Pharmaceutics

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Open AccessEditorial

Association Studies in Clinical Pharmacogenetics

by Pablo Zubiaur and Francisco Abad-Santos

Pharmaceutics 2023, 15(1), 113; https://doi.org/10.3390/pharmaceutics15010113 - 29 Dec 2022

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Abstract

In recent times, the progress of Clinical Pharmacogenetics has been remarkable [...] Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

Research

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12 pages, 597 KiB

Open AccessArticle

Pharmacogenetic Study of the Impact of ABCB1 Single Nucleotide Polymorphisms on the Response to Cyclosporine in Psoriasis Patients

by Alexandr Chernov, Daria Kilina, Tatiana Smirnova and Elvira Galimova

Pharmaceutics 2022, 14(11), 2441; https://doi.org/10.3390/pharmaceutics14112441 - 11 Nov 2022

Cited by 10 | Viewed by 2403

Abstract

Psoriasis is a chronic, T cell-mediated skin disease affecting 2–3% of the Caucasian population. Cyclosporine A is a calcineurin inhibitor that acts selectively on T cells. The cyclosporine A treatment response has been suggested to be modulated by single-nucleotide polymorphisms (SNPs) in the [...] Read more.

Psoriasis is a chronic, T cell-mediated skin disease affecting 2–3% of the Caucasian population. Cyclosporine A is a calcineurin inhibitor that acts selectively on T cells. The cyclosporine A treatment response has been suggested to be modulated by single-nucleotide polymorphisms (SNPs) in the ABCB1 gene. The aim of this research was to evaluate the effect of ABCB1 genetic variants that could affect the response to a cyclosporine treatment in Russian psoriasis patients with the ABCB1 genotype status. The ABCB1 T-129C, G1199A, C1236T, G2677T/A and C3435T SNPs in the 168 patients with psoriasis were genotyped by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and TaqMan SNP genotyping assays. The ABCB1 C1236T, G2677T/A and C3435T SNPs were significantly associated with a negative response to cyclosporine therapy. A very strong association was evident for the C3435T SNP in the ABCB1 gene in the allele, dominant and recessive models (OR = 2.58, OR = 4.01, OR = 2.50, respectively). ABCB1 C1236T and G2677T/A polymorphisms were significantly associated with a negative response to the cyclosporine therapy in the codominant, dominant and recessive models (p ˂ 0.05). Additionally, the haplotype analysis identified that the TGC haplotype is significantly associated with a negative response to cyclosporine therapy in psoriasis patients (p ˂ 0.05). The current study to the best of our knowledge is the first of its kind to be performed in the Russian population. In conclusion, the present results suggest an association between the ABCB1 genetic variants and unresponsiveness to cyclosporine in the Russian population. Further, larger studies are necessary to confirm our findings and replicate them in various ethnic populations before its implementation in the clinical practice. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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13 pages, 603 KiB

Open AccessArticle

Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline

by Pablo Zubiaur, Miriam Matas, Samuel Martín-Vílchez, Paula Soria-Chacartegui, Gonzalo Villapalos-García, Laura Figueiredo-Tor, Sofía Calleja, Marcos Navares-Gómez, Alejandro de Miguel, Jesús Novalbos, Gina Mejía-Abril, Sergio Luquero-Bueno, Manuel Román, Dolores Ochoa and Francisco Abad-Santos

Pharmaceutics 2022, 14(10), 2001; https://doi.org/10.3390/pharmaceutics14102001 - 21 Sep 2022

Cited by 4 | Viewed by 2467

Abstract

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson’s disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in [...] Read more.

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson’s disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC_0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (V_d/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower t_max (i.e., the time to reach the maximum concentration, C_max) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower C_max/DW and higher t_max (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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9 pages, 281 KiB

Open AccessArticle

Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis

by Luis Sainz, Pau Riera, Patricia Moya, Sara Bernal, Jordi Casademont, Cesar Díaz-Torné, Ana Milena Millán, Hye Sang Park, Adriana Lasa and Héctor Corominas

Pharmaceutics 2022, 14(9), 1942; https://doi.org/10.3390/pharmaceutics14091942 - 14 Sep 2022

Cited by 5 | Viewed by 2062

Abstract

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this [...] Read more.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

11 pages, 1001 KiB

Open AccessArticle

Association between Genetic Polymorphisms and Bleeding in Patients on Direct Oral Anticoagulants

by Ha-Young Yoon, Tae-Jin Song, Jeong Yee, Junbeom Park and Hye-Sun Gwak

Pharmaceutics 2022, 14(9), 1889; https://doi.org/10.3390/pharmaceutics14091889 - 7 Sep 2022

Cited by 8 | Viewed by 2466

Abstract

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in [...] Read more.

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56–0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65–0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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12 pages, 1170 KiB

Open AccessArticle

Pharmacogenetic Interventions Improve the Clinical Outcome of Treatment-Resistant Autistic Spectrum Disorder Sufferers

by Maria J. Arranz, Juliana Salazar, Valentin Bote, Alicia Artigas-Baleri, Alexandre Serra-LLovich, Emma Triviño, Jordi Roige, Carlos Lombardia, Martha Cancino, Marta Hernandez, Marc Cendros, Enric Duran-Tauleria, Natalia Maraver and Amaia Hervas

Pharmaceutics 2022, 14(5), 999; https://doi.org/10.3390/pharmaceutics14050999 - 6 May 2022

Cited by 8 | Viewed by 3143

Abstract

BACKGROUND: Autistic spectrum disorders (ASD) are severe neurodevelopmental alterations characterised by deficits in social communication and repetitive and restricted behaviours. About a third of patients receive pharmacological treatment for comorbid symptoms. However, 30–50% do not respond adequately and/or present severe and long-lasting side [...] Read more.

BACKGROUND: Autistic spectrum disorders (ASD) are severe neurodevelopmental alterations characterised by deficits in social communication and repetitive and restricted behaviours. About a third of patients receive pharmacological treatment for comorbid symptoms. However, 30–50% do not respond adequately and/or present severe and long-lasting side effects. METHODS: Genetic variants in CYP1A2, CYP2C19, CYP2D6 and SLC6A4 were investigated in N = 42 ASD sufferers resistant to pharmacological treatment. Clinical recommendations based on their pharmacogenetic profiles were provided within 24–48 h of receiving a biological sample. RESULTS: A total of 39 participants (93%) improved after the pharmacogenetic intervention according to their CGI scores (difference in basal-final scores: 2.26, SD 1.55) and 37 participants (88%) according to their CGAS scores (average improvement of 20.29, SD 11.85). Twenty-three of them (55%) achieved symptom stability (CGI ≤ 3 and CGAS improvement ≥ 20 points), requiring less frequent visits to their clinicians and hospital stays. Furthermore, the clinical improvement was higher than that observed in a control group (N = 62) with no pharmacogenetic interventions, in which 66% responded to treatment (difference in CGI scores: −0.87, SD 9.4, p = 1 × 10⁻⁵; difference in CGAS scores: 6.59, SD 7.76, p = 5 × 10⁻⁸). CONCLUSIONS: The implementation of pharmacogenetic interventions has the potential to significantly improve the clinical outcomes in severe comorbid ASD populations with drug treatment resistance and poor prognosis. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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20 pages, 1132 KiB

Open AccessArticle

Genetic Variant ABCC1 rs45511401 Is Associated with Increased Response to Statins in Patients with Familial Hypercholesterolemia

by Carolina Dagli-Hernandez, Jéssica Bassani Borges, Elisangela da Silva Rodrigues Marçal, Renata Caroline Costa de Freitas, Augusto Akira Mori, Rodrigo Marques Gonçalves, Andre Arpad Faludi, Victor Fernandes de Oliveira, Glaucio Monteiro Ferreira, Gisele Medeiros Bastos, Yitian Zhou, Volker M. Lauschke, Alvaro Cerda, Mario Hiroyuki Hirata and Rosario Dominguez Crespo Hirata

Pharmaceutics 2022, 14(5), 944; https://doi.org/10.3390/pharmaceutics14050944 - 27 Apr 2022

Cited by 5 | Viewed by 3566

Abstract

Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was [...] Read more.

Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid change using molecular docking showed that ABCC1 rs45511401 possibly impairs statin efflux. Deleterious variants in PK genes were not associated with an increased risk of SRAE. In conclusion, the deleterious variant ABCC1 rs45511401 enhanced LDL-c response in Brazilian FH patients. As such, this variant might be a promising candidate for the individualization of statin therapy. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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17 pages, 4024 KiB

Open AccessArticle

Pharmacogenetics of Osteoporosis: A Pathway Analysis of the Genetic Influence on the Effects of Antiresorptive Drugs

by Álvaro del Real, Carmen Valero, José M. Olmos, Jose L. Hernández and José A. Riancho

Pharmaceutics 2022, 14(4), 776; https://doi.org/10.3390/pharmaceutics14040776 - 2 Apr 2022

Cited by 4 | Viewed by 2324

Abstract

Osteoporosis is a skeletal disorder defined by a decreased bone mineral density (BMD) and an increased susceptibility to fractures. Bisphosphonates and selective oestrogen receptor modulators (SERM) are among the most widely used drugs. They inhibit bone resorption by targeting the mevalonate and oestrogen [...] Read more.

Osteoporosis is a skeletal disorder defined by a decreased bone mineral density (BMD) and an increased susceptibility to fractures. Bisphosphonates and selective oestrogen receptor modulators (SERM) are among the most widely used drugs. They inhibit bone resorption by targeting the mevalonate and oestrogen pathways, respectively. The aim of this study was to determine if common variants of genes in those pathways influence drug responses. We studied 192 women treated with oral aminobisphosphonates and 51 with SERMs. Genotypes at 154 SNPs of the mevalonate pathway and 806 in the oestrogen pathway were analyzed. Several SNPs located in genes FDPS and FNTA were associated with the bisphosphonate-induced changes in hip bone mineral density (BMD), whereas polymorphisms of the PDSS1, CYP19A1, CYP1A1, and CYP1A2 genes were associated with SERM-induced changes in spine BMD. After multivariate analyses, genotypes combining genes FDPS and FNTA showed a stronger association with bisphosphonate response (r = 0.34; p = 0.00009), whereas the combination of CYP19A1 and PDSS1 genotypes was associated with the response to SERMs (r = 0.62, p = 0.0003). These results suggest that genotyping genes in these pathways may help predict the response to antiresorptive drugs and hence make personalized therapeutic choices. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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12 pages, 1038 KiB

Open AccessArticle

Associations between the C3orf20 rs12496846 Polymorphism and Both Postoperative Analgesia after Orthognathic and Abdominal Surgeries and C3orf20 Gene Expression in the Brain

by Daisuke Nishizawa, Makoto Nagashima, Shinya Kasai, Junko Hasegawa, Kyoko Nakayama, Yuko Ebata, Ken-ichi Fukuda, Tatsuya Ichinohe, Masakazu Hayashida and Kazutaka Ikeda

Pharmaceutics 2022, 14(4), 727; https://doi.org/10.3390/pharmaceutics14040727 - 28 Mar 2022

Cited by 2 | Viewed by 1895

Abstract

Considerable individual differences are widely observed in the sensitivity to opioid analgesics. We focused on rs12496846, rs698705, and rs10052295 single-nucleotide polymorphisms (SNPs) in the C3orf20, SLC8A2, and CTNND2 gene regions that we previously identified as possibly associated with postoperative analgesia after [...] Read more.

Considerable individual differences are widely observed in the sensitivity to opioid analgesics. We focused on rs12496846, rs698705, and rs10052295 single-nucleotide polymorphisms (SNPs) in the C3orf20, SLC8A2, and CTNND2 gene regions that we previously identified as possibly associated with postoperative analgesia after orthognathic surgery. We investigated associations between these SNPs and postoperative analgesia in 112 patients who underwent major open abdominal surgery in hospitals and were treated with analgesics, including opioids, after surgery. Total genomic DNA was extracted from peripheral blood or oral mucosa samples for genotyping each SNP. Effects of these potent SNPs on gene expression in the brain were also investigated in samples that were provided by the Stanley Foundation Brain Bank. In the association studies, carriers of the G allele of the rs12496846 SNP in the C3orf20 gene region were significantly associated with greater 24 h postoperative analgesic requirements among the three SNPs that were investigated (p = 0.0015), which corroborated a previous study of orthognathic patients (p < 0.0001). In the gene expression analysis, carriers of the G allele of the rs12496846 SNP were significantly associated with lower mRNA expression of the C3orf20 gene (p < 0.0001). These results indicate that this SNP could serve as a marker that predicts analgesic requirements. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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19 pages, 1289 KiB

Open AccessArticle

CYP1A2 mRNA Expression Rather than Genetic Variants Indicate Hepatic CYP1A2 Activity

by Ferenc Fekete, Katalin Mangó, Annamária Minus, Katalin Tóth and Katalin Monostory

Pharmaceutics 2022, 14(3), 532; https://doi.org/10.3390/pharmaceutics14030532 - 27 Feb 2022

Cited by 6 | Viewed by 5532

Abstract

CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of CYP1A2 genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of CYP1A2 genetic variants (−3860G>A, −2467delT, [...] Read more.

CYP1A2, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of several drugs and carcinogenic compounds. Data on the significance of CYP1A2 genetic polymorphisms in enzyme activity are highly inconsistent; therefore, the impact of CYP1A2 genetic variants (−3860G>A, −2467delT, −739T>G, −163C>A, 2159G>A) on mRNA expression and phenacetin O-dealkylation selective for CYP1A2 was investigated in human liver tissues and in psychiatric patients belonging to Caucasian populations. CYP1A2*1F, considered to be associated with high CYP1A2 inducibility, is generally identified by the presence of −163C>A polymorphism; however, we demonstrated that −163C>A existed in several haplotypes (CYP1A2*1F, CYP1A2*1L, CYP1A2*1M, CYP1A2*1V, CYP1A2*1W), and consequently, CYP1A2*1F was a much rarer allelic variant (0.4%) than reported in Caucasian populations. Of note, −163C>A polymorphism was found to result in an increase of neither mRNA nor the activity of CYP1A2. Moreover, hepatic CYP1A2 activity was associated with hepatic or leukocyte mRNA expression rather than genetic polymorphisms of CYP1A2. Consideration of non-genetic phenoconverting factors (co-medication with CYP1A2-specific inhibitors/inducers, tobacco smoking and non-specific factors, including amoxicillin+clavulanic acid therapy or chronic alcohol consumption) did not much improve genotype–phenotype estimation. In conclusion, CYP1A2-genotyping is inappropriate for the prediction of CYP1A2 function; however, CYP1A2 mRNA expression in leukocytes can inform about patients’ CYP1A2-metabolizing capacity. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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12 pages, 632 KiB

Open AccessArticle

Effect of GSTA1 Variants on Busulfan-Based Conditioning Regimen Prior to Allogenic Hematopoietic Stem-Cell Transplantation in Pediatric Asians

by Ai-Hoc Nguyen, Mohitosh Biswas, Apichaya Puangpetch, Santirhat Prommas, Samart Pakakasama, Usanarat Anurathapan, Jiratha Rachanakul, Rattanaporn Sukprasong, Nutthan Nuntharadtanaphong, Nutcha Jongjitsook, Suradej Hongeng and Chonlaphat Sukasem

Pharmaceutics 2022, 14(2), 401; https://doi.org/10.3390/pharmaceutics14020401 - 11 Feb 2022

Cited by 2 | Viewed by 2404

Abstract

Busulfan is widely used as a chemotherapy treatment before hematopoietic stem-cell transplantation (HSCT). However, the response of busulfan is highly variable and unpredictable, whereby the pharmacogenetic interference of glutathione S-transferase (GST) has strong evidence in Caucasians and some adult Asians but not [...] Read more.

Busulfan is widely used as a chemotherapy treatment before hematopoietic stem-cell transplantation (HSCT). However, the response of busulfan is highly variable and unpredictable, whereby the pharmacogenetic interference of glutathione S-transferase (GST) has strong evidence in Caucasians and some adult Asians but not in pediatric Asian patients. This study was aimed at investigating the associations of GST genetic polymorphisms with variations in the pharmacokinetic (PK) properties of busulfan in pediatric Asian patients. This retrospective cohort study recruited 92 pediatric patients. The polymorphism of GSTA1 was genotyped by Sanger sequencing, and GSTM1 and GSTP1 were genotyped by real-time PCR. Drug concentration and PK estimation were identified using an LC-MS/MS method and a noncompartmental model. Statistical analysis was performed by R software. Out of 92 patients, 48 (53%) were males, the mean age was 8.4 ± 5.12 years old, and the average weight was 26.52 ± 14.75 kg. The allele frequencies of GSTA1*B and of GSTM1 and GSTP1* deletions were 16.9%, 68.5%, and 21.2%, respectively. Patients with GSTA1*B had a statistically significant impact on the PK of busulfan, whereas those with GSTM1 and GSTP1 did not (p > 0.05). The carriers of GSTA1*B showed a significant difference compared to noncarriers in terms of t_1/2 (for first dose: 161.9 vs. 134.3 min, p = 0.0016; for second dose: 156.1 vs. 129.8, p = 0.012), CL (88.74 vs. 124.23 mL/min, p = 0.0089), C_max (4232.6 vs. 3675.5 ng/mL, p = 0.0021), and AUC (5310.6 vs. 4177.1 µM/min, p = 0.00033). The augmentation of AUC was around 27.1% in patients carrying the GSTA1*B variant. The GSTA1 polymorphism was significantly associated with variations of the pharmacokinetic properties of busulfan treatment in pediatric Asian patients. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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14 pages, 995 KiB

Open AccessArticle

Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up

by Luis Sendra, Gladys G. Olivera, Rafael López-Andújar, Cristina Serrano, Luis E. Rojas, Eva María Montalvá, María José Herrero and Salvador F. Aliño

Pharmaceutics 2022, 14(2), 354; https://doi.org/10.3390/pharmaceutics14020354 - 3 Feb 2022

Cited by 5 | Viewed by 2229

Abstract

Some gene polymorphisms have been previously associated individually with tacrolimus efficacy and toxicity, but no long-term study to determine the role of pharmacogene variants in the clinical evolution of liver-transplanted patients has been addressed so far. In the present work, we analyzed the [...] Read more.

Some gene polymorphisms have been previously associated individually with tacrolimus efficacy and toxicity, but no long-term study to determine the role of pharmacogene variants in the clinical evolution of liver-transplanted patients has been addressed so far. In the present work, we analyzed the relation between highly-evidenced genetic polymorphisms located in relevant pharmacogenes and the risk of suffering premature death and other comorbidities such as cancer, diabetes mellitus, arterial hypertension, graft rejection, infections and nephrotoxicities in a cohort of 87 patients (8 were excluded due to early loss of follow-up) transplanted at Hospital La Fe in Valencia (Spain) during a 12-year follow-up. Employing a logistic regression model with false discovery rate penalization and Kaplan–Meier analyses, we observed significant association between survival rates and metabolizer genes. In this sense, our results show an association between MTHFR gene variants in donor rs1801133 (HR: 7.90; p-value: 0.032) and recipient rs1801131 (HR: 7.34; p-value: 0.036) and the group of patients who died during the follow-up period, supporting the interest of confirming these results with larger patient cohorts. In addition, donor polymorphisms in UGT1A9 metabolizer gene rs6714486 (OR: 0.13; p-value: 0.032) were associated with a lower risk of suffering from de novo cancer. Genetic variants in CYP2B6 metabolizer gene rs2279343 demonstrated an association with a risk of infection. Other variants in different locations of SLCO1A2, ABCC2 and ABCB1 transporter genes were associated with a lower risk of suffering from type 2 diabetes mellitus, chronic and acute nephrotoxicities and arterial hypertension. Results suggest that pharmacogenetics-derived information may be an important support for personalized drug prescription, clinical follow-up and the evolution of liver-transplanted patients. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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9 pages, 262 KiB

Open AccessArticle

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer

by María Gaibar, Apolonia Novillo, Alicia Romero-Lorca, Diego Malón, Beatriz Antón, Amalia Moreno and Ana Fernández-Santander

Pharmaceutics 2022, 14(2), 242; https://doi.org/10.3390/pharmaceutics14020242 - 20 Jan 2022

Cited by 6 | Viewed by 2497

Abstract

HER2-positive breast cancer (BC) is an aggressive subtype that affects 20–25% of BC patients. For these patients, neoadjuvant therapy is a good option that targets a pathological complete response (pCR) and more breast-conserving surgery. In effect, the outcomes of patients with HER2-positive BC [...] Read more.

HER2-positive breast cancer (BC) is an aggressive subtype that affects 20–25% of BC patients. For these patients, neoadjuvant therapy is a good option that targets a pathological complete response (pCR) and more breast-conserving surgery. In effect, the outcomes of patients with HER2-positive BC have dramatically improved since the introduction of anti-HER2 antibodies such as trastuzumab (TZ) and/or pertuzumab (PZ) added to chemotherapy. This study sought to examine whether correlation exists between copy number variations (CNVs) in several genes related to the PI3K/AKT pathway (HER2, FGFR1, PIK3CA, AKT3 and MDM2) and the efficacy of anti-HER2 neoadjuvant treatment in patients with early HER2-positive BC. Forty-nine patients received TZ or PZ/TZ and chemotherapy as neoadjuvant treatment. Gene CNVs were determined by quantitative polymerase chain reaction on paraffin-embedded biopsy specimens. The response to 6 months of therapy was assessed by Miller–Payne grading of the tumor on surgical resection; grades 4 and 5, indicating >90% tumor reduction, were defined as a good response. A good response was shown by 64.5% and a pCR by 31.2% of patients. When stratified by anti-HER2 antibody received and gene CNV, it was found that patients with FGFR1 gene amplification or those with FGFR1 amplification treated with TZ alone showed a poor response (p = 0.024 and p = 0.037, respectively). In the subset of patients treated with TZ/PZ combined, the pCR rate was significantly lower among those showing FGFR1 amplification (p = 0.021). Although based on a small sample size, our findings suggest that patients with FGFR1 amplification might benefit less from anti-HER2 antibody therapy. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

9 pages, 409 KiB

Open AccessArticle

Genetic Factors of Renin–Angiotensin System Associated with Major Bleeding for Patients Treated with Direct Oral Anticoagulants

by Jeong Yee, Tae-Jin Song, Ha-Young Yoon, Junbeom Park and Hye-Sun Gwak

Pharmaceutics 2022, 14(2), 231; https://doi.org/10.3390/pharmaceutics14020231 - 19 Jan 2022

Cited by 2 | Viewed by 1924

Abstract

The purpose of this study was to identify the renin–angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June [...] Read more.

The purpose of this study was to identify the renin–angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June 2018 to May 2020. To investigate the associations between RAS-related genetic factors and major bleeding, we selected 16 single nucleotide polymorphisms (SNPs) from five genes (namely, AGT, REN, ACE, AGTR1, and AGTR2). Multivariable logistic regression analysis was employed to investigate the independent risk factors for bleeding and to develop a risk scoring system. A total of 172 patients were included in the analysis, including 33 major bleeding cases. Both old age (≥65 years) and moderate to severe renal impairment (CrCl < 50 mL/min) increased the risk of bleeding in the multivariable analysis. Among RAS-related polymorphisms, patients carrying TT genotype of rs5050 and A allele of rs4353 experienced a 3.6-fold (95% CI: 1.4–9.3) and 3.1-fold (95% CI: 1.1–9.3) increase in bleeding, respectively. The bleeding risk increased exponentially with a higher score; the risks were 0%, 2.8%, 16.9%, 32.7%, and 75% in patients with 0, 1, 2, 3, and 4 points, respectively. Although this study is limited to a retrospective study design, this is the first study to suggest RAS-related genetic markers and risk scoring systems, including both clinical and genetic factors, for major bleeding in patients receiving DOAC treatment. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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11 pages, 1276 KiB

Open AccessArticle

Association of a Single-Nucleotide Variant rs11100494 of the NPY5R Gene with Antipsychotic-Induced Metabolic Disorders

by Vera S. Dobrodeeva, Natalia A. Shnayder, Maxim A. Novitsky, Azat R. Asadullin, Elena E. Vaiman, Marina M. Petrova, Oleg V. Limankin, Nikolay G. Neznanov, Natalia P. Garganeeva and Regina F. Nasyrova

Pharmaceutics 2022, 14(2), 222; https://doi.org/10.3390/pharmaceutics14020222 - 18 Jan 2022

Cited by 5 | Viewed by 2434

Abstract

Background: The usage of antipsychotics (APs) is the most robust and scientifically based approach in the treatment of schizophrenia spectrum disorders (SSDs). The efficiency of APs is based on a range of target receptors of the central nervous system (CNS): serotoninergic, dopaminergic, adrenergic, [...] Read more.

Background: The usage of antipsychotics (APs) is the most robust and scientifically based approach in the treatment of schizophrenia spectrum disorders (SSDs). The efficiency of APs is based on a range of target receptors of the central nervous system (CNS): serotoninergic, dopaminergic, adrenergic, histaminergic and cholinergic. Metabolic disorders are the most severe adverse drug reactions (ADRs) and lead to cardiovascular diseases with a high rate of mortality in patients with SSDs. Neuropeptide Y receptor Y5 (NPY5R) is known in the chain of interaction to target receptors for APs, agouti-related peptide receptors and proopiomelanocortin receptors. We studied the association of the single-nucleotide variants (SNVs) rs11100494 and rs6837793 of the NPY5R gene, and rs16147, rs5573, rs5574 of the NPY gene, with metabolic disorders in Russian patients with SSDs. Methods: We examined 99 patients with SSDs (mean age—24.56 years old). The mean duration of APs monotherapy was 8 weeks. The biochemical blood test included levels of glucose, cholesterol, lipoproteins, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein and albumin. Anthropometry included weight, height, waist circumference and hip circumference. We used real-time PCR to study the carriage of major and minor alleles of the SNV rs11100494 (1164C>A) of the NPY5R gene (chromosome localization—4q32.2). Group 1 comprised 25 patients with SSDs taking APs with a change in body weight of more than 6% since the start of APs therapy. Group 2 comprised 74 patients with SSDs taking APs with a change in body weight of less than 6% since the start of APs therapy. Results: We show the significance of genetic risk factors (carriage of major allele C of SNV rs11100494 of the NPY5R gene) for the development of AP-induced weight gain in Russian patients with SSDs. The allele C predisposes to AP-induced weight gain (OR = 33.48 [95% CI: 12.62; 88.82], p-value < 0.001). Additionally, the results of our study demonstrate that first-generation APs (FGAs) are more likely to cause an increase in serum transaminase levels but are less likely to increase body weight. Second-generation APs (SGAs) are more likely to cause weight gain and changes in serum glucose levels. Conclusion: Our study shows the predictive role of the allele C of SNV rs11100494 of the NPY5R gene in the development of AP-induced weight gain. However, we did not find a significant association between biochemical markers and this SNV in Russian patients with SSDs. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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14 pages, 650 KiB

Open AccessArticle

TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients

by Marina Emelyanova, Ilya Pokataev, Igor Shashkov, Elena Kopantseva, Vladimir Lyadov, Rustam Heydarov and Vladimir Mikhailovich

Pharmaceutics 2022, 14(1), 77; https://doi.org/10.3390/pharmaceutics14010077 - 29 Dec 2021

Cited by 2 | Viewed by 2452

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy that has the worst 5-year survival rate of all of the common malignant tumors. Surgery, chemotherapy, and/or chemoradiation remain the main tactics for PDAC treatment. The efficacy of chemotherapy is often compromised because of [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy that has the worst 5-year survival rate of all of the common malignant tumors. Surgery, chemotherapy, and/or chemoradiation remain the main tactics for PDAC treatment. The efficacy of chemotherapy is often compromised because of the substantial risk of severe toxicities. In our study, we focused on identification of polymorphisms in the genes involved in drug metabolism, DNA repair and replication that are associated with inter-individual differences in drug-induced toxicities. Using the microarray, we genotyped 12 polymorphisms in the DPYD, XPC, GSTP1, MTHFR, ERCC1, UGT1A1, and TYMS genes in 78 PDAC patients treated with FOLFIRINOX. It was found that the TYMS rs11280056 polymorphism (6 bp-deletion in TYMS 3′-UTR) predicted grade 1–2 neurotoxicity (p = 0.0072 and p = 0.0019, according to co-dominant (CDM) and recessive model (RM), respectively). It is the first report on the association between TYMS rs11280056 and peripheral neuropathy. We also found that PDAC patients carrying the GSTP1 rs1695 GG genotype had a decreased risk for grade 3–4 hematological toxicity as compared to those with the AA or AG genotypes (p = 0.032 and p = 0.014, CDM and RM, respectively). Due to relatively high p-values, we consider that the impact of GSTP1 rs1695 requires further investigation in a larger sample size. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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13 pages, 276 KiB

Open AccessArticle

Clinical Relevance of Novel Polymorphisms in the Dihydropyrimidine Dehydrogenase (DPYD) Gene in Patients with Severe Fluoropyrimidine Toxicity: A Spanish Case-Control Study

by Paula Soria-Chacartegui, Gonzalo Villapalos-García, Luis A. López-Fernández, Marcos Navares-Gómez, Gina Mejía-Abril, Francisco Abad-Santos and Pablo Zubiaur

Pharmaceutics 2021, 13(12), 2036; https://doi.org/10.3390/pharmaceutics13122036 - 29 Nov 2021

Cited by 9 | Viewed by 2622

Abstract

Among cancer patients treated with fluoropyrimidines, 10–40% develop severe toxicity. Polymorphism of the dihydropyrimidine dehydrogenase (DPYD) gene may reduce DPD function, the main enzyme responsible for the metabolism of fluoropyrimidines. This leads to drug accumulation and to an increased risk of [...] Read more.

Among cancer patients treated with fluoropyrimidines, 10–40% develop severe toxicity. Polymorphism of the dihydropyrimidine dehydrogenase (DPYD) gene may reduce DPD function, the main enzyme responsible for the metabolism of fluoropyrimidines. This leads to drug accumulation and to an increased risk of toxicity. Routine genotyping of this gene, which usually includes DPYD *HapB3, *2A, *13 and c.2846A > T (D949V) variants, helps predict approximately 20–30% of toxicity cases. For DPD intermediate (IM) or poor (PM) metabolizers, a dose adjustment or drug switch is warranted to avoid toxicity, respectively. Societies such as the Spanish Society of Pharmacogenetics and Pharmacogenomics (SEFF), the Dutch Pharmacogenetics Working Group (DPWG) or the Clinical Pharmacogenetics Implementation Consortium (CPIC) and regulatory agencies (e.g., the Spanish Medicines Agency, AEMPS) already recommend DPYD routine genotyping. However, the predictive capacity of genotyping is currently still limited. This can be explained by the presence of unknown polymorphisms affecting the function of the enzyme. In this case-control work, 11 cases of severe fluoropyrimidine toxicity in patients who did not carry any of the four variants mentioned above were matched with 22 controls, who did not develop toxicity and did not carry any variant. The DPYD exome was sequenced (Sanger) in search of potentially pathogenic mutations. DPYD rs367619008 (c.187 A > G, p.Lys63Glu), rs200643089 (c.2324 T > G, p.Leu775Trp) and rs76387818 (c.1084G > A, p.Val362Ile) increased the percentage of explained toxicities to 38–48%. Moreover, there was an intronic variant considered potentially pathogenic: rs944174134 (c.322-63G > A). Further studies are needed to confirm its clinical relevance. The remaining variants were considered non-pathogenic. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

18 pages, 509 KiB

Open AccessArticle

Genetic Polymorphisms Affecting Ranibizumab Response in High Myopia Patients

by David Blánquez-Martínez, Xando Díaz-Villamarín, Alba Antúnez-Rodríguez, Ana Pozo-Agundo, José Ignacio Muñoz-Ávila, Luis Javier Martínez-González and Cristina Lucía Dávila-Fajardo

Pharmaceutics 2021, 13(11), 1973; https://doi.org/10.3390/pharmaceutics13111973 - 20 Nov 2021

Cited by 6 | Viewed by 2814

Abstract

High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world’s population could be nearsighted at the end of this decade. It is characterized by [...] Read more.

High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world’s population could be nearsighted at the end of this decade. It is characterized by at least 6 diopters or axial length > 26 mm and, choroidal neovascularization (CNV) in 5 to 11% of cases. Ranibizumab is a recombinant humanized monoclonal antibody fragment. It is an anti-vascular endothelial growth factor (anti-VEGF) drug used in the treatment of CNV. Many genetic polymorphisms have been associated with interindividual differences in the response to ranibizumab, but these associations were not yet assessed among patients with high myopia and CNV. We performed a retrospective study assessing the association of genetic polymorphisms with response to ranibizumab in patients with CNV secondary to high myopia (mCNV). We included genetic polymorphisms previously associated with the response to drugs used in CNV patients (bevacizumab, ranibizumab, aflibercept, and photodynamic therapy (PDT)). We also included genetic variants in the VEGFA gene. Based on our results, ARMS2 (rs10490924) and CFH (rs1061170) are associated with response to ranibizumab in high myopia patients; and, included VEGFA genetic polymorphisms are not associated with ranibizumab response in our population but might be related to a higher risk of CNV. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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15 pages, 3241 KiB

Open AccessArticle

POLRMT as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients

by Alejandro Velasco-Ruiz, Rocio Nuñez-Torres, Guillermo Pita, Hans Wildiers, Diether Lambrechts, Sigrid Hatse, Danielle Delombaerde, Thomas Van Brussel, M. Rosario Alonso, Nuria Alvarez, Belen Herraez, Christof Vulsteke, Pilar Zamora, Teresa Lopez-Fernandez and Anna Gonzalez-Neira

Pharmaceutics 2021, 13(11), 1942; https://doi.org/10.3390/pharmaceutics13111942 - 16 Nov 2021

Cited by 10 | Viewed by 2640

Abstract

Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability [...] Read more.

Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10⁻⁵). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of POLRMT in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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9 pages, 247 KiB

Open AccessArticle

Association between ADCY9 Gene Polymorphisms and Ritodrine Treatment Outcomes in Patients with Preterm Labor

by Nari Lee, Ha-Young Yoon, Jin-Young Park, Young-Ju Kim, Han-Sung Hwang, Jeong Yee and Hye-Sun Gwak

Pharmaceutics 2021, 13(10), 1653; https://doi.org/10.3390/pharmaceutics13101653 - 10 Oct 2021

Cited by 4 | Viewed by 2061

Abstract

The purpose of this study was to investigate the genetic effects of ADCY9 on ritodrine responses in patients with preterm labor. Five single nucleotide polymorphisms (SNPs) of the ADYC9 gene in 163 patients in preterm labor were genotyped: rs879619, rs2601796, rs2531988, rs2531995, and [...] Read more.

The purpose of this study was to investigate the genetic effects of ADCY9 on ritodrine responses in patients with preterm labor. Five single nucleotide polymorphisms (SNPs) of the ADYC9 gene in 163 patients in preterm labor were genotyped: rs879619, rs2601796, rs2531988, rs2531995, and rs2230739. Additionally, rs598961 of the PDE4B gene and rs1042719 of the ADRB2 gene were included for analysis. Patients with CC genotype of ADCY9 rs879619 had a 2.0-fold (95% confidence interval [CI]: 1.3, 3.2) higher hazard of time to delivery than T allele carriers. Patients with combined genotypes of CC in ADCY9 rs879619, AA in PDE4B rs598961, and GC, CC in ADRB2 rs1042719 showed a greater hazard of time to delivery than patients with other combinations (adjusted hazard ratio [AHR] 3.2; 95% CI: 1.7, 6.3), whereas patients carrying the C allele of ADCY9 rs2531995, G allele of PDE4B rs598961, and GG genotype of ADRB2 rs1042719 had a lower hazard of time to delivery than patients carrying other genotypes (AHR 0.4; 95% CI: 0.2, 0.7). Regarding ritodrine-induced adverse drug events (ADEs), height less than 160 cm and CC genotype of ADCY9 rs2531995 showed a greater risk of ADEs. The results of our study suggest that ADCY9 polymorphisms could affect the efficacy and safety of β₂-adrenergic agonists. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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15 pages, 713 KiB

Open AccessArticle

Variants in COMT, CYP3A5, CYP2B6, and ABCG2 Alter Quetiapine Pharmacokinetics

by Pablo Zubiaur, Paula Fernández-Campos, Marcos Navares-Gómez, Paula Soria-Chacartegui, Gonzalo Villapalos-García, Manuel Román, Gina Mejía-Abril, Dolores Ochoa and Francisco Abad-Santos

Pharmaceutics 2021, 13(10), 1573; https://doi.org/10.3390/pharmaceutics13101573 - 28 Sep 2021

Cited by 5 | Viewed by 3501

Abstract

Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate [...] Read more.

Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase (COMT), other enzymes (e.g., UGT1A1 or UGT1A4), and transporters (e.g., SLCO1B1, ABCB1, or ABCG2). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine’s metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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Review

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17 pages, 665 KiB

Open AccessReview

Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics

by Mercè Brunet and Marçal Pastor-Anglada

Pharmaceutics 2022, 14(9), 1755; https://doi.org/10.3390/pharmaceutics14091755 - 23 Aug 2022

Cited by 20 | Viewed by 4297

Abstract

The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high [...] Read more.

The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C₀/D < 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections. In addition, C₀ tacrolimus intrapatient variability (IPV) has been identified as a potential biomarker to predict poor outcomes related to drug over- and under-exposure. With regard to tacrolimus pharmacodynamics, inconsistent genotype-phenotype relationships have been identified. The aim of this review is to provide a concise summary of currently available data regarding the influence of pharmacogenetics on the clinical outcome of patients with high intrapatient variability and/or a fast metabolizer phenotype. Moreover, the role of membrane transporters in the interindividual variability of responses to tacrolimus is critically discussed from a transporter scientist’s perspective. Indeed, the relationship between transporter polymorphisms and intracellular tacrolimus concentrations will help to elucidate the interplay between the biological mechanisms underlying genetic variations impacting drug concentrations and clinical effects. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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22 pages, 845 KiB

Open AccessReview

-Omic Approaches and Treatment Response in Rheumatoid Arthritis

by Adela Madrid-Paredes, Javier Martín and Ana Márquez

Pharmaceutics 2022, 14(8), 1648; https://doi.org/10.3390/pharmaceutics14081648 - 8 Aug 2022

Cited by 4 | Viewed by 2838

Abstract

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by an aberrant activation of innate and adaptive immune cells. There are different drugs used for the management of RA, including disease-modifying antirheumatic drugs (DMARDs). However, a significant percentage of RA patients do not initially [...] Read more.

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by an aberrant activation of innate and adaptive immune cells. There are different drugs used for the management of RA, including disease-modifying antirheumatic drugs (DMARDs). However, a significant percentage of RA patients do not initially respond to DMARDs. This interindividual variation in drug response is caused by a combination of environmental, genetic and epigenetic factors. In this sense, recent -omic studies have evidenced different molecular signatures involved in this lack of response. The aim of this review is to provide an updated overview of the potential role of -omic approaches, specifically genomics, epigenomics, transcriptomics, and proteomics, to identify molecular biomarkers to predict the clinical efficacy of therapies currently used in this disorder. Despite the great effort carried out in recent years, to date, there are still no validated biomarkers of response to the drugs currently used in RA. -Omic studies have evidenced significant differences in the molecular profiles associated with treatment response for the different drugs used in RA as well as for different cell types. Therefore, global and cell type-specific -omic studies analyzing response to the complete therapeutical arsenal used in RA, including less studied therapies, such as sarilumab and JAK inhibitors, are greatly needed. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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21 pages, 560 KiB

Open AccessEditor’s ChoiceReview

Role of Pharmacogenetics in the Treatment of Acute Myeloid Leukemia: Systematic Review and Future Perspectives

by Álvaro Pinto-Merino, Jorge Labrador, Pablo Zubiaur, Raquel Alcaraz, María José Herrero, Pau Montesinos, Francisco Abad-Santos and Miriam Saiz-Rodríguez

Pharmaceutics 2022, 14(3), 559; https://doi.org/10.3390/pharmaceutics14030559 - 3 Mar 2022

Cited by 7 | Viewed by 3485

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by remarkable toxicity and great variability in response to treatment. Plenteous pharmacogenetic studies have already been published for classical therapies, such as cytarabine or anthracyclines, but such studies remain scarce for newer drugs. There [...] Read more.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by remarkable toxicity and great variability in response to treatment. Plenteous pharmacogenetic studies have already been published for classical therapies, such as cytarabine or anthracyclines, but such studies remain scarce for newer drugs. There is evidence of the relevance of polymorphisms in response to treatment, although most studies have limitations in terms of cohort size or standardization of results. The different responses associated with genetic variability include both increased drug efficacy and toxicity and decreased response or resistance to treatment. A broad pharmacogenetic understanding may be useful in the design of dosing strategies and treatment guidelines. The aim of this study is to perform a review of the available publications and evidence related to the pharmacogenetics of AML, compiling those studies that may be useful in optimizing drug administration. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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11 pages, 2354 KiB

Open AccessReview

The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

by Yubin Song, Hee-Hyun Lim, Jeong Yee, Ha-Young Yoon and Hye-Sun Gwak

Pharmaceutics 2022, 14(3), 501; https://doi.org/10.3390/pharmaceutics14030501 - 24 Feb 2022

Cited by 17 | Viewed by 2902

Abstract

Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis [...] Read more.

Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (e^lnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC_0-∞ (lnGM = 0.43; 95% CI = 0.35–0.50; p < 0.00001) and C_max (lnGM = 0.42; 95% CI = 0.33–0.51; p < 0.00001) than non-carriers, while there was no significant difference in T_max and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC_0-∞ and C_max values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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9 pages, 1464 KiB

Open AccessReview

Association of P450 Oxidoreductase Gene Polymorphism with Tacrolimus Pharmacokinetics in Renal Transplant Recipients: A Systematic Review and Meta-Analysis

by Da-Hoon Lee, Hana Lee, Ha-Young Yoon, Jeong Yee and Hye-Sun Gwak

Pharmaceutics 2022, 14(2), 261; https://doi.org/10.3390/pharmaceutics14020261 - 22 Jan 2022

Cited by 10 | Viewed by 2850

Abstract

There are conflicting results regarding the effect of the P450 oxidoreductase (POR) *28 genotype on the tacrolimus (TAC) pharmacokinetics (PKs) during the early post-transplantation period in adult renal transplant recipients. Thus, we characterized the impact of POR*28 on TAC PKs. We [...] Read more.

There are conflicting results regarding the effect of the P450 oxidoreductase (POR) *28 genotype on the tacrolimus (TAC) pharmacokinetics (PKs) during the early post-transplantation period in adult renal transplant recipients. Thus, we characterized the impact of POR*28 on TAC PKs. We conducted a systematic review on the association between POR*28 and PKs of TAC in adult renal transplant recipients. Structured searches were conducted using PubMed, Web of Science, and Embase. TAC standardized trough concentration (ng/mL per mg/kg) data were extracted. Mean differences (MD) and their corresponding 95% confidence intervals (CIs) were used to identify the differences between the POR*28 genotype and PKs of TAC. The subgroup analysis was conducted according to CYP3A5 expression status. Six studies (n = 1061) were included. TAC standardized trough concentrations were significantly lower in recipients with the POR*28 allele compared to recipients with POR*1/*1 (MD: 8.30 ng/mL per mg/kg; 95% CI: 1.93, 14.67; p = 0.01). In the subgroup analysis, TAC standardized trough concentrations were lower for subjects who were POR*28 carriers than those who were POR*1/*1 in CYP3A5 expressers (MD: 20.21 ng/mL per mg/kg; 95% CI: 16.85, 23.56; p < 0.00001). No significant difference between POR*28 carriers and POR*1/*1 was found in the CYP3A5 non-expressers. The results of our meta-analysis demonstrated a definite correlation between the POR*28 genotype and PKs of TAC. Patients carrying the POR*28 allele may require a higher dose of TAC to achieve target levels compared to those with POR*1/*1, especially in CYP3A5 expressers. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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Other

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26 pages, 871 KiB

Open AccessSystematic Review

Pharmacogenetics and Pain Treatment with a Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Antidepressants: A Systematic Review

by Farzin Zobdeh, Ivan I. Eremenko, Mikail A. Akan, Vadim V. Tarasov, Vladimir N. Chubarev, Helgi B. Schiöth and Jessica Mwinyi

Pharmaceutics 2022, 14(6), 1190; https://doi.org/10.3390/pharmaceutics14061190 - 1 Jun 2022

Cited by 20 | Viewed by 7233

Abstract

Background: This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used for pain treatment. Methods: A systematic literature search was performed according to the preferred reporting items for systematic reviews and [...] Read more.

Background: This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used for pain treatment. Methods: A systematic literature search was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines regarding the human in vivo efficacy and safety of NSAIDs and antidepressants in pain treatment that take pharmacogenetic parameters into consideration. Studies were collected from PubMed, Scopus, and Web of Science up to the cutoff date 18 October 2021. Results: Twenty-five articles out of the 6547 initially detected publications were identified. Relevant medication–gene interactions were noted for drug safety. Interactions important for pain management were detected for (1) ibuprofen/CYP2C9; (2) celecoxib/CYP2C9; (3) piroxicam/CYP2C8, CYP2C9; (4) diclofenac/CYP2C9, UGT2B7, CYP2C8, ABCC2; (5) meloxicam/CYP2C9; (6) aspirin/CYP2C9, SLCO1B1, and CHST2; (7) amitriptyline/CYP2D6 and CYP2C19; (8) imipramine/CYP2C19; (9) nortriptyline/CYP2C19, CYP2D6, ABCB1; and (10) escitalopram/HTR2C, CYP2C19, and CYP1A2. Conclusions: Overall, a lack of well powered human in vivo studies assessing the pharmacogenetics in pain patients treated with NSAIDs or antidepressants is noted. Studies indicate a higher risk for partly severe side effects for the CYP2C9 poor metabolizers and NSAIDs. Further in vivo studies are needed to consolidate the relevant polymorphisms in NSAID safety as well as in the efficacy of NSAIDs and antidepressants in pain management. Full article

(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)

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