Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects

Volosov, Andrew; Xiao-dong, Sun; Perucca, Emilio; Yagen, Boris; Sintov, Amnon; Bialer, Meir

doi:10.1053/cp.1999.v66.103170001

Cited by 79 publications

(48 citation statements)

References 18 publications

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“…Oxcarbazepine is rapidly and extensively metabolized to a mixture of the S(+)and R(-)-licarbazepine, 17 with both appearing in plasma and urine in the proportion of approximately 4/ 1. [18][19][20] Considering that BIA 2-093 gives origin to the S(+) and not the R(-) form of racemic licarbazepine, 9 and oxcarbazepine represents approximately 1% of metabolites of BIA 2-093 (present results), a low enantiomeric dilution is likely to occur after administration of BIA 2-093. Studies are in progress to determine in humans the proportion of S(+) and R(-) enantiomers of racemic licarbazepine after administration of BIA 2-093.…”

Section: Discussionmentioning

confidence: 63%

Safety, Tolerability, and Pharmacokinetic Profile of BIA 2‐093, a Novel Putative Antiepileptic, in a Rising Multiple‐Dose Study in Young Healthy Humans

Almeida

Soares-da-Silva

2004

The Journal of Clinical Pharma

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This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (+/-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t(max)) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R(O), calculated from AUC(0-tau) (day 8)/AUC(0-tau) (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.

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Section: Discussionmentioning

confidence: 63%

Safety, Tolerability, and Pharmacokinetic Profile of BIA 2‐093, a Novel Putative Antiepileptic, in a Rising Multiple‐Dose Study in Young Healthy Humans

Almeida

Soares-da-Silva

2004

The Journal of Clinical Pharma

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“…Pharmacokinetic parameters of eslicarbazepine, R-licarbazepine, and oxcarbazepine following the last dose of a repeated-dose regimen of once-daily 1,200-mg ESL and twice-daily 600-mg OXC to healthy volunteers (plasma profile: n = 7 in each group; CSF profile: n = 6 in each group) Data are given as arithmetic mean ± SD (median and range for t max ). T 1/2 is not stated for OXC administration as the duration of sampling was limited to 12 h. (Volosov et al, 1999). The proportions between eslicarbazepine and R-licarbazepine in the CSF did not differ substantially from those reported in plasma.…”

Section: Discussionmentioning

confidence: 99%

Steady‐state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers

et al. 2012

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SUMMARYPurpose: To evaluate the pharmacokinetics and tolerability of once-daily eslicarbazepine acetate (ESL) and twicedaily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. Methods: Single-center, open-label, randomized, parallelgroup study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1-3 and 1,200 mg on days 4-9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1-3 and 600 mg on days 4-9, twice daily. Plasma and CSF sampling was performed following the last dose. Key Findings: Eslicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both eslicarbazepine (ESL = 1.5; OXC = 1.2) and R-licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively. Significance: In comparison to OXC, administration of ESL resulted in more eslicarbazepine, less R-licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of eslicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supports once-daily dosing of ESL.

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“…9 Oxcarbazepine is rapidly and extensively metabolized to a mixture of the S-and R-licarbazepine, 10 both appearing in plasma and urine in the proportion of approximately 4:1. [11][12][13] Substantial differences in the disposition of oxcarbazepine between young and elderly volunteers were found both for C max and AUC parameters. C max and AUC of the mixture of the S-and Rlicarbazepine, the active metabolite of oxcarbazepine (also know as MHD), were 30% to 60% higher in elderly subjects (60-82 years of age) than in younger subjects (18-32 years of age).…”

Section: Pharmacokinetics Of Eslicarbazepine Acetatementioning

confidence: 99%

Single‐Dose and Steady‐State Pharmacokinetics of Eslicarbazepine Acetate (BIA 2–093) in Healthy Elderly and Young Subjects

Almeida

Falcão

Maia

et al. 2005

The Journal of Clinical Pharma

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Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects

Abstract: The marked differences in serum levels and urinary excretion between the two enantiomers of 10-hydroxycarbazepine are likely to be related primarily to stereoselective presystemic metabolic keto-reduction of the prochiral carbonyl group of the oxcarbazepine molecule.

Cited by 79 publications

References 18 publications

Safety, Tolerability, and Pharmacokinetic Profile of BIA 2‐093, a Novel Putative Antiepileptic, in a Rising Multiple‐Dose Study in Young Healthy Humans

Safety, Tolerability, and Pharmacokinetic Profile of BIA 2‐093, a Novel Putative Antiepileptic, in a Rising Multiple‐Dose Study in Young Healthy Humans

Steady‐state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers

Single‐Dose and Steady‐State Pharmacokinetics of Eslicarbazepine Acetate (BIA 2–093) in Healthy Elderly and Young Subjects

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