Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety
<b>Background/Objectives:</b> 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. Furthermo...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/2/151 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849719781398151168 |
|---|---|
| author | Sofía Calleja Andrea Rodríguez-López Dolores Ochoa Sergio Luquero Marcos Navares-Gómez Manuel Román Gina Mejia-Abril Samuel Martín-Vilchez Francisco Abad-Santos Pablo Zubiaur |
| author_facet | Sofía Calleja Andrea Rodríguez-López Dolores Ochoa Sergio Luquero Marcos Navares-Gómez Manuel Román Gina Mejia-Abril Samuel Martín-Vilchez Francisco Abad-Santos Pablo Zubiaur |
| author_sort | Sofía Calleja |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> 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. <b>Methods</b>: 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. <b>Results</b>: The uncorrected mean (±SD) of AUC<sub>∞</sub> and C<sub>max</sub> were 61,097 ± 14,762 ng*h/mL and 7802 ± 1659 ng/mL, respectively, which were significantly higher in females than in males (<i>p</i> = 0.002 and <i>p</i> = 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 t<sub>1/2</sub> 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. <b>Conclusions</b>: 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. |
| format | Article |
| id | doaj-art-5fec6c8d5a7a4afabc64343b68cc99f1 |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-5fec6c8d5a7a4afabc64343b68cc99f12025-08-20T03:12:05ZengMDPI AGPharmaceuticals1424-82472025-01-0118215110.3390/ph18020151Impact of Genetic Variants on Pregabalin Pharmacokinetics and SafetySofía Calleja0Andrea Rodríguez-López1Dolores Ochoa2Sergio Luquero3Marcos Navares-Gómez4Manuel Román5Gina Mejia-Abril6Samuel Martín-Vilchez7Francisco Abad-Santos8Pablo Zubiaur9Clinical 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, SpainClinical 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, SpainClinical 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, SpainClinical 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, SpainClinical 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, SpainClinical 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, SpainClinical 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, SpainClinical 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, SpainClinical 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, SpainClinical 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<b>Background/Objectives:</b> 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. <b>Methods</b>: 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. <b>Results</b>: The uncorrected mean (±SD) of AUC<sub>∞</sub> and C<sub>max</sub> were 61,097 ± 14,762 ng*h/mL and 7802 ± 1659 ng/mL, respectively, which were significantly higher in females than in males (<i>p</i> = 0.002 and <i>p</i> = 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 t<sub>1/2</sub> 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. <b>Conclusions</b>: 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.https://www.mdpi.com/1424-8247/18/2/151pregabalinpharmacokineticssafetypharmacogenetics |
| spellingShingle | Sofía Calleja Andrea Rodríguez-López Dolores Ochoa Sergio Luquero Marcos Navares-Gómez Manuel Román Gina Mejia-Abril Samuel Martín-Vilchez Francisco Abad-Santos Pablo Zubiaur Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety Pharmaceuticals pregabalin pharmacokinetics safety pharmacogenetics |
| title | Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety |
| title_full | Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety |
| title_fullStr | Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety |
| title_full_unstemmed | Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety |
| title_short | Impact of Genetic Variants on Pregabalin Pharmacokinetics and Safety |
| title_sort | impact of genetic variants on pregabalin pharmacokinetics and safety |
| topic | pregabalin pharmacokinetics safety pharmacogenetics |
| url | https://www.mdpi.com/1424-8247/18/2/151 |
| work_keys_str_mv | AT sofiacalleja impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT andrearodriguezlopez impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT doloresochoa impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT sergioluquero impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT marcosnavaresgomez impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT manuelroman impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT ginamejiaabril impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT samuelmartinvilchez impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT franciscoabadsantos impactofgeneticvariantsonpregabalinpharmacokineticsandsafety AT pablozubiaur impactofgeneticvariantsonpregabalinpharmacokineticsandsafety |