Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis.

OBJECTIVE: To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. METHODS: We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity. RESULTS: A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03-1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06-1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35-3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23-2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94-2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. CONCLUSION: IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.

The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis.

BACKGROUND: Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. OBJECTIVES: The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. METHODS: Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. RESULTS: Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2  = 44%, p < .00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2  = 46%, p < .00001) had significantly higher voriconazole Cmin (µg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2  = 0%, p = .0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2  = 22%, p = .003). Similarly, the Cmin /D (µg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2  = 0%, p = .002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2  = 0%, p = .003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2  = 0%, p < .00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2  = 50%, p = .005). CONCLUSIONS: Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.

Effectiveness of Pharmacist-led Anticoagulation Management on Clinical Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVES: We performed this systematic review and meta-analysis to confirm whether patients benefit more from pharmacist-led anticoagulation management than other models. METHODS: We searched PubMed, Embase, Cochrane Library and reference lists of yielded results conducted up to April 25, 2017. RCTs and observational cohort studies and case-control studies which compared the percentage of time within the target therapeutic range (TTR), the percentage of time within the expanded therapeutic range (TER), haemorrhage events, thrombosis events, mortality, patient satisfaction and/or medicine cost saving of pharmacist-led anticoagulation management with other models, and species were limited to humans. Two investigators evaluated methodology and extracted data from included studies independently. Data analysis were performed by STATA 12.0 software and quality of evidence assessment was performed by GRADEprofiler software. RESULTS: 8 RCTs and 9 observational cohort studies with 9919 patients were included eventually with high quality and no publication bias. In RCTs pooled results, TTR (p=0.548 moderate-quality), TER (p=0.285, moderate-quality), total haemorrhage events (p=0.140, low-quality), minor haemorrhage events (p=0.162, low-quality), major haemorrhage events (p=0.237, low-quality), thrombosis events (p=0.615, low-quality) and mortality (p=0.876, low-quality) was not significant between two groups. In observational studies pooled results, TTR (p=0.000, low-quality) was significant higher in pharmacist-led management group and the risk of total haemorrhage events (p=0.000, moderate-quality), minor haemorrhage events (p=0.000, moderate-quality) and thrombosis events (p=0.000, moderate-quality) were significant lower in pharmacist-led management group. Patient satisfaction and medicine cost saving were descriptively reviewed. CONCLUSIONS: According to the grading of evidence, we concluded that the risk of total haemorrhage events, minor haemorrhage events and thrombosis events significantly decreased in pharmacist-led anticoagulation management group compared with other management models and no significant difference in TTR, TER, major haemorrhage events and mortality between two groups. Longer follow-up period RCT studies with large sample size should be done in the future to confirm effectiveness of pharmacist-led anticoagulation management model. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

The association of adjusted plasma valproic acid concentration with CYP2C9 gene polymorphism in patients with epilepsy: a systematic review and meta-analysis.

BACKGROUND: Valproic acid (VPA) is a common antiepileptic drug used to treat both generalized and partial epilepsy. Although there is increasing evidence to suggest that CYP2C9 gene polymorphisms are associated with interindividual variability of VPA metabolism, the results are debatable. Therefore, in the present study, we conducted a meta-analysis to evaluate the correlation between CYP2C9 gene polymorphisms and adjusted plasma VPA concentration. METHODS: The EMBASE, MEDLINE, and Cochrane Library databases were searched to obtain relevant studies. Eligible articles were reviewed, and data extraction was performed. We calculated 95% confidence intervals (CIs) and mean differences (MDs) to assess the strength of the relationship of CYP2C9 gene polymorphisms with adjusted plasma VPA concentration. RESULTS: The meta-analysis included 6 studies involving 847 patients with epilepsy. The pooled analysis showed that the CYP2C9 A1075C (AA vs. AC) polymorphism was related to the adjusted plasma concentration of VPA (P=0.02, I2= 82%). Additionally, the AC phenotype statistically significantly increased the adjusted plasma VPA concentration in children compared with the mixed age subgroup (P=0.04, I2= 48%). A similar association was observed between the AC phenotype for Asians (P<0.00001, I2=0%) but not for Caucasians (P=0.34, I2=87%). DISCUSSION: Age might be a crucial covariate influencing the dosage-adjusted VPA concentration in patients with epilepsy. A reduced VPA dosage may be recommendable for children, particularly Asian children, who are CYP2C9 A1075C AC carriers. Further studies could provide high-quality evidence to confirm the correlation between VPA pharmacokinetics and CYP2C9 A1075C polymorphisms.

Efficacy and safety of ibrutinib in diffuse large B-cell lymphoma: A single-arm meta-analysis.

This study aimed to evaluate the benefits and risks of patients with diffuse large B-cell lymphoma (DLBCL) treated with ibrutinib. PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched for relevant studies. The pooled overall response (OR), complete response (CR), and partial response (PR) were 57.9 %, 35.0 %, and 20.1 %, respectively. The pooled OR and CR of ibrutinib monotherapy were 41.6 % and 15.2 % and of ibrutinib + rituximab-based therapy were 72.0 % and 47.5 %, respectively. The relapsed/refractory DLBCL achieved a pooled OR and CR of 49.7 % and 27.7 %, respectively. The pooled OR and CR were 64.2 % and 56.9 % in non-germinal center B-cell-like (non-GCB) DLBCL and 68.3 % and 36.0 % in relapsed/refractory central nervous system lymphoma (CNSL), respectively. The pooled median progression-free and overall survival were 4.54 months and 11.5 months, respectively. 70.7 % and 52.6 % patients experienced ≥ grade 3 adverse events and serious adverse events. The ibrutinib-contained therapy was well tolerated and showed the potential to improve tumor response of patients with non-GCB DLBCL and relapsed/refractory CNSL.

The effect of ABCB1 polymorphism on sirolimus in renal transplant recipients: a meta-analysis.

BACKGROUND: Sirolimus (SRL) is an immunosuppressive drug and substrate of the P-glycoprotein (P-GP) encoded by ABCB1. The relationship between ABCB1 polymorphism and the pharmacokinetics of SRL in different studies were conflicting in renal transplant recipients. Thus, this meta-analysis aims to investigate the influence of ABCB1 C3435T, C1236T, and G2677T/A polymorphisms on the dose-adjusted trough level (C/D) of SRL in renal transplant recipients. METHODS: PubMed, Embase, and the Cochrane Library were searched for relevant studies. The quality of each eligible study was assessed according to Newcastle-Ottawa Scale. The STATA 15.0 was adopted to perform the meta-analysis. The fixed-effects model was used for pooled results with low heterogeneity (I2 ≤50%); otherwise, the random-effects model was used. RESULTS: A total of 6 studies were included in the meta-analysis. Results of pooled analysis showed no significant association of SRL C/D ratio with ABCB1 C3435T polymorphism. The subgroup analysis based on different ethnic groups and different time-points after SRL initiation in renal transplant recipients were also conducted. No significant association was observed in these subgroups. Significant associations were showed between ABCB1 C1236T polymorphism and the C/D ratio of SRL in the homozygous model (TT vs. CC; WMD: -45.54; 95% CI: -75.15, -15.94; P=0.003), and also in subgroup of Caucasian (TT vs. CC; WMD: -46.57; 95% CI: -91.90, -1.25; P=0.044 and TT vs. CC + CT; WMD: -52.10; 95% CI: -95.38, -8.82; P=0.018). Significant differences were found in association between the ABCB1 G2677T/A polymorphism and the C/D ratio of SRL, including the homozygous model (TT vs. GG; WMD: -76.47; 95% CI: -126.37, -26.58; P= 0.003), the heterozygous model (GT vs. GG,WMD: 178.62; 95% CI: 125.03, 232.22; P= 0.000), the dominant model (GT + TT vs. GG; WMD: 82.23; 95% CI: 36.28, 128.17; P=0.000), the recessive model (TT vs. GG + GT; WMD: -179.38; 95% CI: -283.33, -75.42; P=0.001), and the over-dominant model (GT vs. GG + TT; WMD: 199.44; 95% CI: 84.84, 314.05; P=0.001). CONCLUSIONS: No significant association exists between ABCB1 C3435T polymorphism and the C/D ratio of SRL in renal transplant recipients. To achieve target therapeutic concentrations, ABCB1 C1236T homozygous mutant TT genotype will require a higher dose of sirolimus than wild type GG, especially in Caucasian renal transplant recipients. ABCB1 G2677T/A TT genotype will also need a higher dose of sirolimus genotype. Genotyping of ABCB1 might help to improve the individualization of SRL for renal transplant recipients. Further studies are expected to provide high-quality evidence.