DOES DOSE-STAGGERING REDUCE METABOLIC DRUG-DRUG INTERACTION BETWEEN CLOZAPINE AND FLUVOXAMINE IN DOG?

Clozapine, an antipsychotic, and fluvoxamine, an antidepressant, are frequently coadministered in the treatment of schizophrenia. Oral coadministration of clozapine with fluvoxamine in humans results in profound increases in serum concentrations of clozapine due to reversible enzyme inhibition. Dose-staggering is a potential way to reduce drug-drug interactions with orally administered drugs. We hypothesized that staggering doses of clozapine and fluvoxamine twelve hours apart will decrease the extent of interaction between clozapine and its known inhibitor, fluvoxamine, in dog. We used the dog model due to similar metabolic profiles between humans and dogs, and for safety reasons, since doses that are well tolerated in schizophrenic patients may cause serious adverse side effects in healthy volunteers. The principle focus of this research work was to validate a computer simulation model that may predict drug-drug interaction potential. An 1-1-PLC method was developed to quantify clozapine and its two major metabolites, clozapine N-oxide and N-desmethyl clozapine in dog plasma. The pharmacokinetics of clozapine was examined for a single dose (IV and oral) and multiple doses (oral) in dog. A two-phase, crossover design was used to determine if staggering multiple oral doses of clozapine and fluvoxamine twelve hours apart could decrease the extent of this drug-drug interaction. Our HPLC method was fast, simple and demonstrated good recovery rates for clozapine and N-desmethyl clozapine. The average half-life, elimination rate constant, volume of distribution, and systemic clearance of clozapine in dog calculated from a single IV bolus dose (1 mg/kg) were 11.2 h (±2.9), 0.067 WI (±0.022), 115 L (±32), and 7.54 L/h (±2.21). The average half-life, elimination rate constant, and oral clearance of clozapine in dog calculated from a single oral dose (5 mg/kg) were 18.5 h (±14.7), 0.081 III (±0.065), and 43.51 L/h (±3.06). The average AUC TO value of clozapine between the simultaneous condition (AUC r o = 757 +181 µg x h/L) and the staggered condition (AUC To = 573 ±72 µg x h/L) approached significance (p = 0.05). Dose-staggering did not appear to decrease the extent of the drug-drug interaction between clozapine and fluvoxamine in dog. The prediction of the computer simulation model could not be confirmed.

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