Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data
Abstract
:1. Introduction
2. Materials and Methods
2.1. Systematic Literature Review
2.2. Study Selection Criteria
2.3. Data Extraction
2.4. Quality Assessment
2.5. Statistical Analysis
3. Results
3.1. General Characteristics of Studies
3.2. Determinants of Voriconazole Trough Concentration
3.3. Impact of Inflammation Modulated by CYP2C19-Mediated Metabolism of VRC
3.4. Quality Assessment
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Study Design | Ethnic Origin, Nationality | Number of Patients | Number of VRC Cmin Determinations | Age (Years) | Sex | VRC Cmin (mg/L) | CRP (mg/L) | Pharmacogenetic Data | Hardy–Weinberg Equilibrium | |
Gautier-Veyret et al., 2015 [19] | Retrospective cohort study | Caucasian, French | 28 | 255 | 52.6 (27.9–61.4) | M: 15 (53.6) F: 13 (46.4) | 1.4 (0.1–5.8) | 8.0 (3.0–436.0) | CYP2C19 CYP3A4 CYP3A5 | Yes |
Gautier-Veyret et al., 2019 [25] | Retrospective case-control study | Caucasian, French | 57 * | 62 | 60.1 (21.0–79.3) | M: 30 (52.6) F: 27 (47.4) | 3.8 (0.1–10.3) | 96.0 (3.0–364.0) | CYP2C19 CYP3A4 CYP3A5 | Yes |
Gautier-Veyret et al., 2020 [26] | Prospective observational study | Caucasian, French | 42 | 150 | 52.8 (22.3–77.6) | M: 30 (71.4) F: 12 (28.6) | 1.3 (0.1–9.7) | 43.0 (3.0–369.0) | CYP2C19 CYP3A4 CYP3A5 | Yes |
Yamada et al., 2015 [30] | Retrospective cohort study | Asian, Japanese | 47 | 47 | 70.6 (29.4–83.2) | M: 32 (68.1) F: 15 (31.9) | 2.4 (0.02–9.6) | 1.98 (0.01–26.8) | CYP2C19 | Yes |
Lamoureux et al., 2015 [15] | Retrospective cohort study | Caucasian, French | 9 | 21 | 68.0 (21.0–79.0) | M: 7 (77.8) F: 2 (22.2) | 0.8 (0.2–4.1) | 17.0 (5.0–172.0) | CYP2C19 CYP3A4 CYP3A5 | Yes |
Veringa et al., 2017 [28] | Prospective observational study | Caucasian, Netherlands | 20 | 219 | 64.0 (19.0–72.0) | M: 13 (65.0) F: 7 (35.0) | 2.8 (0.2–11.2) | 59.0 (1.5–401.0) | CYP2C19 | Yes |
Total | / | / | 203 | 754 | 58.6 (19.0–83.2) | M: 127 (63.0) F: 76 (37.0) | 1.8 (0.02–11.2) | 27.0 (0.01–436) | / | / |
Covariate | Category | Estimate (95% Confidence Interval) | p-Value a |
---|---|---|---|
Demographics Age Weight Voriconazole treatment Daily dose Route of administration Hepatic function ASAT ALAT Inflammation marker CRP Comedication PPI Pharmacogenomics CYP2C19 phenotype b CYP3A4 phenotype CYP3A5 phenotype Combined genetic score c | Per year increase Per kg increase Per mg increase Oral vs. Intravenous Per U/L increase Per U/L increase Per mg/L increase No PPI vs. PPI PM/IM vs. EM RM/UM vs. EM IM vs. EM Non-expressor vs. expressor Per score point increase | 0.016 [0.007–0.025] 0.004 [−0.004–0.013] 0.002 [0.001–0.003]−0.318 [−0.497–−0.138] 5.11*10−5 [−9.61 × 10−5–1.98 × 10−4] 3.18*10−5 [−1.55 × 10−4–2.19 × 10−4] 0.005 [0.004–0.006] −0.078 [−0.329–0.173] 0.104 [−0.197–0.406] −0.350 [−0.685–−0.014] 0.374 [−0.058–0.807] 0.309 [−0.155–0.772] −0.558 [−0.853–−0.263] | <0.001 0.336 <0.001 <0.001 0.497 0.739 <0.001 0.542 0.499 0.043 0.093 0.195 <0.001 |
Model (AIC) | Numbers of Observations, Patients, Studies | Estimate [95% Confidence Interval] | p-Value a |
---|---|---|---|
Model 1 (AIC = 1805) | 754, 203, 6 | ||
Age | 0.014 [0.006–0.022] | <0.001 | |
VRC daily dose | 0.002 [0.002–0.003] | <0.001 | |
CRP level | 0.005 [0.004–0.006] | <0.001 | |
CYP2C19 phenotype b | 0.016 | ||
PM/IM vs. EM | 0.168 [−0.105–0.441] | 0.231 | |
RM/UM vs. EM | −0.322 [−0.627–−0.016] | 0.041 | |
Interaction CRP*CYP2C19 phenotype CRP–PM/IM versus EM CRP–RM/UM versus EM | −9.81*10−4 [−0.003–0.001] 1.63*10−5 [−0.002–0.002] | 0.601 0.340 0.987 | |
Model 2 (AIC = 1183) | 488, 136, 4 | ||
Age | 0.019 [0.009–0.028] | <0.001 | |
VRC daily dose | 0.003 [0.002–0.004] | <0.001 | |
CRP level | 0.006 [0.005–0.007] | <0.001 | |
CYP2C19 phenotype b | 0.012 | ||
PM/IM vs. EM | 0.183 [−0.157–0.523] | 0.294 | |
RM/UM vs. EM | −0.366 [−0.691–−0.042] | 0.029 | |
CYP3A4 phenotype | |||
IM vs. EM | 0.497 [0.128–0.865] | 0.009 | |
Interaction CRP*CYP2C19 phenotype | 0.019 | ||
CRP–PM/IM versus EM | −0.003 [−0.006–−5.39*10−4] | 0.018 | |
CRP–RM/UM versus EM | 7.02*10−4 [−0.002–0.004] | 0.645 | |
Model 3 (AIC = 1178) | 488, 136, 4 | ||
Age | 0.018 [0.009–0.028] | <0.001 | |
VRC daily dose | 0.003 [0.002–0.004] | <0.001 | |
CRP level | 0.006 [0.005–0.007] | <0.001 | |
Genetic score c | −0.555 [−0.813–−0.296] | <0.001 | |
Interaction CRP*genetic score | 0.003 [5.28*10−4–0.006] | 0.018 |
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Bolcato, L.; Khouri, C.; Veringa, A.; Alffenaar, J.W.C.; Yamada, T.; Naito, T.; Lamoureux, F.; Fonrose, X.; Stanke-Labesque, F.; Gautier-Veyret, E. Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data. J. Clin. Med. 2021, 10, 2089. https://doi.org/10.3390/jcm10102089
Bolcato L, Khouri C, Veringa A, Alffenaar JWC, Yamada T, Naito T, Lamoureux F, Fonrose X, Stanke-Labesque F, Gautier-Veyret E. Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data. Journal of Clinical Medicine. 2021; 10(10):2089. https://doi.org/10.3390/jcm10102089
Chicago/Turabian StyleBolcato, Léa, Charles Khouri, Anette Veringa, Jan Willem C. Alffenaar, Takahiro Yamada, Takafumi Naito, Fabien Lamoureux, Xavier Fonrose, Françoise Stanke-Labesque, and Elodie Gautier-Veyret. 2021. "Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data" Journal of Clinical Medicine 10, no. 10: 2089. https://doi.org/10.3390/jcm10102089