Title:Comparative Bioavailability of Two Oral Formulations of Clozapine in Steady State Administered in Schizophrenic Volunteers Under Individualized Dose Regime
Volume: 7
Issue: 4
Author(s): Ney C. do Carmo Borges, Rafael B. Astigarraga, Carlos E. Sverdloff, Paulo R. Galvinas, Bruno C. Borges and Ronilson A. Moreno
Affiliation:
Keywords:
Clozapine, human plasma, liquid-chromatography, mass spectrometry, schizophrenia, Pharmacokinetics, Chromatographic, hepatic metabolism, temperature.
Abstract: In the present study, a novel, fast, sensitive and robust method to quantify clozapine in human plasma using
quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from plasma using a single
protein precipitation extraction technique with methanol and analyzed by high performance liquid chromatography
coupled to the electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS). The method was linear over the
range 20 to 1500 ng.mL-1. The intra-assay precisions ranged from 3.8 to 5.9%, while inter-assay precisions ranged from
4.2 to 6.0%. The intra-assay accuracies ranged from 99.3 to 107.5%, while the inter-assay accuracies ranged from 98.9 to
101.7%. This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity,
specificity and high sample throughput and was used to evaluate the pharmacokinetic profiles and bioequivalence of the
two clozapine formulations in twenty six schizophrenic patients affected by refractory schizophrenia under steady-state
conditions. During the hospitalization period the patients received the 100 mg clozapine formulation tablets corresponding
to the same dose they were using 14 days before hospitalization. The clozapine pharmacokinetic did not differ
significantly after administration of both test and the reference formulations. The Tmax and T1/2 for the test formulation
were 2.26 and 10.92 h, respectively. In addition, the Tmax and T1/2 for the reference formulation were 2.44 and 11.08 h,
respectively. The 90% confidence interval of the mean ratio of lnAUC0-t was within 0.80-1.25 range which indicates that
the test formulation was bioequivalent to the reference formulation when orally administered to schizophrenic patients
regarding both the rate and extent of absorption.
