Toxicity assessment of molindone hydrochloride, a dopamine D2/D5 receptor antagonist in juvenile and adult rats.

Neuroleptic drug molindone hydrochloride is a dopamine D2/D5 receptor antagonist and it is in late stage development for the treatment of impulsive aggression in children and adolescents who have attention deficient/hyperactivity disorder (ADHD). This new indication for this drug would expand the target population to include younger patients, and therefore, toxicity assessments in juvenile animals were undertaken in order to determine susceptibility differences, if any, between this age group and the adult rats. Adult rats were administered molindone by oral gavage for 13 weeks at dose levels of 0, 5, 20, or 60 mg/kg-bw/day. Juvenile rats were dosed for 8 weeks by oral gavage at dose levels of 0, 5, 25, 50, or 75 mg/kg-bw/day. Standard toxicological assessments were made using relevant study designs in consultation with FDA. Treatment-related elevation in serum cholesterol and triglycerides and decreases in glucose levels were observed in both the age groups. Organ weight changes included increases in liver, adrenal gland and seminal vesicles/prostate weights. Decreases in uterine weights were also observed in adult females exposed to the top two doses with sufficient exposure. In juveniles, sexual maturity parameters secondary to decreased body weights were observed, but, were reversed. In conclusion, the adverse effects noted in reproductive tissues of adults were attributed to hyperprolactinemia and these changes were not considered to be relevant to humans due to species differences in hormonal regulation of reproduction. On the whole, there were no remarkable differences in the toxicity profile of the drug between the two age groups.

Determination of molindone enantiomers in human plasma by high-performance liquid chromatography-tandem mass spectrometry using macrocyclic antibiotic chiral stationary phases.

A sensitive and selective bioanalytical assay was developed and validated for the determination of enantiomeric molindone in human plasma using high-performance liquid chromatography-tandem mass spectrometry along with supported liquid extraction procedures. The chiral separation was evaluated and optimized on macrocyclic antibiotic type chiral stationary phases (CSPs) based on teicoplanin aglycone (Chirobiotic TAG) in polar organic, polar ionic, and reversed-phase mode chromatography, respectively. Complete baseline separation was achieved on a Chirobiotic TAG column under isocratic condition in reversed-phase chromatography. The method validation was conducted using a Chirobiotic TAG column (100 mm x 2.1 mm) over the curve range 0.100-100 ng/ml for each molindone enantiomer using 0.0500 ml of plasma sample. The flow rate was 0.8 ml/min and the total run time was 9 min. Supported liquid extraction in a 96-well plate format was used for sample preparation. Parameters including recovery, matrix effect, linearity, sensitivity, specificity, carryover, precision, accuracy, dilution integrity, and stability were evaluated. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels were RSD

Relation of serum molindone levels to serum prolactin levels and antipsychotic response.

The antipsychotic drug molindone is considered to be atypical in its mode of action and to have mild side effects. Currently no data are available on the range of serum levels of this drug during treatment. By means of a high performance liquid chromatographic technique, serum molindone levels were measured in 14 psychotic patients receiving a wide range of doses of this drug. Molindone levels as high as 350 ng/mL were obtained and were not associated with any toxic effects. Significant relations were noted between the serum level of the drug and both serum prolactin level and treatment response. The authors suggest that molindone may have a range of serum levels consistent with therapeutic benefit. Serum molindone and prolactin levels might help assess resistance to molindone treatment.

Neuroleptic bioequivalency: tablet versus concentrate.

Two forms of the antipsychotic neuroleptic molindone were administered to newly admitted psychotic patients. A coated tablet was administered for ten days, followed by administration of liquid concentrate in equivalent doses for four days. Plasma was analyzed by gas chromatography with electron capture for the parent compound following each dosing phase. Our data suggest that oral doses of the tablet and concentrate forms of this neuroleptic are equivalent in clinical bioavailability.

Bioavailability of oral and intramuscular molindone hydrochloride in schizophrenic patients.

This study was designed to assess the bioequivalence of intramuscular molindone hydrochloride and marketed oral molindone. Ten schizophrenic patients (mean age, 30.2 years) received oral molindone in single daily doses of 100 or 150 mg for four to eight days followed by intramuscular molindone in single daily doses of 50 or 75 mg for four days. On the last day each molindone formulation was given, plasma samples were collected at baseline and at 0.5, 1, 2, 4, 6, 8, and 12 hours after administration. The pharmacokinetic measures of area under the curve and maximum concentration show that intramuscular molindone is 1.49 to 1.67 times more bioavailable than oral molindone. This finding indicates that once a patient's acute psychotic episode has been stabilized with intramuscular molindone, therapy can continue without interruption by substituting 1.5 mg of oral molindone for every 1 mg of intramuscular molindone. The time to maximum concentration occurred significantly earlier (P = 0.05) with intramuscular molindone (0.6 hours) than with oral molindone (1.1 hours). Elimination half-life values were approximately two hours for both formulations.

Neuroleptic serum levels measured by radioreceptor assay and clinical response in schizophrenic patients.

Serum neuroleptic levels and clinical response have been compared serially in 10 schizophrenic patients treated with a variety of neuroleptics using a novel radioreceptor assay for neuroleptics. In this assay the drug in serum completes with [3H]spiroperidol for binding to dopamine receptors on membranes of the caudate nucleus. Serum neuroleptic levels, expressed in terms of dopamine receptor occupancy, were similar for most neuroleptics at therapeutic doses. Thioridazine levels were substantially higher than those of other neuroleptics.