Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Clinical Trial Design
2.3. Pharmacokinetic and Safety Analysis
2.4. Genotyping and Phenotyping
2.5. Statistical Analysis
3. Results
3.1. Demographic Characteristics
3.2. Pharmacokinetics
3.3. Pharmacogenetics
3.4. Safety
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Clinical Trial | EUDRA-CT | Conditions | Dose | Sample Size * (BE Study) | Sample Size * (PG Study) |
---|---|---|---|---|---|
A | 2020-004710-35 | Fasting | Single, 50 mg | 36 (19/17) | 22 (12/10) |
B | 2021-000283-29 | Fed | Single, 50 mg | 36 (18/18) | 30 (15/15) |
C | 2021-000285-15 | Fasting | Multiple, 50 mg every 24 h | 36 (19/17) | 27 (11/16) |
n | Age Years | Height m | Weight kg | BMI kg/m2 | |
---|---|---|---|---|---|
Sex | |||||
Male | 38 | 28.50 (24.00–34.25) | 1.76 (0.06) | 75.96 (11.64) | 24.85 (22.30–27.20) |
Female | 41 | 30.00 (24.00–33.50) | 1.62 (0.06) * | 63.92 (10.21) * | 24.33 (21.88–27.37) |
Origin | |||||
European | 18 | 26.00 (23.75–31.75) | 1.73 (0.09) | 76.81 (14.61) | 26.24 (22.40–27.82) |
Latin American | 61 | 31.00 (25.00–34.50) | 1.67 (0.09) * | 67.61 (10.99) * | 24.33 (21.84–26.55) |
Trial | |||||
A | 22 | 25.00 (23.00–31.50) | 1.70 (0.09) | 68.30 (11.71) | 24.49 (21.04–26.38) |
B | 30 | 28.50 (24.00–43.00) | 1.68 (0.09) | 68.63 (12.32) | 23.66 (21.01–27.53) |
C | 27 | 32.00 (26.00–33.00) | 1.68 (0.10) | 72.06 (13.21) | 25.64 (23.15–27.58) |
Total | 79 | 30.00 (24.00–34.00) | 1.68 (0.09) | 69.71 (12.43) | 24.58 (22.12–27.25) |
n | AUC/DW kg·ng·h/mL·mg | Cmax/DW kg·ng/mL·mg | tmax h | t1/2 h | CL/F L/kg·h | |
---|---|---|---|---|---|---|
Sex | ||||||
Female | 41 | 577.02 (189.54) | 60.84 (29.19–74.58) | 4.50 (3.94–5.31) | 26.50 (8.21) | 1.81 (1.44–2.41) |
Male | 38 | 529.27 (177.04) | 48.31 (30.22–67.24) | 4.44 (3.76–5.13) | 26.34 (5.22) | 2.03 (1.64–2.61) |
Origin | ||||||
European | 18 | 582.84 (202.00) | 54.80 (40.65–72.87) | 4.69 (4.19–4.91) | 25.27 (5.16) | 1.75 (1.55–2.33) |
Latin American | 61 | 545.56 (179.29) | 48.74 (27.06–71.30) | 4.41 (3.75–5.31) | 26.75 (7.33) | 1.92 (1.52–2.57) |
Trial | ||||||
A | 22 | 633.34 (149.93) | 58.58 (50.19–67.74) | 4.31 (3.97–5.00) | 27.63 (3.89) | 1.77 (1.40–1.94) |
B | 30 | 397.84 (106.91) * | 24.85 (19.40–33.98) * | 5.13 (4.41–6.25) * | 30.62 (7.04) | 2.72 (2.21–3.35) * |
C | 27 | 663.03 (157.77) | 73.88 (63.14–93.71) | 4.25 (3.63–4.50) | 20.77 (4.51) $ | 1.64 (1.26–1.81) |
Total | 79 | 554.06 (184.03) | 50.72 (29.50–72.54) | 4.50 (3.88–5.13) | 26.42 (6.90) | 1.91 (1.52–2.51) |
Gene | Genotype/Phenotype | n | AUC/DW | Cmax/DW | tmax | t1/2 | CL/F | |
---|---|---|---|---|---|---|---|---|
kg·ng·h/mL·mg | kg·ng/mL·mg | h | h | L/kg·h | ||||
CYP2D6 | Phenotype | UM | 2 | 451.77 (231.42) | 45.37 [19.63–71.11] | 4.94 [4.75–5.13] | 20.42 (3.90) | 2.60 [1.64–3.55] |
NM | 55 | 547.97 (199.06) | 48.74 (28.59–72.57) | 4.38 (3.75–5.13) | 25.80 (6.01) | 1.94 (1.45–2.71) | ||
IM | 18 | 585.61 (188.13) | 50.24 (36.42–67.93) | 4.88 (3.97–5.78) | 29.97 (8.68) * | 1.73 (1.50–2.70) | ||
UGT1A3 | rs2008584 | A/A | 16 | 548.38 (162.14) | 58.17 (31.72–83.83) | 4.06 (3.38–4.48) * | 24.35 (6.62) | 1.84 (1.67–2.49) |
A/G | 34 | 564.37 (212.65) | 47.89 (25.47–72.54) | 4.69 (3.94–5.66) | 25.70 (5.44) | 1.84 (1.33–2.74) | ||
G/G | 26 | 537.28 (170.40) | 48.67 (28.80–67.93) | 4.69 (3.88–5.16) | 29.03 (8.39) | 1.92 (1.64–2.46) | ||
UGT1A4 | rs2011425 | T/T | 64 | 541.38 (187.75) | 48.49 (28.39–73.09) | 4.50 (3.75–5.25) | 25.28 (6.67) | 1.93 (1.55–2.69) |
T/G | 14 | 587.99 (147.20) | 57.32 (30.52–66.27) | 4.31 (3.97–4.88) | 31.14 (5.96) * | 1.75 (1.52–1.98) | ||
NAT2 | Phenotype | RA | 7 | 602.63 (159.64) | 60.84 (48.74–65.11) | 4.00 (3.26–4.25) | 27.80 (7.77) | 1.75 (1.68–1.93) |
IA | 34 | 589.33 (196.52) | 61.37 (36.10–76.70) | 4.38 (3.75–5.16) | 24.61 (4.98) | 1.81 (1.33–2.38) | ||
SA | 37 | 516.32 (173.40) | 40.91 (24.85–68.97) * | 4.75 (4.06–5.56) | 27.74 (8.04) | 2.19 (1.66–2.67) | ||
SLC6A2 | rs12708954 | C/C | 56 | 522.63 (182.61) * | 48.31 (24.23–70.35) | 4.45 (3.75–5.09) | 26.56 (7.34) | 1.93 (1.65–2.81) * |
C/A | 21 | 648.45 (162.98) | 65.11 (41.05–78.25) | 4.63 (3.94–5.56) | 26.29 (6.01) | 1.67 (1.31–1.99) | ||
A/A | 2 | 442.73 (95.66) | 47.11 [36.51–57.72] | 5.06 [4.88–5.25] | 23.94 (2.07) | 2.35 [1.98–2.71] | ||
SLC19A1 | rs1051266 | A/A | 16 | 498.20 (190.51) | 37.45 (20.53–53.46) * | 4.50 (4.03–6.25) | 27.92 (5.87) | 2.31 (1.50–3.26) |
A/G | 34 | 598.00 (181.87) | 60.74 (41.65–74.22) | 4.33 (3.75–5.03) | 25.72 (5.63) | 1.81 (1.43–2.21) | ||
G/G | 27 | 537.43 (182.46) | 48.18 (23.61–71.11) | 4.50 (3.76–5.13) | 26.12 (8.87) | 1.92 (1.61–2.74) |
Clinical Trial | ADRs | n | AUC ng·h/mL | Cmax ng/mL |
---|---|---|---|---|
A | no | 20 | 470.43 (108.04) | 45.42 (34.53–51.28) |
yes | 2 | 449.80 (19.61) | 44.90 [43.71- 46.09] | |
B | no | 24 | 282.60 (85.10) | 16.81 (12.28–24.08) |
yes | 6 | 359.96 (92.85) | 20.28 (12.15–24.60) | |
C | no | 25 | 476.37 (161.56) | 52.75 (43.61–63.79) |
yes | 2 | 505.72 (22.20) | 54.95 [51.33–58.57] | |
Total | no | 69 | 407.25 (152.77) | 26.21 (17.99–47.39) |
yes | 10 | 407.08 (94.52) | 40.52 (20.99–51.82) |
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Soria-Chacartegui, P.; Cendoya-Ramiro, P.; González-Iglesias, E.; Martín-Vílchez, S.; Rodríguez-Lopez, A.; Mejía-Abril, G.; Román, M.; Luquero-Bueno, S.; Ochoa, D.; Abad-Santos, F. Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron. Pharmaceutics 2024, 16, 1077. https://doi.org/10.3390/pharmaceutics16081077
Soria-Chacartegui P, Cendoya-Ramiro P, González-Iglesias E, Martín-Vílchez S, Rodríguez-Lopez A, Mejía-Abril G, Román M, Luquero-Bueno S, Ochoa D, Abad-Santos F. Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron. Pharmaceutics. 2024; 16(8):1077. https://doi.org/10.3390/pharmaceutics16081077
Chicago/Turabian StyleSoria-Chacartegui, Paula, Patricia Cendoya-Ramiro, Eva González-Iglesias, Samuel Martín-Vílchez, Andrea Rodríguez-Lopez, Gina Mejía-Abril, Manuel Román, Sergio Luquero-Bueno, Dolores Ochoa, and Francisco Abad-Santos. 2024. "Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron" Pharmaceutics 16, no. 8: 1077. https://doi.org/10.3390/pharmaceutics16081077