Zvonimir Petric¹, Paulo Paixão¹, Augusto Filipe², Jose Guimarães Morais¹
¹ Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa). Faculty of Pharmacy, Lisbon, Portugal ² Medical Department, Tecnimede, Sintra, Portugal
Objectives: Vinpocetine holds a dual status as both a prescription drug in the EU and an ingredient in dietary supplements. Its anatomical therapeutic chemical (ATC) code is N06BX18; group psychoanaleptics (06), subgroup of psychostimulants and nootropics (B). The pharmacological properties of vinpocetine range from neuroprotection, antioxidant, and anticonvulsive effects to multifaceted anti-inflammatory effects. Despite renewed scientific interest in vinpocetine, debates persist regarding its pharmacological attributes, as the understanding of the pharmacokinetic-pharmacodynamic (PKPD) context remains unclear. In addition, safety concerns (e,g., reproductive and developmental toxicity) have led some countries to ban the inclusion of vinpocetine in dietary supplements [1]. Apovincaminic acid (AVA), an active metabolite of vinpocetine, is commonly used as a surrogate for vinpocetine exposure [1,2]. Evidence indicates that AVA also serves as the primary mediator enhancing neuronal excitability, a property harnessed by individuals who self-identify as “biohackers” or “neurohackers”. The objective was to develop a population pharmacokinetic model for apovincaminic acid (AVA), a surrogate for vinpocetine exposure, using the immediate-release formulation of vinpocetine registered as a drug in the EU.
Methods: Pharmacokinetic data for AVA concentration measurements was obtained through a relative bioavailability study. This study utilized an open crossover design, involving 12 healthy male subjects who received a single 20 mg dose of vinpocetine on an empty stomach. Population PK analysis of AVA was performed using a non-linear mixed effect (NLME) modeling approach within the Lixoft Suite software, i.e., Monolix (version 2021R2, Lixoft SAS, a Simulations Plus company, USA), via the stochastic approximation expectation maximization (SAEM) algorithm [3]. Demographic data, such as race, height, and weight, were documented for each participant, and written informed consent was obtained before the commencement of the study. The study was conducted in accordance with the Declaration of Helsinki.
Results: The population (pop) PK model development procedure was evaluated using three criteria: (1) reduced estimated log-likelihood (-2 log-likelihood objective function value for hierarchical models) and information criteria (corrected Bayesian Information Criteria), (2) goodness-of-fit plots, and (3) visual prediction checks (VPCs). The Pop PK model of AVA, utilizing data from twelve healthy male individuals, reveals that AVA can be effectively characterized by a two-compartment model. This model incorporates zero-order input with Tlag, linear elimination, proportional residual error (0.13), and correlation between Q/F and CL/F (0.72). The estimated fixed effects of the model parameters are: Tlag=0.2 h (RSE=2.88%), Tk0=0.91 h (RSE=7.18%), CL/F= 53.37 L/h (RSE=5.22%), V1/F=57.06 L (RSE=3.92%), V2/F= 103.07 L (RSE=21.4%), Q/F=17.67 L (RSE=24.4%), while the following standard deviation of the random effects are: Tlag=0.088 (RSE=25.2%), Tk0=0.22 (RSE=23.8%), CL/F=0.16 (RSE=23.5%), V2/F=0.33 (RSE=48.1%), and Q/F=0.47 (RSE=24.3%). None of the continuous covariates had a relevant impact on explaining the inter-individual variability.
Conclusions: We propose the first pop PK model characterizing AVA as a vinpocetine exposure proxy, based on the EU-registered formulation of vinpocetine. This pop PK model of AVA serves as a crucial tool, enabling the exploration of diverse “what-if” dosing scenarios for vinpocetine across various indications, including those subtly suggested.
References:
[1] Petric, Z.; Paixão, P.; Filipe, A.; Guimarães Morais, J. Clinical Pharmacology of Vinpocetine: Properties Revisited and Introduction of a Population Pharmacokinetic Model for Its Metabolite, Apovincaminic Acid (AVA). Pharmaceutics, 15, 2502, 2023.
[2] Zhang YS, Li JD, Yan C. An update on vinpocetine: New discoveries and clinical implications. Eur J Pharmacol. 15;819:30-34, 2018.
[3]Monolix 2021R2, Lixoft SAS, a Simulations Plus company and Simulx 2021R2, Lixoft SAS, a Simulations Plus company, USA, 2022.
Reference: PAGE 32 (2024) Abstr 10761 [www.page-meeting.org/?abstract=10761]
Poster: Methodology - Model Evaluation