Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.

AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.

Impact of CYP2C19 Genotype and Liver Function on Voriconazole Pharmacokinetics in Renal Transplant Recipients.

BACKGROUND: Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intraindividual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine. METHODS: A total of 125 trough concentrations (Cmin) from 56 patients were evaluated, retrospectively. Nonlinear mixed effect model was used to describe a PPK model that was internally validated by bootstrap method. Potential covariates included demographic characteristics, physiological and pathological data, concomitant medications, and CYP2C19 genotype. RESULTS: A 1-compartment model with first-order absorption and elimination was fit to characterize the VRC pharmacokinetics in renal transplant recipients (RTRs). Aspartate aminotransferase (AST) had a significant influence on clearance (CL) while CYP2C19 genotype had a major impact on the volume of distribution (V). The parameters of CL and V were 4.76 L/h and 22.47 L, respectively. The final model was V (L) = 22.47 × [1 + 2.21 × (EM = 1)] × [1 + 4.67 × (IM = 1)] × [1 + 3.30 × (PM = 1)] × exp (0.96); CL (L/h) = 4.76 × (AST/33)^(-0.23) × exp (0.14). VRC Cmin in intermediate metabolizers was significantly higher than in extensive metabolizers. CONCLUSIONS: Liver function and CYP2C19 polymorphism are major determinants of VRC pharmacokinetic variability in RTRs. Genotypes and clinical biomarkers can determine the initial scheme. Subsequently, therapeutic drug monitoring can optimize clinical efficacy and minimize toxicity. Hence, this is a feasible way to facilitate personalized medicine in RTRs. In addition, it is the first report about PPK of VRC in RTRs.

The Effect of Voriconazole on Tacrolimus in Kidney Transplantation Recipients: A Real-World Study.

Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection.

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients.

Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R2  = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events.

[Association of gene polymorphisms of cytokine and cytokine receptor with type III prostatitis].

OBJECTIVE: To explore the role of the gene polymorphism of cytokine and cytokine receptors in the pathogenesis of type III prostatitis. METHODS: We genotyped 24 outpatients diagnosed with type III prostatitis and 51 healthy volunteer controls for the single nucleotide polymorphisms of 13 cytokines and cytokine receptors at 22 sites by Sequence Specific Primer -PCR (SSP-PCR). RESULTS: The patients exhibited significantly higher frequencies of the genotypes of IL-10-819 T/T (62.5%) and IL-10-592 A/A (62.5%), the haplotype of IL-10 (-1082/-819/-592) ATA (75.0%) and the diploid genotype of IL-10 (-1082/-819/-592) ATA/ATA (62.5%), than with the healthy controls (31.3% , 31.3%, 25.0% and 31.2%) (P < 0. 05). CONCLUSION: Our data suggested that anti-inflammation cytokine IL-10 gene polymorphisms were associated with the pathogenesis of type III prostatitis.

Cancer risks in recipients of renal transplants: a meta-analysis of cohort studies.

Renal transplantation is associated with an increased risk of cancers at multiple sites; however, the relationships between increased cancer risk and participant characteristics remain unclear. We searched PubMed, Embase, and the Cochrane Library to identify prospective observational studies performed up to July 2017. Totally 11 prospective studies reported data on 79,988 renal transplant recipients were included. Renal transplant recipients were found to display a higher risk of all cancers (standard incidence ratio [SIR]: 2.89; 95% CI: 2.13-3.91; P < 0.001), gastric cancer (SIR: 1.93; 95% CI: 1.60-2.34; P < 0.001), colon cancer (SIR: 1.85; 95% CI: 1.53-2.23; P < 0.001), pancreatic cancer (SIR: 1.53; 95% CI: 1.23-1.91; P < 0.001), hepatocellular carcinoma (SIR: 2.45; 95% CI: 1.63-3.66; P < 0.001), lung cancer (SIR: 1.68; 95% CI: 1.29-2.19; P < 0.001), thyroid cancer (SIR: 5.04; 95% CI: 3.79-6.71; P < 0.001), urinary bladder cancer (SIR: 3.52; 95% CI: 1.48-8.37; P = 0.004), renal cell cancer (SIR: 10.77; 95% CI: 6.40-18.12; P < 0.001), non-melanoma skin cancer (SIR: 12.14; 95% CI: 6.37-23.13; P < 0.001), melanoma (SIR: 2.48; 95% CI: 1.08-5.67; P = 0.032), Hodgkin's lymphoma (SIR: 4.90; 95% CI: 3.09-7.78; P < 0.001), non-Hodgkin lymphoma (SIR: 10.66; 95% CI: 8.54-13.31; P < 0.001), lip cancer (SIR: 29.45; 95% CI: 17.85-48.59; P < 0.001), breast cancer (SIR: 1.11; 95% CI: 1.00-1.24; P = 0.046), and ovarian cancer (SIR: 1.60; 95% CI: 1.23-2.07; P < 0.001). However, renal transplantation did not significantly influence the risks of uterine cancer (P = 0.171), and prostate cancers (P = 0.188). Our findings suggest that patients who receive renal transplantation have an increased risk of cancer at most sites, apart from uterine and prostate cancers patients.

[Evaluation of 126 radical cystectomy with orthotopic ileal or sigmoidocolic neobladder].

OBJECTIVE: To evaluate the long-term clinical effects of orthotopic ileal or sigmoidocolic neobladder. METHODS: One hundred and twenty six patients with bladder cancer who underwent radical cystectomy and orthotopic ileal or sigmoidocolic neobladder from 1989 to 2001 were followed up, the clinical data was collected and analysed. Hautmann orthotopic ileal neobladder was performed on 84 cases and orthotopic sigmoidocolic neobladder was performed on 42 cases; Lymph node clearing during surgery was performed on 62 cases, chemotherapy and radiotherapy was performed on 64 cases after surgery. The continence and complications were compared between sigmoidocolic group and ileal group, the tumor recurrent rate and the 5-year survival rate were compared between lymphnode clearing group and chemoradical therapy group. RESULTS: Complete follow up was performed in 122 cases. Ureter broaden and urine backflow rate were higher in sigmoidocolic group than in ileal group (P < 0.05), nocturnal continence rate in sigmoidocolic group was higher than in ileal group (P < 0.05); Post-surgical tumor recurrent rate in lymphnode clearing group was lower than in chemoradical therapy group (P < 0.05), the 5-year survival rate in lymphnode clearing group was higher than in chemoradical therapy group (P < 0.05). The overall short-term complication rate was 15.9% (20/126), the overall long-term complication rate was 9.8% (12/122). CONCLUSION: The effects of orthotopic ileal or sigmoidocolic neobladder were satisfactory with low complication rate, lymphnode clearing during the surgery can increase the 5-year survival rate when compared with the chemoradical group.

[Slowing progression of chronic allograft nephropathy by conversion from cyclosporin A to tacrolimus].

OBJECTIVE: To investigate the feasibility and safety of substituting tacrolimus(FK506) for cyclosporin A(CsA) on delaying the pace of renal dysfunction in patients with biopsy-proven chronic allograft nephropathy(CAN). METHODS: Seventy-three renal transplantation patients with CAN proved by allograft biopsy were collected in this study. Patients were randomly divided into 2 groups. Patients were either converted to FK506(FK506 group, n=43) or remained on their initial CsA-based immunosuppression(CsA group, n=30). The clinical data at study entry and after 12 months including blood urea nitrogen(BUN), serum creatinine(SCr), glomerular filtration rate(GFR), 24-hour urine protein excretion, serum total cholesterol(TC), triglyceride(TG), low density lipoprotein(LDL) and the side effects of calcineurin inhibitors were monitored during a follow-up of over 12 months. RESULTS: Twelve months later, the level of SCr was statistically reduced and GFR levels were obviously elevated in the FK506 group as compared with CsA group [(194.8+/-42.5)micromol/L vs. (245.4+/-52.8)micromol/L and (50.14+/-3.92)mL/(min.1.73 m(2)) vs. (40.58+/-2.49)mL/(min.1.73 m2), P<0.01]. Quantity of 24-hour urine protein excretion in the FK506 group was (2.0+/-0.5)g which is significantly lower than (3.9+/-0.7)g in the CsA group(P<0.01). TC, TG, and LDL levels remained unchanged in the CsA group, while those were statistically reduced in the FK506 group respectively [(5.19+/-0.73)mmol/L vs. (6.94+/-1.37)mmol/L, (1.86+/-0.84)mmol/L vs. (3.14+/-1.38)mmol/L, (3.03+/-0.71)mmol/L vs. (3.82+/-0.89)mmol/L, P<0.01]. Tremor obviously increased (P<0.01) and hypertension obviously decreased (P<0.05) in the FK506 group compared with the CsA group. CONCLUSION: FK506 treatment can greatly improve the proteinuria and hyperlipidemia. Conversion from CsA to FK506 is an effective and safe alternative therapy for delaying the progression of renal dysfunction induced by CAN.

[Surgical strategy for ectopic kidneys: analysis of 35 cases].

OBJECTIVE: To explore the surgical strategy for ectopic kidney and evaluate the clinical outcomes. METHODS: From January 2000 to October 2009, 35 cases of ectopic kidney were treated surgically in our hospital. Definite diagnoses were established in all the cases by ultrasound, intravenous urography (IVU), cystoscope, CT, magnetic resonance urography (MRU) and radionuclide imaging before the surgery. In these patients, 26 had ipsilateral ectopic ureteral orifice (including 5 with bilateral duplicated kidneys and ureter), 9 had moderate or severe hydronephrosis (including 3 with ectopic kidney calculi), and 24 had dysplastic kidney (24/35). All the patients underwent operations, including 26 with ectopic nephrectomy, 7 with ectopic ureterovesical reimplantation, and 3 with ectopic renal pelvis incision. RESULTS: The clinical effect was satisfactory in all the cases during the follow up of 7 to 29 months. CONCLUSION: Appropriate surgical approaches according to the concurrent deformities and complications can achieve good clinical results in patients with ectopic kidneys.