Evaluation of pharmacokinetic parameters, safety and tolerability of single and multiple doses of Vespireit®: results of phase I clinical trial.

Objective: to evaluate the pharmacokinetic parameters, safety and tolerability of Vespireit^® (INN buspirone), prolonged-release tablets, 15 mg (JSC “Valenta Pharm”, Russia), which is being developed as a drug for the treatment of functional vertigo, in healthy volunteers with a single oral dose of 15 and 30 mg on an empty stomach or after meals and multiple doses in a daily dose of 15 mg.

Material and methods. JSC “Valenta Pharm” conducted an open-label, three-stage, randomized, two-periods, cross-over comparative clinical trial of Vespireit^®. At stages 1 and 2, healthy volunteers were screened and randomized into two equal groups (Group 1 and Group 2), as well as the distribution of participants in Group 3. Then, at stage 1, healthy volunteers (n=24) took Vespireit^® once at a dose of 15 mg on an empty stomach or after meals, at stage 2, volunteers (n=24) took Vespireit^® once at a dose of 30 mg on an empty stomach or after meals. Stage 3 was conducted in 18 volunteers as a non-randomized, non-comparative study with Vespireit^® 15 mg on an empty stomach once daily for 5 days. During the study, blood samples were collected from each subject to determine the concentration of test compounds in blood plasma and subsequently calculate their pharmacokinetic parameters. Quantitative determination of buspirone and its two metabolites, 6-hydroxybuspirone (6OH-bus) and 1-(2-pyrimidinyl)-piperazine (1-PP), was performed by a validated high-performance liquid chromatography method with tandem mass spectrometric detection. During the study, tolerability and safety were also evaluated: adverse events, vital signs, laboratory parameters and electrocardiogram parameters were recorded.

Results. When the study drug Vespireit^®, prolonged-release tablets, was administered once at a dose of 15 mg to healthy volunteers after a meal, an increase in the relative bioavailability and relative degree of absorption of buspirone was observed compared with the fasting state, which was accompanied by a 1.5- and 2.5-fold increase in the AUC_0–t and C_max of buspirone, respectively. In addition, the C_max of 6-OH-bus increased 1.4-fold and the C_max of 1-PP increased 1.2-fold. Meal had no effect on the AUC_0–t of 6-OH-bus and 1-PP. When the study drug was administered once at a dose of 30 mg after a meal, an increase in the relative bioavailability and relative degree of absorption of buspirone was observed compared with fasting, which was accompanied by an increase in the AUC_0–t and C_max by 1.5- and 2.1-fold, respectively. A 1.2-fold increase in the C_max of 6-OH-bus was also observed. Food had no effect on the AUC_0–t of 6-OH-bus and on the AUC_0–t and C_max of 1-PP. No accumulation of buspirone and its metabolites was observed with repeated dosing.

Conclusion. In the study, the values of pharmacokinetic parameters of the new drug Vespireit^® in the prolonged-release tablets dosage form were determined both with single administration on an empty stomach and after meals and with multiple administration. The differences and advantages over buspirone preparations in the form of immediate-release tablets are shown: higher relative bioavailability of buspirone with a reduction in interindividual differences in bioavailability and C_max, more stable plasma concentration of buspirone with reduced peak values of the active substance and metabolite 1-PP, a 1.2-fold increase in AUC_0–∞, a 2-fold increase in T_1/2, and a 2-fold increase in the degree of retardation (MRT) for buspirone, a 1.4-fold increase in C_max and MRT of 6-OH-bus, a decrease in AUC_0–∞, AUC_0–t, and T_1/2 of metabolite 1-PP, and a decrease in the ratio of the concentration of 1-PP to the concentration of buspirone and to 6-OH-bus. A favorable safety profile of Vespireit^® was demonstrated.

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