbazepine Parameters S-Lic R-Lic S-Lic R-Lic tmax (h) 0.25 NC 0.25 0.25 Cmax (ng/mL) 41304 NC 1024 69946 AUC0-t (ng ⁇ h/mL) 186669 NC 4582 203705 AUC0- ⁇ (ng ⁇ h/mL) 258278 NC NC 231716 t1 ⁇ 2 (h) 7.93 NC NC 8.11 MRT (h) 11.71 NC NC 10.12 NC not calculated due to absence of measurable concentrations of the analyte.
  • PK pharmacokinetic parameters for S-licarbazepine and R-licarbazepine after the oral administration of 350 mg/kg S-licarbazepine or 350 mg/kg R-licarbazepine to CD-1 mice.
  • Brain PK after S-Licarbazepine after R-Licarbazepine Parameters S-Lic R-Lic S-Lic R-Lic tmax (h) 1.00 NC NC 0.75 Cmax (ng/mL) 12308 NC NC 8533 AUC0-t (ng ⁇ h/mL) 108610 NC NC 51516 AUC0- ⁇ (ng ⁇ h/mL) 111302 NC NC NC 60037 t1 ⁇ 2 (h) 4.87 NC NC NC 7.91 MRT (h) 7.84 NC NC 11.34 NC not calculated due to absence of measurable concentrations of the analyte.
  • AEDs that fall into the category of P-gp or MRP substrates include all major voltage-gated sodium channel blockers that are the mainstay treatment of monotherapy and adjunctive therapy of patients afflicted with epilepsy, such as phenyloin, phenobarbital, carbamazepine, oxcarbazepine, felbamate and lamotrigine.
  • Levetiracetam is an exception that has been reported not to be a substrate for either P-gp or MRP1/2, as suggested by the finding that neither inhibition of P-gp nor MRP1/MRP2 by verapamil and probenecid, respectively, increased the brain penetration of levetiracetam.
  • Eslicarbazepine acetate administered once-daily, was demonstrated to be very efficacious in partial epilepsy refractory patients (Maia et al., 2004), a characteristic that may relate to the preferential metabolism into S-licarbazepine, escaping drug efflux transporters, such as P-gp and MRP. It should be underlined that approximately 25% became seizure free 1 month after initiation of eslicarbazepine acetate therapy (Almeida et al., 2007).
  • P-gp and/or MRP inhibitors to overcome drug resistance and facilitate access to organs and cells that express high levels of these transporters is still a matter of debate.
  • inhibition of P-gp and/or MRP may facilitate drug transfer of P-gp and MRP substrates, it may also compromise safety, since these transport restrict to a major extent the access to a wide range of xenobiotics, some of which are endowed with considerable unwanted effects (Schinkel et al., 2003; Schinkel et al., 1996).
  • drugs such as eslicarbazepine acetate and S-licarbazepine, which are not substrate for P-gp and/or MRP, rather than use drugs that transported through transporters, such as R-licarbazepine, phenyloin, phenobarbital, carbamazepine, oxcarbazepine, felbamate and lamotrigine, in combination with P-gp and/or MRP inhibitors.

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