Tolerability and Pharmacokinetic Comparison of Oral, Intramuscular, and Intravenous Administration of Levosulpiride After Single and Multiple Dosing in Healthy Chinese Volunteers.

PURPOSE: The aim of this study was to characterize the pharmacokinetic (PK) properties and assess the safety profiles of different formulations of levosulpiride in healthy Chinese volunteers.

METHODS

Levosulpiride was administered to 42 healthy male and female (1:1) subjects in tablet (PO) and injectable (IM and IV) dosage forms. Blood samples were collected at regular intervals after single and multiple drug administration. The concentration of levosulpiride in plasma was determined by a validated liquid chromatography tandem mass spectrometry method. Noncompartmental analysis was performed to estimate PK parameters. One-way ANOVA was used to test for linearity and assess the effect of sex on the PK properties of the drug. Adverse effects were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and electrocardiography.

FINDINGS: Levosulpiride exhibited linear pharmacokinetic properties over the dose range of 25 to 100 mg by PO route and 25 to 75 mg by IM route. The corresponding mean AUC0-t increased from 449 to 1443 ng/h/mL and from 2874 to 7559 ng/h/mL, respectively. After repeated PO and IM administration, steady state was reached on day 4 of multiple dosing with accumulation index of 1.8 and on day 2 of multiple dosing with accumulation index of 1.3, respectively. The bioavailability of levosulpiride via IM and PO routes was 96.8% and 23.4%, respectively. No significant differences were observed on PK properties between male and female subjects. More than half (23 of 42 [54.8%]) of healthy volunteers experienced one or more adverse events in total, including constipation, diarrhea, drowsiness, skin rash, and extrapyramidal reactions.

IMPLICATIONS: The regimen of 50-mg levosulpiride tablets 3 times daily and 50-mg levosulpiride injection (IM) twice daily provided similar accumulation coefficient, and the former reached steady state much more slowly. The bioavailability of levosulpiride after oral administration was poor and the absorption rate was slower compared with IM administration, which imply delayed clinical efficacy for patients with dyspepsia or neuropsychiatric disorders. On multiple dosing, levosulpiride exhibited poor tolerability with high incidence of adverse reactions. There was no need to adjust administration regimen based on sex. ClinicalTrials.gov Identifier: NCT02481583.