CYP3A5 Genotype Research Articles

The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients.

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 invitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression invitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity.

Effects of Clarithromycin and Ketoconazole on FK506 Metabolism in Different CYP3A4 Genotype Recombinant Metabolic Enzyme Systems.

This study aimed to investigate the effects of clarithromycin and ketoconazole on the pharmacokinetic properties of tacrolimus in different CYP3A4 genotype recombinant metabolic enzyme systems, so as to understand the drug interactions and their mechanisms further. The experiment was divided into three groups: a blank control group, CYP3A4*1 group and CYP3A4*18 recombinant enzyme group. Each group was added with tacrolimus (FK506) of a series of concentrations. Then 1 umol/L clarithromycin or ketoconazole was added to the recombinant enzyme group and incubated in the NADPH system for 30 minutes to examine the effects of clarithromycin and ketoconazole on the metabolizing enzymes' activity of different genotypes. The remaining concentration of FK506 in the reaction system was determined using UPLC-MS/MS, and the enzyme kinetic parameters were calculated using the software. The metabolism of CYP3A4*18 to FK506 was greater than that of CyP3А4*1B. Compared with the CYP3A4*1 group, the metabolic rate and clearance of FK506 in the CYP3A4*18 group significantly increased, with Km decreasing. Clarithromycin and ketoconazole inhibit the metabolism of FK506 by affecting the enzyme activity of CYP3A4*1B and CYP3A4*18B. After adding clarithromycin or ketoconazole, the metabolic rate of FK506 significantly decreased in CYP3A4*1 and CYP3A4*18, with Km increasing, Vmax and Clint decreasing. Compared with CYP3A4*1, CYP3A4*18 has a greater metabolism of FK506, clarithromycin and ketoconazole can inhibit both the enzymatic activities of CYP3A4*1 and CYP3A4*18, consequently affecting the metabolism of FK506 and the inhibitory on CYP3A4*1 is stronger.

The impact of CYP3A5*3 on oral quetiapine: A population pharmacokinetic model in Chinese bipolar disorder patients

BackgroundThere is great interindividual difference in the plasma concentration of quetiapine, and optimizing quetiapine therapy to achieve a balance between efficacy and safety is still a challenge. In our study, a population pharmacokinetic (PPK) model considering genetic information was developed with the expectation of comprehensively explaining this observation in Chinese patients with bipolar disorder. MethodsPatients who were dispensed quetiapine and underwent the therapeutic drug monitoring (TDM) were included. The genotypes of CYP3A5*3, CYP2D6*10, and ABCB1 C3435T/G2677T were analyzed. Finally, a multivariable linear regression model was applied to describe the PPK of quetiapine considering the covariates weight, height and genotype information. ResultsA total of 175 TDM points from 107 patients were adopted for PPK model development. Resultantly, the CL/F of quetiapine in CYP3A5 expressers was 81.1 CL/h, whereas it was 43.6 CL/h in CYP3A5 nonexpressers. The interindividual variability in CL/F was 47.7 %. However, neither the ABCB1 nor CYP2D6 genotype was significantly associated with the predictor of quetiapine clearance in our study. LimitationsOnly trough concentrations were collected, and the span between different points was relatively wide, impeding the application of the typical nonlinear compartment model for PPK analysis. In addition, this was a single-center study which limited the sample of wild-type CYP3A5 carriers. ConclusionsThe currently established PPK model of quetiapine considering the contribution of the CYP3A5 genotype could efficiently predict the population and individual pharmacokinetic parameters of Chinese bipolar disorder patients, which could better guide the personalized therapy with quetiapine, thus to achieve the best clinical response.

Impacts of genetic polymorphisms and cancer cachexia on naldemedine pharmacokinetics and bowel movements in patients receiving opioid analgesics.

Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4β-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.

Association between CYP3A4, CYP3A5 and ABCB1 genotype and tacrolimus treatment outcomes among allogeneic HSCT patients.

Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.

Interaction between tacrolimus and calcium channel blockers based on CYP3A5 genotype in Chinese renal transplant recipients.

To investigate the effect of calcium channel blockers (CCBs) on tacrolimus blood concentrations in renal transplant recipients with different CYP3A5 genotypes. This retrospective cohort study included renal transplant recipients receiving tacrolimus-based immunosuppressive therapy with or without CCBs in combination. Patients were divided into combination and control groups based on whether or not they were combined with CCBs, and then further analyzed according to the type of CCBs (nifedipine/amlodipine/felodipine). Propensity score matching was conducted for the combination and the control groups using SPSS 22.0 software to reduce the impact of confounding factors. The effect of different CCBs on tacrolimus blood concentrations was evaluated, and subgroup analysis was performed according to the patients' CYP3A5 genotypes to explore the role of CYP3A5 genotypes in drug-drug interactions between tacrolimus and CCBs. A total of 164 patients combined with CCBs were included in the combination groups. After propensity score matching, 83 patients with nifedipine were matched 1:1 with the control group, 63 patients with felodipine were matched 1:2 with 126 controls, and 18 patients with amlodipine were matched 1:3 with 54 controls. Compared with the controls, the three CCBs increased the dose-adjusted trough concentration (C0/D) levels of tacrolimus by 41.61%-45.57% (P < 0.001). For both CYP3A5 expressers (CYP3A5*1*1 or CYP3A5*1*3) and non-expressers (CYP3A5*3*3), there were significant differences in tacrolimus C0/D between patients using felodipine/nifedipine and those without CCBs (P < 0.001). However, among CYP3A5 non-expressers, C0/D values of tacrolimus were significantly higher in patients combined with amlodipine compared to the controls (P = 0.001), while for CYP3A5 expressers, the difference in tacrolimus C0/D values between patients with amlodipine and without was not statistically significant (P = 0.065). CCBs (felodipine/nifedipine/amlodipine) can affect tacrolimus blood concentration levels by inhibiting its metabolism. The CYP3A5 genotype may play a role in the drug interaction between tacrolimus and amlodipine. Therefore, genetic testing for tacrolimus and therapeutic drug monitoring are needed when renal transplant recipients are concurrently using CCBs.

Drug-drug interaction between tacrolimus and caspofungin in Chinese kidney transplant patients with different CYP3A5 genotypes.

The effect of drug-drug interaction between tacrolimus and caspofungin on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. To investigate the effect of caspofungin on the blood concentration and dose of tacrolimus under different CYP3A5 genotypes. We conducted a retrospective cohort study in The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital from January 2015 to December 2022. All kidney transplant patients were divided into the combination or non-combination group based on whether tacrolimus was combined with caspofungin or not. Patients were subdivided into CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3). Data from the combination and the non-combination groups were matched with propensity scores to reduce confounding by SPSS 22.0. A total of 200 kidney transplant patients receiving tacrolimus combined with caspofungin or not were enrolled in this study. Statistical analysis was conducted on the dose-corrected trough concentrations (C0/D) and dose requirements (D) of tacrolimus using independent sample two-sided t-test and nonparametric tests to investigate the impact on patients with different. In this study, the C0/D values of tacrolimus were not significantly different between the combination and non-combination groups (p = 0.054). For CYP3A5 expressers, there was no significant difference in tacrolimus C0/D or D values between the combination and non-combination groups (p = 0.359; p = 0.851). In CYP3A5 nonexpressers, the C0/D values of tacrolimus were significantly lower in the combination than in the non-combination groups (p = 0.039), and the required daily dose of tacrolimus was increased by 11.11% in the combination group. Co-administration of caspofungin reduced tacrolimus blood levels and elevated the required daily dose of tacrolimus. In CYP3A5 non-expressers, co-administration of caspofungin had a significant effect on tacrolimus C0/D values. An approximate 10% increase in the weight-adjusted daily dose of tacrolimus in CYP3A5 non-expressers is recommended to ensure the safety of tacrolimus administration.

Influence of Cyp3A4, Cyp3A5 and ABCB1 Polymorphisms on Tacrolimus Concentrations and Rejection Risk in Indian Kidney Transplant Recipients

Background: Tacrolimus metabolism is known to be determined by gene polymorphisms. Cyp3A5 genotype has most widely been seen to be associated with tacrolimus metabolism. Studies on other genes have produced mixed results. Objective: We studied the association of three polymorphisms CYP3A4*1B (-392 G&gt;A), CYP3A5 (6986 A&gt;G), and ABCB1 (3435 T&gt;C) on tacrolimus levels and their association with either rejection or nephrotoxicity (infection or tacrolimus toxicity) in renal transplant recipients from India. Materials and Methods: In this prospective cohort study, patients who underwent kidney transplantation between July 2018 and July 2023 were studied. Inclusion criteria: Patients who underwent Kidney Transplantation and were (i) on tacrolimus-based immunosuppression and (ii) not on medications known to interact with calcineurin inhibitors, such as ketoconazole, phenytoin, and diltiazem, were studied. Tacrolimus levels, tacrolimus concentration/dose (C/D) and tacrolimus C/D per kg body weight, at monthly time points posttransplant for 6 months and biopsy-proven rejection, infection, tacrolimus toxicity, and acute tubular necrosis data were collected. Results: Three hundred and twenty-seven patients were included in the study. Two hundred and fifty-seven were male and 70 were female. A total of 1402 tacrolimus samples were collected, with an average of 3.2 ± 2.1 samples per patient. Tacrolimus levels were significantly lower in the Cyp3A5 AG and AA GG genotypes versus GG (5.27 ± 2.95 and 6.22 ± 2.79 vs. 8.05 ± 4.83, P &lt; 0.001) as were C/D (3.45 ± 2.29 and 3.37 ± 1.91 vs. 6.47 ± 4.44, P &lt; 0.001) and C/D/W (52.45 ± 33.98 and 52.19 ± 32.61 vs. 98.09 ± 73.80, P &lt; 0.001). Cyp3A5 AA and AG had higher rejection rates than GG (20% vs. 13 vs. 8%, P = 0.03). The relative risk of rejection with A versus G polymorphism was 1.9 (confidence interval: 1.03–3.58), P = 0.03. Cyp3A4 and ABCB1 polymorphism studies did not show any association with the parameters studied. Conclusion: Our study showed that Cyp3A5 gene polymorphisms were significantly associated with tacrolimus metabolism, rejection episodes, and rejection risk. Cyp3A4 and ABCB1 were not significantly associated with the parameters studied.

Cyp3A4 *1G polymorphism is associated with alcohol drinking: A 5-year retrospective single centered population-based study in China.

We investigated the epidemiology of Cytochrome P450 (CYP) 3A4 genotype and the relationship between CYP3A4 genotype and alcohol drinking habits. A single-centered retrospective study was conducted on 630 patients who underwent CYP3A4*1G genetic testing. Their relevant information on epidemiology and etiology was collected. Laboratory testing, including CYP3A4*1G genotype, liver function tests, and serum lipid measurements were performed. Bi-variate logistic regressions were used to examine the relationship between variables. The relationship between alcohol drinking and CYP3A4*1G genotype was estimated. Demographic and clinical features were analyzed. Participants with drinking history were divided into non-heavy drinking and heavy drinking groups. Liver function and dyslipidemia of participants with drinking histories were compared between CYP3A4*1G mutation (GA+AA) and wild-type (GG) groups. Participants with CYP3A4*1G mutation(GA+AA) had an increased adjusted odds ratio (AOR) of 2.56 (95% CI, 1.4-4.65; P = 0.00) for alcohol abuse when compared with participants without CYP3A4 mutation (GG). In the subgroup of participants with alcohol abuse, there are no significant differences in liver injury levels and serum lipid levels between CYP3A4*1G mutant and wild-type groups. Patients with CYP3A4*1G mutation had an increased AOR of cardiac-vascular diseases and malignant diseases compared with patients without CYP3A4*1G mutation. The epidemiology had no difference between GA and AA group. The study indicated that there was association between alcohol drinking and CYP3A4*1G genetic mutation. In the subgroup of participants with alcohol abuse, there are no significant differences in liver injury and dyslipidemia between CYP3A4*1G mutant and wild-type groups. CYP3A4*1G mutation was also related to cardiac-vascular diseases and malignant diseases.

Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype.

Tacrolimus extended-release tablets have been Food and Drug Administration-approved for use in the de novo kidney transplant population. Dosing requi rements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression. Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus, but this has not been established for tacrolimus extended-release tablets in the de novo setting. To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype. Single-arm, prospective, single-center, open-label, observational study (ClinicalTrials.gov: NCT037 13645). Life cycle pharma tacrolimus (LCPT) orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight. If weight is more than 120% of ideal body weight, an adjusted body weight was used. LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL. Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion. Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (6 d vs 13.5 d vs 4.5 d; P = 0.025). Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (16 mg vs 16 mg vs 12 mg; P = 0.010) (0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg; P = 0.018). CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers (7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL; P = 0 0.008). No differences were identified with regards to kidney graft function at 30-d post-transplant. Serious adverse events were reported for 13 (36%) patients. Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacro limus to achieve target trough concentrations. We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers.

Vincristine Disposition and Neurotoxicity Are Unchanged in Humanized CYP3A5 Mice.

Previous studies have suggested that the incidence of vincristine-induced peripheral neuropathy (VIPN) is potentially linked with cytochrome P450 (CYP)3A5, a polymorphic enzyme that metabolizes vincristine in vitro, and with concurrent use of azole antifungals such as ketoconazole. The assumed mechanism for these interactions is through modulation of CYP3A-mediated metabolism, leading to decreased vincristine clearance and increased susceptibility to VIPN. Given the controversy surrounding the contribution of these mechanisms, we directly tested these hypotheses in genetically engineered mouse models with a deficiency of the entire murine Cyp3a locus [Cyp3a(-/-) mice] and in humanized transgenic animals with hepatic expression of functional and nonfunctional human CYP3A5 variants. Compared with wild-type mice, the systemic exposure to vincristine was increased by only 1.15-fold (95% confidence interval, 0.84-1.58) in Cyp3a(-/-) mice, suggesting that the clearance of vincristine in mice is largely independent of hepatic Cyp3a function. In line with these observations, we found that Cyp3a deficiency or pretreatment with the CYP3A inhibitors ketoconazole or nilotinib did not influence the severity and time course of VIPN and that exposure to vincristine was not substantially altered in humanized CYP3A5*3 mice or humanized CYP3A5*1 mice compared with Cyp3a(-/-) mice. Our study suggests that the contribution of CYP3A5-mediated metabolism to vincristine elimination and the associated drug-drug interaction potential is limited and that plasma levels of vincristine are unlikely to be strongly predictive of VIPN. SIGNIFICANCE STATEMENT: The current study suggests that CYP3A5 genotype status does not substantially influence vincristine disposition and neurotoxicity in translationally relevant murine models. These findings raise concerns about the causality of previously reported relationships between variant CYP3A5 genotypes or concomitant azole use with the incidence of vincristine neurotoxicity.

Effects of CYP3A5 Genotypes on Thrombocytopenia in Liver Transplantation Patients Treated with Tacrolimus.

Thrombocytopenia is a complication after liver transplantation. This study's aims were to evaluate the role of CYP3A5 genotypes on tacrolimus-induced thrombocytopenia after orthotopic liver transplantation. In this retrospective case-control study, data from 100 patients who underwent deceased-donor liver transplantation (DDLT) were divided into CYP3A5*3 genotype (donor/recipient) tacrolimus fast- (A*/A*, n = 22), intermediate- (A*/GG, n = 20; GG/A*, n = 31) and slow-metabolizer (GG/GG, n = 27) groups. Platelet count changes and prognosis for 180 days after surgery were compared. Platelet counts declined significantly after DDLT, especially on postoperative day (POD) 3, and continued at low levels for a week thereafter in all groups. In the GG/GG group, platelet counts on POD3 (50.29 ± 5.44 × 109/L) were the lowest among the groups (A*/A*, 71.00 ± 6.22 × 109/L; A*/GG, 57.95 ± 6.21 × 109/L; GG/A*, 75.90 ± 5.56 × 109/L) (p = 0.006). Compared with the A*/A* genotype, tacrolimus nadir levels were significantly higher in GG/GG genotype patients, who also exhibited a higher incidence of hemorrhage (22.2%, p = 0.011). A combination of a nadir blood concentration of tacrolimus ≥ 4.74 ng/mL and spleen size ≥ 165.5 mm was a risk factor for increased thrombocytopenia after DDLT on POD3, with an AUC of 0.735 (sensitivity, 77.2%; specificity, 41.7%). A high blood concentration of tacrolimus after the early stage of DDLT is a major risk factor for hemorrhage. For the CYP3A5 genotype (GG/GG), controlling the blood concentration of tacrolimus below the target concentration until POD3 can avoid thrombocytopenia-related complications.

A population pharmacokinetic model for individualized regimens of finasteride according to CYP3A5 genotype and liver function

A population pharmacokinetic model for individualized regimens of finasteride according to CYP3A5 genotype and liver function

Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam.

Patients with prostate cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8-fold) and oral administration (2.4-fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study, CYP3A activity defined by midazolam clearance (CL) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A-modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously on 2 consecutive days. Plasma concentrations were measured with a validated liquid chromatography-tandem mass spectrometry method. Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam CL was 1.26-fold higher in patients with PCa compared to patients with other solid tumors (geometric mean [coefficient of variation], 94.1 [33.5%] L/h vs 74.4 [39.1%] L/h, respectively; P= .08). Intravenous midazolam CL did not significantly differ between the 2 groups (P = .93). Moreover, the metabolic ratio of midazolam to 1'-hydroxy midazolam did not differ between the 2 groups for both oral administration (P = .67) and intravenous administration (P = .26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be explained neither by a difference in midazolam CL nor by a difference in metabolic conversion rate of midazolam.

Tacrolimus and Diabetes in Kidney Transplantation: The Impact of Cyp3a5 Gene Polymorphism

To explore the correlation between single nucleotide polymorphisms (SNPs) of CYP3A4 rs2740574 and CYP3A5 rs776746 and post-transplant diabetes mellitus (PTDM) in Chinese renal allograft recipients treated with tacrolimus. A total of 244 patients treated with tacrolimus were included in this study, wherein DNA sequencing was detected through fluorescence in situ hybridization, and SNP genotyping was performed. Among the 244 patients, 44 (18%) developed PTDM. The PTDM group exhibited higher preoperative body mass index and fasting plasma glucose levels, with higher creatinine values one year after surgery. The CYP3A4 rs2740574 genotype was found to be unique in its homozygous AA form. For CYP3A5 rs776746, the genotypes were distributed as follows: 28 (11.5%) cases with AA, 101 (41.4%) cases with AG, and 115 (47.1%) cases with GG, respectively (P=.042). The AA genotype showed a statistically significant difference from both AG and GG genotypes. Furthermore, the A allele of CYP3A5 rs776746 was found to be associated with an increased risk for PTDM development. The occurrence of tacrolimus-related PTDM is associated with body mass index, fasting plasma glucose levels, and CYP3A5 genotype before renal transplantation. Post-transplant diabetes mellitus is correlated with unfavorable long-term renal graft function, whereas the expression of the CYP3A5 rs776746 gene is linked to an elevated risk of PTDM.

Development of a predictive nomogram for switching immunosuppressive drugs in pediatric liver transplant recipients

BackgroundTacrolimus (TAC) is the preferred calcineurin inhibitor (CNI) for pediatric liver transplant recipients. However, some recipients may not achieve the desired therapeutic window concentration of TAC, leading to poor prognosis. This study aimed to develop a clinical model that can predict the effectiveness of TAC in pediatric liver transplant recipients and help clinicians quickly identify cyclosporin as an alternative.MethodsWe retrospectively analyzed data from 2,032 pediatric liver transplant recipients who underwent surgery at Renji Hospital, Shanghai Jiaotong University School of Medicine between 2006 and 2019. Demographic, comorbidity and pre-operative laboratory data were collected, and a nomogram was constructed using multivariate logistic regression analysis to estimate the risk of poor therapeutic outcomes for TAC-based immunosuppression.ResultsThe constructed nomogram included seven parameters, namely recipient CYP3A4 genotype, pre-transplant cholangitis, GRWR, spleen long diameter, serum albumin, graft volume reduction, and donor CYP genotype. The nomogram showed good discriminative ability with an area under the receiver operating characteristic curve (AUC) of 74.5% and good calibration. Decision curve analysis indicated a high potential clinical application of the model.ConclusionThis simple clinical model effectively predicts the risk of poor therapeutic outcomes in pediatric liver transplant recipients who receive TAC-based immunosuppression. Clinicians can use the model to identify cyclosporin as an alternative quickly, potentially improving patient prognosis.

Caffeine, CYP1A2 Genotype, and Exercise Performance: A Systematic Review and Meta-analysis.

This study aimed to summarize and meta-analyze existing evidence regarding the influence of CYP1A2 genotypes on the acute effects of caffeine for exercise performance and to investigate the interaction between genotype, dosage, and timing of caffeine supplementation. Six databases were searched for studies determining the effect of caffeine (except mouth rinsing) on exercise performance between CYP1A2 genotypes. Three-level meta-analyses were performed using standardized mean differences (SMD; Hedge's g ) to determine the effect of caffeine on exercise outcomes within and between CYP1A2 genotypes (AA, AC, and CC). Meta-regressions were performed for dose, timing, and presence of reported conflict of interests (RCOI). A meta-analysis was also performed with placebo values to assess for imbalances between genotypes. Thirteen studies, totaling 119 outcomes and 440 participants, were included (233 AA, 175 AC, ad 34 CC). Caffeine improved performance for AA (SMD = 0.30, 95% confidence interval [CI] = 0.21-0.39, P < 0.0001) and AC (SMD = 0.16, 95% CI = 0.06-0.25, P = 0.022) but worsened performance for CC (SMD = -0.22, 95% CI = -0.44 to -0.01, P < 0.0001). Dose affected only CC, with greater doses generating more positive SMD (CC-dose estimate: +0.19/1 mg·kg -1 body mass, 95% CI = 0.04-0.33, P = 0.01). Timing influenced only CC, with better performance with later onset of exercise after supplementation (CC-timing estimate: +0.01/min, 95% CI = 0.00-0.02, P = 0.02). RCOI only affected SMD of CC (CC-RCOI estimate: -0.57, 95% CI = -1.02 to -0.12, P = 0.01). After excluding studies with RCOI, no influence of genotype was seen (all P ≥ 0.19). Small, nonsignificant differences were seen in placebo between genotypes (SMD AA vs CC: -0.13; AA vs AC: -0.12; AC vs CC: -0.05; all P ≥ 0.26). Caffeine improved performance for AA and AC but worsened performance for CC. Dose and timing moderated the efficacy of caffeine for CC only. Caution is advised because baseline differences and studies with RCOI could have influenced these results.

Population pharmacokinetic models of tacrolimus in paediatric solid organ transplant recipients: A systematic review.

This study aimed to provide up-to-date information on paediatric population pharmacokinetic models of tacrolimus and to identify factors influencing tacrolimus pharmacokinetic variability. Systematic searches in the Web of Science, PubMed, Scopus, Science Direct, Cochrane, EMBASE databases and reference lists of articles were conducted from inception to March 2023. All population pharmacokinetic studies of tacrolimus using nonlinear mixed-effect modelling in paediatric solid organ transplant patients were included. Of the 21 studies reviewed, 62% developed from liver transplant recipients and 33% from kidney transplant recipients. Most studies used a 1-compartment model to describe tacrolimus pharmacokinetics. Body weight was a significant predictor for tacrolimus volume of distribution (Vd/F). The estimated Vd/F for 1-compartment models ranged from 20 to 1890 L, whereas the peripheral volume of distribution (Vp/F) for 2-compartment models was between 290 and 1520 L. Body weight, days post-transplant, CYP3A5 genotype or haematocrit were frequently reported as significant predictors of tacrolimus clearance. The estimated apparent clearance values range between 0.12 and 2.18 L/h/kg, with inter-individual variability from 13.5 to 110.0%. Only 29% of the studies assessed the generalizability of the models with external validation. This review highlights the potential factors, modelling approaches and validation methods that impact tacrolimus pharmacokinetics in a paediatric population. The clinician could predict tacrolimus clearance based on body weight, CYP3A5 genotype, days post-transplant or haematocrit. Further research is required to determine the relationship between pharmacogenetics and tacrolimus pharmacodynamics in paediatric patients and confirm the applicability of nonlinear kinetics in this population.

CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Voriconazole in Chinese Kidney Transplant Patients.

The effect of drug-drug interaction (DDI) between tacrolimus and voriconazole on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-voriconazole DDI in Chinese kidney transplant patients. All kidney transplant patients were divided into combination and non-combination groups based on whether tacrolimus was combined with or without voriconazole. Each group was subdivided into CYP3A5 expresser (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 nonexpresser (CYP3A5*3/*3). A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between combination and non-combination groups, respectively. Tacrolimus C0/D was also compared between CYP3A5 expresser and nonexpresser in both groups. The C0/D values of tacrolimus were significantly different between CYP3A5 expresser and nonexpresser in combination group (378.20 [219.38, 633.48] ng/mL/[mg/kg/d] vs 720.00 [595.35, 1681.50] ng/mL/[mg/kg/d], P = 0.0010). Either in CYP3A5 expresser or nonexpresser, we found a statistically significant difference in tacrolimus C0/D between combination and non-combination group (P < 0.0001). The increase in CYP3A5 nonexpresser was 1.38 times higher than that in CYP3A5 expresser (320.93% vs 232.19%). The median C0/D values were 90.38% higher in kidney transplant recipients with CYP3A5*3/*3 genotype than in those with CYP3A5*1/*1 or CYP3A5*1/*3 genotype when treated with both tacrolimus and voriconazole. A CYP3A5 genotype-dependent DDI was found between tacrolimus and voriconazole. Therefore, personalized therapy accounting for CYP3A5 genotype detection and therapeutic drug monitoring is necessary for kidney transplant patients when treating with tacrolimus and voriconazole.

Dosage optimization of tacrolimus based on the glucocorticoid dose and pharmacogenetics in adult patients with systemic lupus erythematosus

BackgroundThe purpose of the study was to develop a genotype-incorporated population pharmacokinetic (PPK) model of tacrolimus (TAC) in adults with systemic lupus erythematosus (SLE) to investigate the factors influencing TAC pharmacokinetics and to develop an individualized dosing regimen based on the model. In addition, a non-genotype-incorporated model was also established to assess its predictive performance compared to the genotype-incorporated model. MethodsA total of 365 trough concentrations from 133 adult SLE patients treated with TAC were collected to develop a genotype-incorporated PPK model and a non-genotype-incorporated PPK model of TAC using a nonlinear mixed-effects model (NONMEM). External validation of the two models was performed using data from an additional 29 patients. Goodness-of-fit diagnostic plots, bootstrap method, and normalized predictive distribution error test were used to validate the predictive performance and stability of the final models. The goodness-of-fit of the two final models was compared using the Akaike information criterion (AIC). The dosing regimen was optimized using Monte Carlo simulations based on the developed optimal model. ResultsThe typical value of the apparent clearance (CL/F) of TAC estimated in the final genotype-incorporated model was 14.3 L h−1 with inter-individual variability of 27.6%. CYP3A5 polymorphism and coadministered medication were significant factors affecting TAC-CL/F. CYP3A5 rs776746 GG genotype carriers had only 77.3% of the TAC-CL/F of AA or AG genotype carriers. Omeprazole reduced TAC-CL/F by 3.7 L h−1 when combined with TAC, while TAC-CL/F increased nonlinearly as glucocorticoid dose increased. Similar findings were demonstrated in the non-genotype-incorporated PPK model. Comparing these two models, the genotype-incorporated PPK model was superior to the non-genotype-incorporated PPK model (AIC = 643.19 vs. 657.425). Monte Carlo simulation based on the genotype-incorporated PPK model indicated that CYP3A5 rs776746 AA or AG genotype carriers required a 1/2–1 fold higher dose of TAC than GG genotype carriers to achieve the target concentration. And as the daily dose of prednisone increases, the dose of TAC required to reach the target concentration increases appropriately. ConclusionsWe developed the first pharmacogenetic-based PPK model of TAC in adult patients with SLE and proposed a dosing regimen based on glucocorticoid dose and CYP3A5 genotype according to the model, which could facilitate individualized dosing for TAC.