Bioavailability of carbamazepine from four different products and the occurrence of side effects

Olling, M.; Mensinga, Tjeerd T.; Barends, D. M.; Groen, C.; Lake, O. A.; Meulenbelt, Jan

doi:10.1002/(sici)1099-081x(199901)20:1<19::aid-bdd152>3.0.co;2-q

Cited by 46 publications

(24 citation statements)

References 29 publications

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“…The details of this four-way, randomized BE trial have been described by Olling et al [10] In short, 18 volunteers participated, but only 16 completed the study. Two 200-mg tablets of CBZ were administered in the morning of the first study day.…”

Section: Subjects and Study Designmentioning

confidence: 99%

“…In a Food and Drug Administration (FDA)-sponsored study, Meyer et al [9] explored the relationship between the dissolution rate and concentration profiles of CBZ tablets in subjects with known clinical failures. The relationship between CBZ concentration profiles and clinical effects has been investigated in healthy volunteers [10] and patients [11]. The study of Olling et al [10] was a fourarm bioequivalence (BE) trial.They compared three generic formulations with the brand-name product.Their goal was to determine which absorption rate-dependent BE metric had the best discriminatory power, including the prediction of adverse effects.…”

Section: Introductionmentioning

confidence: 99%

“…The relationship between CBZ concentration profiles and clinical effects has been investigated in healthy volunteers [10] and patients [11]. The study of Olling et al [10] was a fourarm bioequivalence (BE) trial.They compared three generic formulations with the brand-name product.Their goal was to determine which absorption rate-dependent BE metric had the best discriminatory power, including the prediction of adverse effects. Four BE metrics were compared: maximum concentration (Cmax), time of the peak concentration (Tmax), Cmax/AUC [12,13] (where AUC is the area under the concentration-time curve), and the area until Tmax [partial AUC (AUCP)] [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…In the present study a pharmacokineticpharmacodynamic (PK-PD) model is proposed to characterize acute CBZ toxicity based on the data of Olling et al [10]. By building a PK-PD model, an attempt is made to answer the original question posed by Olling et al [10] ('which metric is the most sensitive indicator of toxicity?')…”

Section: Introductionmentioning

confidence: 99%

“…By building a PK-PD model, an attempt is made to answer the original question posed by Olling et al [10] ('which metric is the most sensitive indicator of toxicity?') and also to gain insight into the occurrence and mechanism of the absorption rate-dependent pharmacological response.…”

Section: Introductionmentioning

confidence: 99%

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Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

Tóthfalusi

Speidl

Endrényi

2007

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The occurrence of central nervous system-related adverse effects has been apparently related to the absorption rate of carbamazepine (CBZ).• However, the differing absorption rate metrics of four carbamazepine formulations in a bioequivalence study were unclearly associated with the incidence of adverse effects. WHAT THIS STUDY ADDS• The relationship between the incidence of most neurological adverse effects and the absorption rate of CBZ was quantitatively established.• A mixed-effect PK-PD model demonstrated the rapid development of acute tolerance to these effects.• Characterization of PD and PK-PD sensitivities showed that clinically significant differences in toxicity can exist between bioequivalent CBZ formulations. AIMSTo assess whether, using the current regulatory criteria, therapeutically important differences can exist between bioequivalent carbamazepine (CBZ) tablets. A secondary goal was to demonstrate quantitatively the relationship between the risk of neurological adverse effects to orally ingested CBZ and the rate of absorption. METHODSResults of a bioequivalence study by Olling et al. (Biopharm Drug Dispos 1999; 20: 19-28) were reanalysed. Following an exploratory data analysis step, a mixed-effect pharmacokinetic-pharmacodynamic (PK-PD) model was built to describe the dependence of adverse events on the CBZ concentration. RESULTSRapid development of tolerance was demonstrated for most neurological adverse effects, with a characteristic half-life of 02.29 h and an initial EC50 of 2.33 mg l -1. The resulting tolerance PK-PD model was characterized further using the tools and terminology of sensitivity analysis. It was demonstrated that the maximum concentration (Cmax) exhibits poor PK and PD sensitivities, and that clinically significant differences can exist between formulations which otherwise comply with the bioequivalence requirements. In contrast, another PK metric, the partial AUC, was a much better marker of the early neurological adverse events observable during the absorption phase of the drug. CONCLUSIONSIn clinical and regulatory considerations, the development of acute tolerance for adverse effects of CBZ must be taken into account. Partial AUC reflects more sensitively the risk of adverse events than Cmax. Instead of the current trend of tightening of the bioequivalence criteria for narrow therapeutic index drugs, the use of alternative, more sensitive PK metrics is proposed.

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Section: Subjects and Study Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

Tóthfalusi

Speidl

Endrényi

2007

Brit J Clinical Pharma

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Assessing bioequivalence of generic antiepilepsy drugs

Krauss

Caffo

Chang

et al. 2011

Annals of Neurology

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Effect of the timing of food intake on the absorption and bioavailability of carbamazepine immediate‐release tablets in beagle dogs

Cheng

Liu

et al. 2012

Biopharm & Drug Disp

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The effect of dosing time on the bioavailability of carbamazepine immediate-release (IR) tablets was investigated when administered to beagle dogs who were fasting, with co-administration of food (Co-food), and 0.5 h before food and 2 h after food. The study was conducted using a single dose of 200 mg (tablets/solution) with a 2 week washout period in a crossover design. Food intake significantly increased the rate and extent of tablet absorption. The C(max) (µg·ml⁻¹, 8.13/3.65) and t(max) (h, 1.83/0.92) were increased more than two-fold and the AUC₀₋₂₄ (µg·h·ml⁻¹, 20.09/8.19) was 2.5 times that of the values obtained under fasting conditions. The bioavailability of the tablets under fasting conditions was 91.2%, but increased to 223.5%, 182.8% and 148.4% in the Co-food, 0.5 h before food and 2 h after food groups, respectively (p < 0.05). Although there was no significant difference in the C(max) or AUC₀₋₂₄ between the treatments with food, the absorption appeared to be reduced to some extent when the tablets were given 2 h after food. The oral bioavailability of CBZ IR tablets was significantly affected by the timing of the food intake. This is maybe favored by the fluctuations in the level of bile salts with the timing of food intake. To obtain acute therapy for a drug with narrow therapeutic window, attention should be given to the dosing time and food intake interactions.

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Bioavailability of carbamazepine from four different products and the occurrence of side effects

Cited by 46 publications

References 29 publications

Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

Assessing bioequivalence of generic antiepilepsy drugs

Effect of the timing of food intake on the absorption and bioavailability of carbamazepine immediate‐release tablets in beagle dogs

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