Carbamazepine substitution in severe partial epilepsy: implication of autoinduction of metabolism

1. Eight healthy subjects took part in a balanced, double‐blind, crossover comparison of conventional carbamazepine (Tegretol, Ciba‐ Geigy Ltd, CBZ‐C) and a novel controlled‐release formulation (Tegretol CR Divitabs, Ciba‐Geigy Ltd; CBZ‐CR). An initial single dose of either preparation was followed 1 week later by a 2 week course of 200 mg twice daily. 2. Following the single dose, CBZ‐CR produced a concentration plateau from 6‐56 h at 50‐60% of the CBZ‐CR peak. 3. After 2 weeks' treatment, CBZ daytime levels measured as area under the concentration‐time curve over a dosage interval were 7% lower with CBZ‐ CR, but this difference was not statistically significant. 4. CBZ‐CR showed less diurnal fluctuation (12%) of CBZ than CBZ‐C (24%; P less than 0.025) with less rapid changes in concentration (P less than 0.02). 5. Diurnal fluctuation of free CBZ and of CBZ 10,11 epoxide, the active metabolite, did not differ significantly between the two preparations. 6. Auto‐induction of CBZ metabolism resulted from the administration of both formulations. The mean elimination half‐life was 23 h (CBZ‐C) and 25 h (CBZ‐CR) after dose 29 compared with a base‐line value of 37 h (both P less than 0.02). Antipyrine metabolism was also induced to a similar extent in both legs of the study (P less than 0.01). 7. No significant alteration in psychomotor function was demonstrated with either preparation. 8. CBZ‐CR fulfils the criteria for a controlled‐release preparation with comparable apparent bioavailability to CBZ‐C. Further pharmacokinetic and, more importantly, pharmacodynamic studies are required in epileptic patients to confirm a clinical advantage over the currently available formulation.

Section: Discussionsupporting

confidence: 85%

A double‐blind comparison of conventional and controlled‐release carbamazepine in healthy subjects.

Larkin

McLellan

Munday

et al. 1989

“…Its major pathway of elimination is via the formation of CBZ 10,11 epoxide, although hydroxylation and direct N-glucuronidation also take place (Eichelbaum et al, 1985). CBZ displays dose-dependent hetero-and autoinduction , which may result in temporary loss of seizure control in some patients (Macphee & Brodie, 1985). Neurotoxic side effects such as diplopia, ataxia, dizziness and headache may manifest over a wide range of plasma concentrations (Hoppener et al, 1980;Blennow, 1983;Tomson, 1984;Macphee et al, 1986c).…”

Section: Analysesmentioning

confidence: 99%

Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

Macphee

Mitchell

Wiseman

et al. 1988

1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design.2 VPA alone had no effect on antipyrine clearance, urinary 6p-hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady-state concentration (90 ± 6 mg 1-1) well within the target range (50-100 mg I-1) for the drug.3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P < 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P < 0.02) and half-life of unbound CBZ 16% longer (P < 0.02) during VPA treatment. CBZ-10, 11 epoxide (CBZ-E) levels (52%) and CBZ-E/ CBZ ratios (45%) were both elevated by concurrent VPA (P < 0.05) and free CBZ fraction was increased by 7% (P < 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P < 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P < 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide. The effect of VPA on the psychomotor profile of a large single dose of CBZ was minimal. 6 Further studies in epileptic patients receiving both these anticonvulsant drugs are warranted to appraise the extent and clinical relevance of their interaction.

“…Hyponatraemia, on the other hand, may be as common with OXC as with CBZ (Nielson et al, 1988 An important drawback to the clinical use of CBZ is its ability to induce hepatic monooxygenase enzymes (Wagner & Schmid, 1987). Chronic dosing shortens its elimination half-life (Eichelbaum et al, 1975;Rapeport et al, 1983) thus reducing steady-state concentrations which occasionally results in breakthrough seizures (Macphee & Brodie, 1985). The extent of this process contributes to the three-fold variation in trough and peak plasma CBZ concentrations in patients receiving the same daily dose (Macphee et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

Larkin

Mckee

Forrest

et al. 1991

114

1 Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2 Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3 Antipyrine metabolism, urinary 6-,-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4 Elimination half-lives (mean ± s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 ± 1.1 h; after 13.9 ± 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 ± 2.2 ,umol 1-1) were higher than predicted (16.5 + 4 ,umol 1-1).5 Antipyrine metabolism, urinary 6-13-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6 OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.