Bioequivalence Study Of A Fixed-Dose Combination Tablet Containing Melitracen 10 mg And Flupentixol 0.5 mg In Healthy Chinese Volunteers Under Fasted And Fed Conditions.

PURPOSE: A fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation. METHODS: The study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½, CL/F, and Vd/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs). RESULTS: The present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of Cmax, AUC0-t, and AUC0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.

Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride.

The objective of the present study was to develop fast dissolving oral film of the antipsychotic drug, flupentixol dihydrochloride, to enhance its bioavailability, optimize its therapeutic effect when used to treat depression with anxiety, and increase the convenience and compliance by the mentally ill, developmentally disable, elderly, and pediatric patients. Six formulae were prepared with different concentrations of water-soluble polymers vis. hydroxypropyl methylcellulose (HPMC E5) and carboxymethyl cellulose (CMC) by solvent casting technique. The prepared films were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern, and drug content. Physical compatibility between the drug and excipients was guaranteed in the selected formulation (2% HPMC) by means of differential scanning calorimetry analysis and Fourier-transform infrared spectroscopy. This formulation revealed high stability after testing according to the International Conference on Harmonisation guidelines. In vivo studies based on single phase parallel design were carried out for the optimized formulation in healthy human volunteers. The concentration of flupentixol dihydrochloride in plasma samples was analyzed by a developed validated LC-MS/MS assay method and the pharmacokinetic parameters of the established formulation were compared with the commercially available oral tablets. Faster rate of absorption of flupentixol could be obtained from the oral film formulation and the relative bioavailability was found to be 151.06% compared to the marketed product.

Validation of a sensitive LC/MS/MS method for simultaneous quantitation of flupentixol and melitracene in human plasma.

A sensitive method has been developed and validated, using LC/ESI-MS/MS, for simultaneous quantitation of flupentixol and melitracen--antidepressant drugs, in human plasma. The quantitation of the target compounds was determined in a positive ion mode and multiple reaction monitoring (MRM). The method involved a repeated liquid-liquid extraction with diethyl ether and analytes were chromatographed on a C(8) chromatographic column by elution with acetonitrile-water-formic acid (36:64:1, v/v/v) and analyzed by tandem mass spectrometry. The method was validated over the concentration ranges of 26.1-2090 pg/ml for flupentixol and 0.206-4120 ng/ml for melitracen. The correlation coefficients of both analyst were >0.998 for six sets of calibration curves. The recovery was 60.9-75.1% for flupentixol, melitracen and internal standard. The lower limit of quantitation (LLOQ) detection was 26.1 pg/ml for flupentixol and 0.206 ng/ml for melitracen. Intra- and inter-day precision of the assay at three concentrations were 2.15-5.92% with accuracy of 97.6-103.0% for flupentixol and 0.5-6.36% with accuracy of 98.7-101.7% for melitracen. Stability of compounds was established in a battery of stability studies, i.e., bench-top, autosampler and long-term storage stability as well as freeze/thaw cycles. The method proved to be suitable for bioequivalence study of flupentixol and melitracen in healthy human male volunteers.

Effect of flupenthixol on subjective and cardiovascular responses to intravenous cocaine in humans.

The effects of oral flupenthixol and intramuscular (i.m.) flupenthixol decanoate in combination with intravenous (i.v.) cocaine were evaluated in male cocaine abusers. Participants resided at an inpatient research unit for 27 days followed by an 11-day outpatient period. Oral flupenthixol (2.5 or 5.0 mg; p.o.) followed by flupenthixol decanoate (10 or 20 mg; i.m.) and placebo were investigated in individuals who were randomly assigned to one of three groups under double-blind conditions (placebo, low or high dose flupenthixol). During the inpatient period, participants had four fixed cocaine dosing sessions; each session they were administered four doses of i.v. cocaine (approx. 48 mg/70 kg), spaced 14 min apart. These sessions occurred once before medication (baseline phase), once following oral medication (oral phase), and twice following intramuscular medication (IM phase). Out of 23 participants, 18 completed the study; 4 of the 5 non-completers were in the high dose flupenthixol group. Overall, there were few subjective, cardiovascular, or cocaine pharmacokinetic differences between the placebo group and the low dose flupenthixol group, indicating that the low dose of flupenthixol was well tolerated, but ineffective. In the high dose flupenthixol group, two out of seven individuals (29%) experienced a dystonic reaction following oral flupenthixol and were medically discharged. Taken together, these findings indicate that flupenthixol is not a good candidate for treating cocaine abusers.

Quantification of the antipsychotics flupentixol and haloperidol in human serum by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatography (HPLC) method was developed for quantification of both isomers of the thioxanthene neuroleptic flupentixol and of the butyrophenone derivative haloperidol in human serum. After extraction with diethyl ether-n-heptane (50:50, v/v), an isocratic normal-phase HPLC system with a Hypersil cyanopropyl silica column (250x4.6 mm, 5 microm particle size) was used with ultraviolet detection at 254 nm and elution with a mixture of 920 ml acetonitrile, 110 ml methanol, 30 ml 0.1 M ammonium acetate, and 50 microl triethylamine. The limit of quantitation of 0.5 ng/ml and 0.3 ng/ml for flupentixol and haloperidol, respectively, was sufficient to quantify both compounds in serum after administration of clinically adjusted doses. The suitability of the described method for therapeutic drug monitoring and clinical pharmacokinetic studies was assessed by analysis of more than 100 trough level serum samples.

Large variations of plasma levels during maintenance treatment with depot neuroleptics.

BACKGROUND: Stability of neuroleptic medication has been associated with optimal clinical effect and minimal side-effects. Depot administration is assumed to yield better stability. METHOD: Thirty patients on depot neuroleptic treatment were followed during three years with repeated measurements of plasma level and concurrent ratings of clinical symptoms and side-effects. RESULTS: Of 120 blood samples 35 (29%) measurements were outside +/-2 s.d. measurement error (expected 5%). Perphenazine levels were more variable (46%) than haloperidol (25%) and flupenthixol (12.5%). No relationship was found between side-effect ratings and fluctuations of plasma levels. CONCLUSION: Depot neuroleptic medication does not eliminate a clinically unwanted and sometimes marked variation in plasma level.

Sensitive gas-liquid chromatographic method for the assay of the neuroleptic drug cis(Z)-flupentixol in human serum or plasma.

A gas-liquid chromatographic (GLC) assay suitable for the analysis of the cis(Z)-stereoisomer of the antipsychotic drug flupentixol in human serum or plasma was developed. The minimal quantifiable concentration was 0.5 ng/ml and the day-to-day coefficient of variation was 11.2% at 1 ng/ml and 8.7% at 10 ng/ml. Following addition of perphenazine as the internal standard (I.S.) and aqueous NaOH, samples (2 ml) are extracted with n-hexane-isoamyl alcohol (98.5:1.5, v/v) (solvent), back-extracted to 0.1 M HCl and after one washing-step and addition of aqueous NaOH again extracted into 100 microliters solvent. After evaporation to dryness, the extract is reconstituted in 20 microliters solvent and evaporated to approximative 10 microliters. A 4-microliter aliquot is injected cool on-column onto the GLC system. A gas chromatograph HP 5890 with on-column injection port, nitrogen-phosphorus detector (NPD), a HP-1 25 m x 0.32 mm I.D., 0.52 micron capillary and hydrogen (3 ml/min, automated pressure control) as the carrier gas was applied. The negative influence of light on the assay was measured and discussed. The suitability of this method for clinical pharmacokinetic studies and therapeutic drug monitoring (TDM) was determined by the analysis of serum samples of 12 schizophrenic patients.

Plasma homovanillic acid and treatment response in a large group of schizophrenic patients.

Plasma levels of homovanillic acid (pHVA), a metabolite of dopamine, were measured in ninety-five Chinese schizophrenic patients free of neuroleptics for at least four weeks. These patients were treated with classical antipsychotics for six weeks. Pretreatment pHVA was positively correlated with the subsequent clinical response (r = 0.408, p < 0.0001). Good responders (BPRS improvement > or = 50%, n = 47) had higher pretreatment pHVA levels than poor responders (BPRS improvement < 50%, n = 48) (15.7 +/- 8.4 ng/ml versus 9.9 +/- 3.7 ng/ml, p < 0.0001). A higher than 15 ng/ml pretreatment pHVA level was associated with a more consistent clinical response to the subsequent treatment. Using a pHVA level of 12 ng/ml as a demarcation point, 72% of patients (34 of 47) who had pHVA > or = 12 responded whereas 65% (31 of 48) who had < 12 did not respond (chi-square = 13.02, p < 0.0001). These results suggest that higher pretreatment pHVA levels may predict a better clinical response to antipsychotics. Based upon the pHVA findings, two hypothetical subtypes of schizophrenia are proposed.

Rationalizing neuroleptic polypharmacy in chronic schizophrenics: effects of changing to a single depot preparation.

This study investigated the effects of transferring patients on combined depot and oral neuroleptics to a single depot preparation; a secondary objective was to assess the effects of transferring patients from one depot neuroleptic to another. It was found that, whereas transferring from one depot preparation (flupenthixol) to another (fluphenazine) had no clear disadvantage for the patients, changing over from a combined oral and depot (fluphenazine) regimen to equivalent doses of depot alone resulted in an unacceptably high rate of relapse. The reasons for this may relate to either the unique pharmacokinetics of these drugs or subtle qualitative differences between them. It is suggested that caution is necessary whenever attempts are made to rationalize polypharmacy in schizophrenic patients.

Modelling drug kinetics with brain stimulation: dopamine antagonists increase self-stimulation.

The rewarding effects of brain stimulation and drugs are believed to depend on a common neural system. However, the pattern of responding produced by drug reinforcers is different from the pattern produced by conventional brain stimulation. Furthermore, pharmacological antagonists of reinforcement increase the rate of drug self-administration but depress self-stimulation. To test the hypothesis that the differences in the characteristics of brain stimulation and drugs as reinforcers are due to differences in the kinetics of drugs and brain stimulation, we modelled drug kinetics with frequency-modulated trains of brain stimulation. We report that animals will self-administer such brain stimulation in a manner that resembles drug self-administration and that, under these conditions, dopamine antagonists can increase the rate of self-stimulation.

Pharmacokinetic interaction between imipramine and antidepressant neuroleptics in rats.

Antidepressant neuroleptics, perazine (PZ), levomepromazine (LMZ) and flupenthixol (FPX) given to rats jointly with imipramine (IMI) for 2 weeks affected the plasma concentration of IMI only slightly but markedly elevated the concentration of its metabolite, desipramine (DMI). In the brain PZ significantly elevated both IMI and DMI concentrations while LMZ and FPX showed a tendency to increase the concentration of IMI and decrease the concentration of DMI. All three neuroleptics markedly decreased the DMI/IMI ratio in the brain and (except FPX) increased it in the plasma. Given alone for two weeks PZ, LMZ, FPX did not affect the levels of cytochromes P-450 and b-5 in liver microsomes. Chronic treatment with IMI significantly elevated the concentration of cytochrome P-450 in the liver and had a tendency to increase the concentration of cytochrome b-5. FPX, but not PZ or LMZ abolished this effect. Neuroleptics coadministered with IMI to rats did not affect the activity of the enzymes responsible for the IMI biotransformation as compared with IMI-treated animals. The neuroleptics added to the incubation mixture in vitro inhibited IMI hydroxylation noncompetitively. The demethylation was inhibited competitively by LMZ but noncompetitively by PZ and FPX. The inhibitory effect of neuroleptics on the hydroxylation was much more marked than that on the demethylation. FPX was the weakest inhibitor of IMI metabolism among the neuroleptics studied.

Antidepressant effects of flupenthixol.

Strong evidence exists that flupenthixol, not presently distributed in the United States, is an effective antidepressant. Its advantages over available antidepressants include its safety with respect to overdose and in combination with other medications, low dependency risk, rapid onset of action, and availability in depot preparation. Flupenthixol also may be useful as a mood elevator for schizophrenics, an alternative mood stabilizer for patients with bipolar disease, and a facilitator for cocaine withdrawal.

Age-related differential recovery rates of rat striatal D-1 dopamine receptors following irreversible inactivation.

We report here the effects of age on the steady state levels of [3H]flupentixol-labeled striatal D-1 dopamine receptors and their recovery rates following irreversible blockade in mature (4 months old) and senescent (28 months old) male Fischer 344 rats. Senescent rats exhibited significantly reduced (-22%) Bmax levels of D-1 dopamine receptors compared with their mature counterparts. In addition, the time course of recovery of D-1 dopamine receptors following irreversible receptor inactivation by a single injection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was significantly slower in senescent animals. This slower recovery rate was the result of decreases in both receptor production rate and receptor degradation rate constants compared with mature rats. Although EEDQ irreversibly inactivated D-1 dopamine receptors, it was without effect on dopamine uptake sites. A chronic, 21 day reserpine treatment did not significantly alter the Bmax nor the rate of recovery of D-1 dopamine receptors with respect to values in age-matched non-reserpine-treated rats. These data indicate that both the steady state levels of striatal D-1 dopamine receptors and the 'turnover' of these receptors are significantly affected as a consequence of natural aging.

Depot neuroleptic medication and serum levels by radioreceptor assay: prolactin concentration, electrocardiogram abnormalities and six-month outcome.

Twenty-six chronic schizophrenic patients on well-established depot neuroleptic regimes with stable doses (16 on fluphenazine decanoate, 10 on flupenthixol decanoate) had serum neuroleptic levels measured by radioreceptor assay (RRA) and were followed for six months. The serum prolactin (PRL) concentration and resting electrocardiogram (ECG) were also taken at the beginning of the study period. Correlations had previously been noted between RRA measured neuroleptic levels and outcome in both acute and chronic patients on oral medication. However, in this study of depot medication no significant correlations were found between serum neuroleptic concentration, serum prolactin concentration and the clinical state or outcome. The prevalence (33%) and type of ECG abnormality observed was similar to that previously reported.