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Volume 18
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Article

Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety

by
Sofía Calleja
1,
Andrea Rodríguez-López
1,
Dolores Ochoa
1,
Sergio Luquero
1,
Marcos Navares-Gómez
1,
Manuel Román
1,
Gina Mejia-Abril
1,
Samuel Martín-Vilchez
1,
Francisco Abad-Santos
1,2,* and
Pablo Zubiaur
1,*
1
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Faculty of Medicine, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IIS-Princesa), 28006 Madrid, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2025, 18(2), 151; https://doi.org/10.3390/ph18020151
Submission received: 29 December 2024 / Revised: 13 January 2025 / Accepted: 22 January 2025 / Published: 23 January 2025
(This article belongs to the Section Pharmacology)
Versions Notes

Abstract

Background/Objectives: Pregabalin is a useful therapeutic option for patients with anxiety or neuropathic pain. Genetic variants in certain genes encoding for transporters related to absorption and distribution could have an impact on the efficacy and safety of the drug. Furthermore, extreme phenotypes in metabolic enzymes could alter pregabalin-limited metabolism. Methods: In this study, we included 24 healthy volunteers participating in a bioequivalence clinical trial and administered pregabalin 300 mg orally; 23 subjects were genotyped for 114 variants in 31 candidate genes, and we explored their impact on pregabalin pharmacokinetics and safety. Results: The uncorrected mean (±SD) of AUC∞ and Cmax were 61,097 ± 14,762 ng*h/mL and 7802 ± 1659 ng/mL, respectively, which were significantly higher in females than in males (p = 0.002 and p = 0.001, respectively), with no differences in dose/weight (DW)- corrected exposure metrics. NAT2 slow acetylators (SAs) showed a 16–18% increase in exposure compared to intermediate (IAs) and normal (NAs) acetylators; NAT2 SAs exhibited a 25% higher t1/2 as compared with NAT2 IAs and 58% higher compared to NAT2 NAs. In contrast, neither the NAT2 phenotype nor other genetic variants were related to pregabalin adverse drug reaction (ADR) occurrence. On the contrary, sex and sex-related exposure differences (i.e., females and their higher exposure compared to males) were the main predictors of ADR occurrence. Conclusions: Our findings suggest that NAT2 could be partially responsible for the minor proportion of pregabalin metabolism, but the effect of NAT2 phenotype does not seem clinically relevant. Therefore, pharmacogenetic biomarkers appear to play a restrained role in pregabalin pharmacotherapy.
Keywords: pregabalin; pharmacokinetics; safety; pharmacogenetics pregabalin; pharmacokinetics; safety; pharmacogenetics

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MDPI and ACS Style

Calleja, S.; Rodríguez-López, A.; Ochoa, D.; Luquero, S.; Navares-Gómez, M.; Román, M.; Mejia-Abril, G.; Martín-Vilchez, S.; Abad-Santos, F.; Zubiaur, P. Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety. Pharmaceuticals 2025, 18, 151. https://doi.org/10.3390/ph18020151

AMA Style

Calleja S, Rodríguez-López A, Ochoa D, Luquero S, Navares-Gómez M, Román M, Mejia-Abril G, Martín-Vilchez S, Abad-Santos F, Zubiaur P. Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety. Pharmaceuticals. 2025; 18(2):151. https://doi.org/10.3390/ph18020151

Chicago/Turabian Style

Calleja, Sofía, Andrea Rodríguez-López, Dolores Ochoa, Sergio Luquero, Marcos Navares-Gómez, Manuel Román, Gina Mejia-Abril, Samuel Martín-Vilchez, Francisco Abad-Santos, and Pablo Zubiaur. 2025. "Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety" Pharmaceuticals 18, no. 2: 151. https://doi.org/10.3390/ph18020151

APA Style

Calleja, S., Rodríguez-López, A., Ochoa, D., Luquero, S., Navares-Gómez, M., Román, M., Mejia-Abril, G., Martín-Vilchez, S., Abad-Santos, F., & Zubiaur, P. (2025). Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety. Pharmaceuticals, 18(2), 151. https://doi.org/10.3390/ph18020151

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