Administration Of Carbamazepine Research Articles

Carbamazepin-Hypersensitivitätssyndrom mit Leukopenie und Hepatitis – Kasuistik zweier Fälle

Drug hypersensitivity syndrome is a severe form of hypersensitivity to the antiepileptic agent carbamazepine, particularly in presence of visceral and hematological manifestations that must be evidenced and treated in time. Two cases of female patients with carbamazepine-induced hypersensitivity syndrome are reported. Both patients had prominent general complaints (febricity, weakness). The first patient had leukopenia, lymphadenopathy and rash, while the other one had urticaria, angioedema and hepatitis after administration of carbamazepine. Hypersensitivity reactions induced by antiepileptics widely applied in the practice may be severe and life-threatening if blood elements are involved via the immune or nonimmune mechanisms and if they result in hepatitis.

Influence of Coadministered Antiepileptic Drugs on Serum Antiepileptic Drug Concentrations in Epileptic Patients — Quantitative Analysis Based on Suitable Transforming Factor

AbstractFor Abstract see ChemInform Abstract in Full Text.

An open-label, fixed sequence, two period study to evaluate the potential induction of GW572016 metabolism by carbamazepine

3081 Background: GW572016 is an oral, dual EGFR/ErbB2 tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer growth. In vitro studies indicate that GW572016 is metabolized predominantly by CYP3A4 and CYP3A5, and to lesser extent by CYP2C19. Therefore, the potential for a drug-drug interaction exists when GW572016 is co-administered with drugs that modulate CYP3A4 activity. The objective of this study was to assess the effect of carbamazepine (CBZ), an inducer of CYP3A4, on the pharmacokinetics (PK) of GW572016. Methods: This was an open-label, fixed sequence, two period crossover study in healthy adult subjects. In Period 1, subjects received a single oral dose of 250 mg GW572016, followed by a 1-week washout period. During Period 2, subjects received CBZ 100 mg BID for Days 1–3 and 200 mg BID for Days 4–20. On Day 21, a single oral dose of GW572016 was co-administered with CBZ and plasma samples for PK analysis of GW572016 were obtained over a 48-hour period. Results: Twenty-four subjects (2 F: 22 M), median age 34.5 years (range 20–47 years) were enrolled in this study. Geometric least square means and 90% confidence interval estimates for AUCinf,Cmax and t1/2 ratios are listed in the table below. Carbamazepine treatment resulted in a 72% and 58% decrease in the GW572016 AUCinf and Cmax, respectively. There was no statistically significant effect of CBZ on the half-life of GW572016. Conclusion: In conclusion, exposure following a single oral dose of GW572016 was reduced after administration of CBZ for 21 days. Dose adjustment may be necessary to avoid therapeutic failure when GW572016 is co-administered with CYP3A4 inducers such as CBZ. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline

Influence of coadministered antiepileptic drugs on serum antiepileptic drug concentrations in epileptic patients -quantitative analysis based on suitable transforming factor

We conducted a study to clarify the most suitable transforming factor related to the daily dose of antiepileptic drugs (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C(t) was revealed to be dependent on only one variable in terms of the transformed daily dose (D'). C(t) was proportional to the power function of D' for VPA and CBZ and was linearly proportional to D' for ZNS and PB. The L/D ratio is expressed as a linear function of C(t) for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C(t) of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C(t) to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C(t) to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0.80, respectively. VPA, CBZ, and PHT significantly increased (P<0.05) the L/D ratio of PB to 1.47, 1.18, and 1.19, respectively. The daily PHT dose was decreased to 0.89, 0.91, 0.90, and 0.84 the dose of PHT alone to maintain C(t) in the therapeutic range when VPA, CBZ, ZNS, and PB were coadministered, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated C(t) values were calculated using the value of each alteration ratio and compared with the measured ones. Each mean of prediction error was about 20%. Our results appear valid and these alteration ratios should be available for clinical use.

The effect of carbamazepine on human corticomuscular coherence

EEG recordings from motor cortex show oscillations at approximately 10 and 20 Hz. The 20-Hz oscillations are coherent with contralateral EMG; in most studies those at 10 Hz are not. However, significant 10-Hz coherence has recently been reported in a group of epileptic patients, all of whom were taking the anticonvulsant drug carbamazepine (CBZ). In a double blind study, we investigated the effects of CBZ on corticomuscular coherence in eight healthy human subjects (all male). Subjects performed a precision grip task against an auxotonic load, whilst left sensorimotor EEG and EMGs from five muscles in the right hand and forearm were recorded. CBZ (100 mg) or a placebo was then given orally, and 6 h later subjects were re-tested. One week separated CBZ and placebo experiments in each subject. Coherence averaged across subjects and muscles during the hold phase of the task was maximal at 21 Hz; it increased significantly ( P < 0.05, Z-test) by 89% after CBZ administration. This was significantly greater than a much smaller increase following placebo, which itself may reflect an effect of the time of day when experiments were performed. There was no significant approximately 10-Hz coherence either before or after CBZ administration. CBZ did not significantly alter EEG power at either 10 or 20 Hz. Recently, we showed that diazepam markedly increases the power of approximately 20-Hz motor cortical oscillations with little effect on coherence. We show here that CBZ raises coherence without altering EEG power. This pharmacological dissociation may indicate an important role for corticomuscular coherence in motor control.

Assessment of copper status in epileptic patients treated with anticonvulsant drugs by measuring the specific oxidase activity of ceruloplasmin

Significant increases in serum levels and decreases in hair copper levels have been previously described in epileptic patients treated with anticonvulsant drugs. A condition not directly related to copper nutriture, such as chronic treatment with these drugs, could increase the serum concentrations of copper and ceruloplasmin and would mask a possible copper deficiency produced by drug-increased biliary copper excretion. Serum immunoreactive ceruloplasmin concentration and its oxidase activity were determined in 90 adult epileptic patients treated with phenobarbital ( n=60), phenytoin ( n=70), carbamazepine ( n=33) and valproic acid ( n=8). The levels of ceruloplasmin and oxidase activity were significantly higher ( P<0.001) than in an age and gender-matched control group ( n=49). The significant correlations ( P<0.01) between ceruloplasmin and the urinary excretion of d-glucaric acid, serum gamma-glutamyltransferase (GGT) and drug score in the patients group, would suggest that phenobarbital-type enzyme-inducing agents may increase the hepatic synthesis of ceruloplasmin. In 11 patients with a β-globulin migrating GGT isoform (GGT3), a sensitive marker of cholestasis, the levels of ceruloplasmin, oxidase activity and total GGT activity were significantly higher ( P<0.05) than in the group of 79 patients without the GGT3 isoform; consequently, in some cases a drug-induced cholestasis may also contribute to the increase of serum copper and ceruloplasmin. The values obtained for the specific oxidase activity of ceruloplasmin (activity per unit mass of enzyme protein) suggest that in the most of the cases, chronic administration of phenobarbital, phenytoin, carbamazepine or valproic acid, does not produce marginal or moderate copper deficiency.

Pharmacological Biotin Supplementation Maintains Biotin Status and Function in Rats Administered Dietary Carbamazepine

Biotin status and function are decreased during oral carbamazepine (CBZ) administration in both humans and rats, but it is not known whether biotin supplementation can prevent these decreases. To test the effectiveness of pharmacologic biotin supplementation during CBZ administration, 55 rats were randomly divided into 4 groups (0.06 mg biotin/kg diet +/- 3.75 g CBZ/kg diet and 6.0 mg biotin/kg diet +/- 3.75 g CBZ/kg diet). CBZ and biotin-supplemented diets began on d 5 and 26, respectively, and continued through d 68. Rats (n = 5/group) were killed on d 5, 26, 47 or 68. CBZ reduced serum and liver free biotin (P < 0.05), whereas biotin supplementation during CBZ administration maintained biotin status. CBZ also decreased specific activities and abundance of biotinylated pyruvate and acetyl CoA carboxylases (PC and ACC, P < 0.05) in brain and liver, whereas biotin supplementation prevented these decreases for ACC. Specific activity of PC was maintained upon biotin supplementation, but the abundance of biotinylated PC remained significantly decreased. Brain and serum lactate were elevated after 68 d of CBZ treatment and were reduced to control lactate concentrations upon biotin supplementation (P < 0.05). Conversion of lactate to pyruvate and simultaneous generation of NADH during biotin supplementation could explain how increases in PC activity occur without changes in the abundance of biotinylated PC because we found NADH to be an activator of PC activity in vitro. These results support the use of biotin supplementation as a concurrent strategy during CBZ administration to help maintain biotin status, function of biotin-dependent enzymes and decrease CBZ-induced lactate accumulation.

Dietary Carbamazepine Administration Decreases Liver Pyruvate Carboxylase Activity and Biotinylation by Decreasing Protein and mRNA Expression in Rats

Clinical data demonstrate that certain antiepileptic drugs including carbamazepine (CBZ) decrease serum biotin concentration 45-50% and increase urine and serum organic acids, which is suggestive of reduced function of biotin-dependent enzymes. However, little is known about biotin-dependent enzyme function at the tissue level in patients undergoing long-term CBZ treatment. We recently established that dietary CBZ administration to rats increases brain lactate and also decreases specific enzymatic activity and the relative abundance of hepatic biotinylated pyruvate carboxylase (PC). To examine the mechanism of altered activity and abundance of biotinylated PC, the effect of orally administered CBZ on hepatic PC protein and mRNA expression was examined in rats consuming a physiologically relevant level of dietary biotin (0.06 mg/kg). Rats were fed 0 or 3.4 g CBZ/kg diet for 28 d, a dose designed to achieve clinically relevant serum CBZ concentrations. Hepatic biotinylated PC and PC activity were significantly reduced by approximately 43 and 30%, respectively, in the drug-treated group. Liver PC protein expression and mRNA were approximately 43 and 35% lower, respectively, in the drug-treated group than in controls. Brain biotinylated PC was significantly lower (29%), whereas specific enzymatic activity was 175% higher in rats consuming the 3.4 g CBZ/kg diet. Brain, but not serum, lactate was significantly higher in rats consuming CBZ. Taken together, the lower PC protein and mRNA expression provide a plausible biochemical mechanism to explain the decreased abundance of biotinylated hepatic PC observed in previous studies.

Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones.

Administration of carbamazepine (CBZ) causes hypersensitivity reactions clinically characterized by skin involvement, eosinophilia, and systemic symptoms. These reactions have an immune etiology; however, the role of T cells is not well defined. The aim of this study was to characterize the specificity, phenotype, and cytokine profile of CBZ-specific T cells derived from hypersensitive individuals. Proliferation of blood lymphocytes was measured using the lymphocyte transformation test. CBZ-specific T cell clones were generated by serial dilution and characterized in terms of their cluster of differentiation and T cell receptor V beta phenotype. Proliferation, cytotoxicity, and cytokine secretion were measured by [(3)H]thymidine incorporation, (51)Cr release, and enzyme-linked immunosorbent assay, respectively. HLA blocking antibodies were used to study the involvement of antigen-presenting cells. The specificity of the drug T cell receptor interaction was studied using CBZ metabolites and other structurally related compounds. Lymphocytes from hypersensitive patients (stimulation index: 32.1 +/- 24.2 [10 microg ml(-1)]) but not control patients (stimulation index: 1.2 +/- 0.4 [10 microg ml(-1)]) proliferated upon stimulation with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for further analysis. All 10 clones were either CD4+ or CD4+/CD8+, expressed the alpha beta T cell receptor, secreted IFN-gamma, and were cytotoxic. T-cell recognition of CBZ was dependent on the presence of HLA class II (DR/DQ)-matched antigen-presenting cells. The T cell receptor of certain clones could accommodate some CBZ metabolites, but no cross-reactivity was seen with other anticonvulsants or structural analogs. These studies characterize drug-specific T cells in CBZ-hypersensitive patients that are phenotypically different from T cells involved in other serious cutaneous adverse drug reactions.

Lipoprotein(a) concentration increases during treatment with carbamazepine.

Treatment with carbamazepine (CBZ) is known to affect apolipoprotein B-containing lipoprotein concentrations in serum. However, little is known about the effects of anticonvulsant drugs (AEDs) on lipoprotein(a) [Lp(a)], although Lp(a) has been characterized as independent cardiovascular risk factor. We investigated prospectively the effect of CBZ on lipoprotein(a) concentration in normolipidemic healthy adults. Twenty male volunteers were included in the study. Lp(a) levels were determined before and 69 +/- 19 days after CBZ administration by using an enzyme-linked immunoassay. CBZ (mean plasma concentration, 6.6 +/- 0.6 microg/ml) caused a significant increase in Lp(a) concentrations, with a median change of +19.5% (95% CI: +8.2, +53.3; p < 0.001). Total cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides also increased significantly. Although the precise mechanism of action of CBZ on Lp(a) elevation remains uncertain, it might be related to its enzyme-inducing properties. During treatment with CBZ, special focus should be given to elevated LDL cholesterol and Lp(a) concentrations with regard to increased risk for atherosclerotic vascular diseases.

Half Pitch Lower Sound Perception Caused by Carbamazepine

We report a 16-year-old woman with secondary generalization of partial seizure, who complained of an auditory disturbance after carbamazepine (CBZ) administration. She had been taking sodium valproate (VPA) from the age of 15. However, her seizures remained poorly controlled. We changed her antiepileptic drug from VPA to CBZ. At 1 week after CBZ administration, she noticed that electone musical performances were heard as a semitone lower. When oral administration of CBZ was stopped, her pitch perception returned to normal. If she had not been able to discern absolute pitch, she might have been unable to recognize her lowered pitch perception. Auditory disturbance caused by CBZ is reversible and very rare.

Effects of concomitant antiepileptic drugs on serum carbamazepine concentration in epileptic patients: quantitative analysis based on extracellular water volume as a transforming factor.

The effects of concomitant antiepileptic drugs on the serum carbamazepine concentration (C1) were analyzed quantitatively. Primidone (PRM), phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS), clonazepam (CZP), and ethosuximide (ETS) were coadministered with carbamazepine (CBZ). Routine therapeutic drug monitoring data, obtained from epileptic patients who were treated with the repetitive oral administration of CBZ fine granules/tablets, were used for the analysis. A total of 119 patients were administered CBZ alone, and 91, 39, 19, and 6 patients were coadministered one, two, three, and more than four different antiepileptic drugs, respectively. Using the data obtained from the patients administered CBZ alone, Ct could be expressed approximately as a function of the daily dose per extracellular water volume (D/VECW) as Ct = A(D/VECW)B (A, B: parameter). By comparing the regression line on log Ct vs. log(D/VECW) for CBZ alone with that for CBZ plus another concomitant drug, Ct was thus found to be affected at each definite ratio by PB and PHT, but not by VPA and ZNS. We postulated a model showing that Ct is affected by each concomitant antiepileptic drug i at each definite ratio. We defined the parameter Ri(i = 1, 2, ..., 7) representing the effect of each concomitant antiepileptic drug on Ct. A linear polynomial expression, in which both members of this model are converted into common logarithms, was used for a multiple regression analysis. The analysis clarified that PB and PHT lowered Ct to 0.770 and 0.710 the value of CBZ alone, respectively. On the other hand, VPA and ZNS did not affect Ct. The number of patients coadministered PRM, CZP, and/or ETS was not sufficient to detect the effect on Ct based on a test of significance. In the case of the addition or discontinuation of concomitant antiepileptic drugs in the same patient, the estimated Ct values were calculated using the value of each Ri and compared with the measured Ct values. Both values were in good agreement, and thus our results appear valid.

Carbamazepine-induced abnormal pitch perception

A 7-year-old boy began to complain that his pitch perception was decreased just after oral medication with carbamazepine was initiated for the treatment of epilepsy. When he played the piano, he felt as if he had played a musical note of almost a half pitch lower than he had. His pitch perception recovered soon after the cessation of carbamazepine. A 14-year-old girl noted a lowered pitch of music sounds while she played the piano just after the administration of carbamazepine for the treatment of epilepsy. Carbamazepine was withdrawn and the auditory symptoms disappeared. Both patients were musically trained. Reversible pitch perception abnormalities are a rare adverse effect of carbamazepine, however, the clinical features of the reported cases were similar; they were musically trained, young, female and Japanese. Although the mechanism remains unclear, we have to pay attention to this subtle adverse effect when we treat epileptic patients with carbamazepine.

Anti-epileptic drugs-induced de novo absence seizures

The authors present three patients with de novo absence epilepsy after administration of carbamazepine and vigabatrin. Despite the underlying diseases, the prognosis for drug-induced de novo absence seizure is good because it subsides rapidly after discontinuing the use of the offending drugs. The γ-aminobutyric acid-transmitted thalamocortical circuitry accounts for a major part of the underlying neurophysiology of the absence epilepsy. Because drug-induced de novo absence seizure is rare, pro-absence drugs can only be considered a promoting factor. The underlying epileptogenecity of the patients or the synergistic effects of the accompanying drugs is required to trigger the de novo absence seizure. The possibility of drug-induced aggravation should be considered whenever an unexpected increase in seizure frequency and/or new seizure types appear following a change in drug treatment. By understanding the underlying mechanism of absence epilepsy, we can avoid the inappropriate use of anticonvulsants in children with epilepsy and prevent drug-induced absence seizures.

Neurologic and Cardiac Progression of Glycogenosis Type VII Over an Eight-Year Period

Little is known about the progression of phosphofructokinase deficiency (glycogenosis type VII, Tarui's disease). We describe a 66-year-old woman who had this disease diagnosed in 1997. Initial manifestations had included simple partial seizures since 1977, anginal chest pain since 1982, and muscle cramps since 1983. To prevent recurrent myocardial infarction, anticoagulation therapy with phenprocumon was initiated. Cardiac involvement progressed over an 8-year period, manifesting as low-voltage electrocardiogram (ECG), ectopic supraventricular tachycardia, thickened mitral valve, mitral valve insufficiency, enlarged left atrium, left ventricular hypertrophy, and diastolic dysfunction. Progression of neurologic involvement manifested as complex partial seizures, double vision, reduced tendon reflexes, central facial palsy, bradydiadochokinesia, and distal weakness of the upper extremities. Discontinuance of oral anticoagulation after 19 years, initiation of enalapril therapy, and administration of carbamazepine markedly improved the patient's condition.

The Abundance and Function of Biotin-Dependent Enzymes Are Reduced in Rats Chronically Administered Carbamazepine

The effect of dietary antiepileptic drug administration on the metabolism and function of the water-soluble vitamin biotin was analyzed in a physiologically relevant rat model of biotin nutriture. Administration of carbamazepine (CBZ) in semipurified rat diet at 1.5 and 2.9 g/kg for 19 d did not reduce growth rate or food intake. After this dietary treatment, brain lactic acid and ammonia concentrations were significantly elevated, but no changes in these metabolites occurred in the liver. Urinary biotin excretion was altered and the concentrations of biotin sulfoxides and biocytin in the serum were elevated. Brain biotin was unaffected, but concentrations of bisnorbiotin and biocytin were significantly reduced by dietary administration of CBZ. The relative abundance of hepatic acetyl CoA carboxylase 1 and 2, pyruvate carboxylase (PC), methylcrotonyl CoA carboxylase and propionyl CoA carboxylase was significantly reduced by CBZ, whereas the relative abundance of biotinylated PC was significantly reduced in the brain. In agreement with the carboxylase abundance data, the activity of hepatic PC was significantly reduced in rats consuming CBZ-containing diets. These data demonstrate that administration of the antiepileptic medication CBZ, even with food, reduces the abundance and function of biotin-dependent enzymes in the liver and brain, partially accounting for the metabolic alterations, including organic acidemia, that are observed clinically.

Decreased bioavailability of carbamazepine suppository after its intrarectal and intracolostomal administration to rectal-resected or colostoma-constructed rabbits

The pharmacokinetics of carbamazepine (CBZ), one of the useful analgesic adjunctive agents for palliative care, and its major active metabolite, CBZ-10,11-epoxide (CBZ-E), were investigated after the intrarectal and intracolostomal administration of CBZ to rabbits with rectal-resection or colostoma-construction. In rectal-resected rabbits, the bioavailability of CBZ and the plasma level of CBZ-E after rectal administration were significantly lower than those in normal rabbits, and furthermore these values after intracolostomal administration to colostoma-constructed rabbits tended to be lower than those in rectal-resected ones. This decreased bioavailability of CBZ was thought to be not due to an increased first-pass effect, but to the lower CBZ absorption ability in the upper rectum and colon, since absorption profile of CBZ was not affected by first-pass metabolism. When the dose was increased based upon the difference in the absolute bioavailability values in the rectal-resected and colostoma-constructed rabbits, the decreased plasma levels of CBZ were restored to the control levels incompletely, and the elimination of CBZ and CBZ-E was retarded. These findings suggest that owing to the similarity of their pharmacokinetics in rabbit and man, the increment of dosages of CBZ should be avoided, when CBZ suppositories are administered to rectal-resected or colostoma-constructed patients.

Normally developed infant with a suppression burst pattern on electroencephalography in the neonatal period.

The background activity on neonatal electroencephalography (EEG) is a good prognostic indicator. An EEG suppression burst pattern usually indicates severe brain dysfunction and has been considered to be associated with a serious neurodevelopmental outcome. We report here a 2-year-old girl who developed generalized convulsions without any perinatal brain insult at 3 days of age. At that time, her EEG constantly showed a suppression burst pattern, and her prognosis was considered to be poor. However, her seizures were well controlled with the oral administration of carbamazepine, and the suppression burst pattern on EEG disappeared at 27 days of age. Unexpectedly, she developed normally for the following 2 years. Although children with normal development, despite the appearance of suppression burst, are extremely rare, and the reason why this patient showed a favorable outcome remains unknown, the clinical course of this patient proved that an EEG suppression burst pattern is not always associated with a poor prognosis.

Pharmacoepidemiologic investigation of clonazepam relative clearance by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.

The effects of drug-drug interactions on clonazepam clearance were examined through a retrospective analysis of serum concentration data from pediatric and adult epileptic patients. Patients received clonazepam as monotherapy or in combination with other antiepileptic drugs. A total of 259 serum clonazepam concentrations gathered from 137 patients were used in a population analysis of drug-drug interactions on clonazepam clearance. Data were analyzed using a nonlinear mixed-effects modeling (NONMEM) technique. The final model describing clonazepam clearance was CL = 152 x TBW(-0.181) x DIF, where CL is clearance (ml/kg/h), TBWis total body weight (kg), and DIF (drug interaction factor) is a scaling factor for concomitant medication with a value of 1 for patients on clonazepam monotherapy, 1.18 for those patients receiving concomitant administration of clonazepam and one antiepileptic drug (carbamazepine or valproic acid), and 2.12 x TBW(-0.119) for those patients receiving concomitant administration of clonazepam and more than two antiepileptic drugs. Clonazepam clearance decreased in a weight-related fashion in children, with minimal changes observed in adults. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance. Concomitant administration of clonazepam and valproic acid resulted in a 12% increase in clonazepam clearance. Concomitant administration of clonazepam with two or more antiepileptic drugs resulted in a 23% to 75% increase in clonazepam clearance.

Pharmacoepidemiologic investigation of a clonazepam-carbamazepine interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.

Nonlinear mixed effects modeling was used to estimate the effects of clonazepam-carbamazepine interaction on clearance values using 359 serum levels gathered from 183 pediatric and adult epileptic patients (age range, 0.3-26.8 years) during their clinical routine care. Patients received the administration of clonazepam and/or carbamazepine. The final model describing clonazepam clearance was CL = 179.0 x TBW(-0.231) x 1.22(CBZ), where CL is total body clearance (mL/kg/h) and TBW is total body weight (kg); CBZ = 1 for concomitant administration of carbamazepine and CBZ = zero otherwise. The final model describing carbamazepine clearance was CL = 92.7 x TBW(-0.394) x DOSE(0-397) x 0.795(CZP), where DOSE is the daily dose of carbamazepine (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance and a 20.5% decrease in carbamazepine clearance.