Clinical Pharmacology of Vinpocetine: Properties Revisited and Introduction of a Population Pharmacokinetic Model for Its Metabolite, Apovincaminic Acid (AVA)

Abstract

This paper examines the use of vinpocetine in the context of clinical pharmacology. The main and active metabolite of vinpocetine is apovincaminic acid (AVA). Due to the scarce information in the literature on AVA pharmacokinetics, we propose a population pharmacokinetic (PopPK) model for AVA based on a study in healthy volunteers with three different formulations of vinpocetine. The suggested PopPK model (and simulations) could be helpful in ensuring the more effective and safer use of the vinpocetine in the future given the increasing range of suggested indications for its use.

Keywords: apovincaminic acid; pharmacology; population pharmacokinetic model; simulation; vinpocetine.

Figure 1

Chemical structures of vinpocetine and vinca alkaloids (from left to right: vinpocetine (A), apovincamine (B), and vincamine (C)). Vinpocetine is also known as ethyl apovincaminate (an ethyl group is depicted by an arrow). Figures are computed using an open-source tool [10].

Figure 2

Measured mean plasma concentrations of AVA (formulations #1, #2, and #3, plots (A), (B), and (C), respectively) with error bars (standard deviation) on a log-linear scale. (Concentration of AVA in μg/L, time in h).

Figure 3

GOF plot indicating that the individual predictions fitted well along the identity line relative to observed concentrations (joined data for all three formulations of vinpocetine). Dashed line is 90% prediction interval.

Figure 4

Plot (A): Joined VPC of AVA. The figure presents the VPC with the prediction intervals for the 10th, 50th, and 90th percentiles. The model describes the observed data well, and model predictions are within the prediction interval. Plot (B): Stratified VPC plots by formulations (#1, #2, #3). Minor outliers were not deemed significant, as the overall model captures the data well. (Concentration of AVA in μg/L, time in h).

Figure 5

(a). Simulated AVA concentration vs. time plots from 50 virtual individuals (i.e., from one virtual trial replicate) who took vinpocetine tablets (5 mg/10 mg/15 mg) three times a day (every 8 h). The red line marks the concentration range between the lower 5% of Cmin values and the higher 95% of the Cmax values, which are considered to be safe and efficacious based on the clinical therapeutic regimen of 5 mg three times a day. (Concentration of AVA in μg/L, time in h). (b). Simulated AVA concentration vs. time plots from 50 virtual individuals (i.e., from one virtual trial replicate) who took vinpocetine tablets (15 mg/30 mg/60 mg) once a day (every 24 h). The red line marks the concentration range between the lower 5% of Cmin values and the higher 95% of the Cmax values, which are considered to be safe and efficacious based on the clinical therapeutic regimen of 5 mg three times a day. (Concentration of AVA in μg/L, time in h). (c). Summary statistics of the AVA Cmax values based on the simulated dosage regimens of vinpocetine from ten trial replicates. The concentration of AVA on the y-axis is expressed in micrograms per liter (μg/L). (d). Summary statistics of the AVA Cmin values based on the simulated dosage regimens of vinpocetine from ten trial replicates. The concentration of AVA on the y-axis is expressed in micrograms per liter (μg/L).

Figure 5

(a). Simulated AVA concentration vs. time plots from 50 virtual individuals (i.e., from one virtual trial replicate) who took vinpocetine tablets (5 mg/10 mg/15 mg) three times a day (every 8 h). The red line marks the concentration range between the lower 5% of Cmin values and the higher 95% of the Cmax values, which are considered to be safe and efficacious based on the clinical therapeutic regimen of 5 mg three times a day. (Concentration of AVA in μg/L, time in h). (b). Simulated AVA concentration vs. time plots from 50 virtual individuals (i.e., from one virtual trial replicate) who took vinpocetine tablets (15 mg/30 mg/60 mg) once a day (every 24 h). The red line marks the concentration range between the lower 5% of Cmin values and the higher 95% of the Cmax values, which are considered to be safe and efficacious based on the clinical therapeutic regimen of 5 mg three times a day. (Concentration of AVA in μg/L, time in h). (c). Summary statistics of the AVA Cmax values based on the simulated dosage regimens of vinpocetine from ten trial replicates. The concentration of AVA on the y-axis is expressed in micrograms per liter (μg/L). (d). Summary statistics of the AVA Cmin values based on the simulated dosage regimens of vinpocetine from ten trial replicates. The concentration of AVA on the y-axis is expressed in micrograms per liter (μg/L).

Figure 5

(a). Simulated AVA concentration vs. time plots from 50 virtual individuals (i.e., from one virtual trial replicate) who took vinpocetine tablets (5 mg/10 mg/15 mg) three times a day (every 8 h). The red line marks the concentration range between the lower 5% of Cmin values and the higher 95% of the Cmax values, which are considered to be safe and efficacious based on the clinical therapeutic regimen of 5 mg three times a day. (Concentration of AVA in μg/L, time in h). (b). Simulated AVA concentration vs. time plots from 50 virtual individuals (i.e., from one virtual trial replicate) who took vinpocetine tablets (15 mg/30 mg/60 mg) once a day (every 24 h). The red line marks the concentration range between the lower 5% of Cmin values and the higher 95% of the Cmax values, which are considered to be safe and efficacious based on the clinical therapeutic regimen of 5 mg three times a day. (Concentration of AVA in μg/L, time in h). (c). Summary statistics of the AVA Cmax values based on the simulated dosage regimens of vinpocetine from ten trial replicates. The concentration of AVA on the y-axis is expressed in micrograms per liter (μg/L). (d). Summary statistics of the AVA Cmin values based on the simulated dosage regimens of vinpocetine from ten trial replicates. The concentration of AVA on the y-axis is expressed in micrograms per liter (μg/L).