Association of Valproic Acid and Its Main Metabolites' Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring.

Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 µg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 µg/mL versus 4.83 µg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.

Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.

Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50 of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasma of M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood-brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2 < 12 ng/mL and CM2 ≥ 12 ng/mL were 17.0 and 27.1 months, respectively, P = 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2.

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 µg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 µg/mL vs. 23.45 µg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 µg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.

ABCC2 rs2273697 is associated with valproic acid concentrations in patients with epilepsy on valproic acid monotherapy.

Valproic acid (VPA), a widely used antiepileptic drug, is characterized by intensive inter-individual variability in concentration. Both efflux and influx transporters are reported to play important roles in the disposition of VPA, however, no comprehensive investigation into the association of the single nucleotide polymorphism (SNP) in ABC/SLC families with VPA concentration are reported. In the present study, we investigated the association of 12 SNPs in ABCC2, ABCC4, ABCG2, MCT1, MCT2, and OATP2B1 in 187 Chinese patients with epilepsy on VPA monotherapy with the trough concentrations of VPA. The data showed that VPA concentration in patients with ABCC2 rs2273697 AA genotype was significantly higher than that in those with GA+GG genotypes (p=0.000). The findings of the present study suggest that ABCC2 polymorphisms influence VPA concentrations in patients with epilepsy on VPA monotherapy, which may affect the treatment outcomes.

Simultaneous quantification of imatinib and its main metabolite N-demethyl-imatinib in human plasma by liquid chromatography-tandem mass spectrometry and its application to therapeutic drug monitoring in patients with gastrointestinal stromal tumor.

The aim of this study was to improve and validate a more stable and less time-consuming method based on liquid chromatography and tandem mass spectrometry (LC- MS/MS) for the quantitative measurement of imatinib and its metabolite N-demethyl-imatinib (NDI) in human plasma. Separation of analytes was performed on a Waters XTerra RP18 column (50 × 2.1 mm i.d., 3.5 µm) with a mobile phase consisting of methanol-acetonitrile-water (65:20:15, v/v/v) with 0.05% formic acid at a flow-rate of 0.2 mL/min. The Quattro MicroTM triple quadruple mass spectrometer was operated in the multiple-reaction-monitoring mode via positive electrospray ionization interface using the transitions m/z 494.0 → 394.0 for imatinib, m/z 479.6 → 394.0 for NDI and m/z 488.2 → 394.0 for IS. The method was linear over 0.01-10 µg/mL for imatinib and NDI. The intra- and inter-day precisions were all <15% in terms of relative standard deviation, and the accuracy was within ±15% in terms of relative error for both imatinib and NDI. The lower limit of quantification was identifiable and reproducible at 10 ng/mL. The method was sensitive, specific and less time-consuming and it was successfully applied in gastrointestinal stromal tumor patients treated with imatinib.

The POR rs1057868-rs2868177 GC-GT diplotype is associated with high tacrolimus concentrations in early post-renal transplant recipients.

AIM: Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients. METHODS: A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d). RESULTS: Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62- and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C0D7/D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers. CONCLUSION: The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients.

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population.

The field of pharmacogenomics was initiated in the 1950s and began to thrive after the completion of the human genome project 10 years ago. Thus far, more than 100 drug labels and clinical guidelines referring to pharmacogenomic biomarkers have been published, and several key pharmacogenomic markers for either drug safety or efficacy have been identified and subsequently adopted in clinical practice as pre-treatment genetic tests. However, a tremendous variation of genetic backgrounds exists between different ethnic groups. The application of pharmacogenomics in the Chinese population is still a long way off, since the published guidelines issued by the organizations such as US Food and Drug Administration require further confirmation in the Chinese population. This review highlights important pharmacogenomic discoveries in the Chinese population and compares the Chinese population with other nations regarding the pharmacogenomics of five most commonly used drugs, ie, tacrolimus, cyclosporine A, warfarin, cyclophosphamide and azathioprine.

Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation.

AIM: Co-administration of diltiazem can reduce the dosage of cyclosporine (CsA) in patients with renal transplantation. In this study, we investigated how diltiazem altered the relationship between MDR1 genetic polymorphisms and CsA concentration in Chinese patients with renal transplantation. METHODS: A total of 126 renal transplant patients were enrolled. All the patients received CsA (2-4 mg·kg(-1)·d(-1)), and diltiazem (90 mg/d) was co-administered to 76 patients. MDR1-C1236T, G2677T/A, and C3435T polymorphisms were genotyped. The whole blood concentration was measured using the FPIA method, and the adjusted trough concentrations were compared among the groups with different genotypes. RESULTS: In all patients, MDR1-C1236T did not influence the adjusted CsA trough concentration. With regard to MDR1-3435, the adjusted CsA trough concentration was significantly higher in TT carriers than in CC and CT carriers when diltiazam was co-administered (58.83±13.95 versus 46.14±7.55 and 45.18±12.35 ng/mL per mg/kg, P=0.011), and the differences were not observed in patients without diltiazam co-administered. With regard to MDR1-2677, the adjusted CsA trough concentration was significantly higher in TT carriers than in GG and GT carriers when diltiazam was co-administered (61.31±12.93 versus 52.25±7.83 and 39.70±7.26 ng/mL per mg/kg, P=0.0001). The differences were also observed in patients without diltiazam co-administered (43.27±5.95 versus 35.22±7.55 and 29.54±5.35 ng/mL per mg/kg, P=0.001). The adjusted CsA trough blood concentration was significantly higher in haplotype T-T-T and haplotype T-T-C carriers than in non-carriers, regardless of diltiazem co-administered. CONCLUSION: MDR1 variants influence the adjusted CsA trough concentration in Chinese patients with renal transplant, and the influence more prominent when diltiazem is co-administered.

Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients.

AIM: To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients. METHODS: A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 -1818T>C, I399C>T, -118T9/10, -440C>T, -331T>C, UGT2B7 IVS1+985A>G, 211G>T, -900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics. RESULTS: The dose-adjusted MPA AUC0-12 h of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC0-12 h of the patients with the UGT1A7 622CC and UGT1A9 -440CT/-331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and -440C/-331T homozygotes. Furthermore, the genotypes UGT1A9 -1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC0-12 h. CONCLUSION: The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.

In vivo to in vitro effects of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on the CYP3A/P-glycoprotein-mediated absorption and metabolism of tacrolimus.

We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.

[Advances in the research of pharmacogenomics of cyclophosphamide].

Cyclophosphamide (CPA) is the most common alkylating antineoplastic agent, as well as a strong immunosuppressant that is frequently applied to autoimmune diseases and organ transplantation. It is metabolized by cytochrome P450 oxidases (CYPs) to its active metabolite which played a critical role in therapy. CPA has serious and even fatal side effects, and its efficacy and adverse reactions are significantly varied among individuals. In this review, the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the disposition of CPA with the efficacy and adverse effects of CPA were summarized, thereby providing fundamental reference for further pharmacogenomic study of CPA.

[Effects of carbamazepine on plasma concentrations of valproic acid and its toxic metabolite in epileptic patients].

To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.

Early proactive monitoring of DNA-thioguanine in patients with Crohn's disease predicts thiopurine-induced late leucopenia in NUDT15/TPMT normal metabolizers.

BACKGROUND: Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines. Dose optimization guided by nudix hydrolase 15 (NUDT15) has significantly reduced the early leucopenia rate, but there are no definitive biomarkers for late risk leucopenia prediction. AIM: To determine the predictive value of early monitoring of DNA-thioguanine (DNATG) or 6-thioguanine nucleotides (6TGN) for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn's disease (CD). METHODS: Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations. Late leucopenia was defined as a leukocyte count < 3.5 × 109/L over two months. RESULTS: Of 148 patients studied, late leucopenia was observed in 15.6% (17/109) of NUDT15/thiopurine methyltransferase (TPMT) normal and 64.1% (25/39) of intermediate metabolizers. In patients suffering late leucopenia, early DNATG levels were significantly higher than in those who did not develop late leucopenia (P = 4.9 × 10-13). The DNATG threshold of 319.43 fmol/µg DNA could predict late leucopenia in the entire sample with an area under the curve (AUC) of 0.855 (sensitivity 83%, specificity 81%), and in NUDT15/TPMT normal metabolizers, the predictive performance of a threshold of 315.72 fmol/µg DNA was much more remarkable with an AUC of 0.902 (sensitivity 88%, specificity 85%). 6TGN had a relatively poor correlation with late leucopenia whether in the entire sample (P = 0.021) or NUDT15/TPMT normal or intermediate metabolizers (P = 0.018, P = 0.55, respectively). CONCLUSION: Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD, especially the former.

Individualization of tacrolimus dosage basing on cytochrome P450 3A5 polymorphism--a prospective, randomized, controlled study.

We investigated how cytochrome P450 (CYP) 3A5 polymorphism affects pharmacokinetics of tacrolimus and its interaction with diltiazem in Chinese kidney transplant recipients. Sixty-two CYP3A5 expressers and 58 non-expressers were, respectively, randomized to receive diltiazem supplement or not. Their pharmacokinetic profiles were acquired on 14th day, sixth month, and 18th month post-transplant and compared among groups. A dosing equation was fit based on above data with CYP3A5 genotype and diltiazem co-administration as variables. Then, necessary initial doses with or without diltiazem were calculated and used in 11 CYP3A5 expressers, respectively, when another 11 expressers received routine doses as control. Trough concentration was measured on the third-day post-transplant and patients failed to reach target range were presented in percentage. These two parameters were compared among three groups. Patients were followed up until June 2010, kidney function, biopsy-proved acute rejection, and other adverse events were monitored. Results showed that CYP3A5 expressers needed more tacrolimus to reach therapeutic concentration window and were more susceptible to diltiazem-induced concentration increase than CYP3A5 non-expressers. CYP3A5 polymorphism-guided dosing equation helped to determine appropriate initial doses of tacrolimus in individuals. In conclusion, CYP3A5 polymorphism profoundly influences pharmacokinetics of tacrolimus and helps to individualize tacrolimus dose.

Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients.

AIM: Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation. METHODS: A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4(*)1G, CYP3A5(*)3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 -94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation. RESULTS: The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 -94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the -94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026]. CONCLUSION: These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.

Genetic polymorphisms of UGT1A8, UGT1A9, UGT2B7 and ABCC2 in Chinese renal transplant recipients and a comparison with other ethnic populations.

Mycophenolate mofetil (MMF), a widely used immunosuppressant, is characterized by highly variable pharmacokinetics. UGT1A8, UGT1A9, UGT2B7 and ABCC2 have been proved to be critical genes associated with inter-individual variation of MMF pharmacokinetics. In this study, we investigated the genetic polymorphisms of UGT1A8*2, UGT1A8*3, UGT1A9 C-2152T, UGT1A9 T-275A, UGT1A9 T98C, UGT2B7*2, ABCC2 C-24T and ABCC2 C3972T in 200 Chinese renal transplant recipients and compared them with those in other ethnic groups reported in the literature, to start the exploration of a better use of MMF in Chinese. A much higher frequency of UGT1A8*2 variant allele was found in Chinese than in Caucasians and Africans, while the UGT2B7*2 variant allele was significantly rarer in Chinese than in Caucasians and Africans. For ABCC2, -24T allele was more common and 3972T allele was less common in Chinese than in Caucasians and Africans. However, none of the SNPs in UGT1A9 were present in our study population. The findings of this study suggest that Chinese renal transplant recipients may exhibit a response profile to MMF that is different from those of other ethnic groups.

[Systematic evaluation of the incidence of the knee donor area after autobone cartilage mosaic xentoplasty].

OBJECTIVE: To provide an overview of the incidence of knee donor -site morbidity after autologous osteochondral mosaicplasty. METHODS: A comprehensive search was conducted in PubMed, EMbase, Wanfang Medical Network, and CNKI databases from January 2010 to April 20, 2021. Relevant literature was selected based on predefined inclusion and exclusion criteria, and data were evaluated and extracted. The correlation between the number and size of transplanted osteochondral columns and donor-site morbidity was analyzed. RESULTS: A total of 13 literatures were included, comprising a total of 661 patients. Statistical analysis revealed an incidence of knee donor-site morbidity at 8.6% (57/661), with knee pain being the most common complaint, accounting for 4.2%(28/661). There was no significant correlation between the number of osteochondral columns and postoperative donor-site incidence (P=0.424, N=10), nor between the diameter size of osteochondral columns and postoperative donor-site incidence(P=0.699, N=7). CONCLUSION: Autologous osteochondral mosaicplasty is associated with a considerable incidence of knee donor-site morbidity, with knee pain being the most frequent complaint. There is no apparent correlation between donor-site incidence and the number and size of transplanted osteochondral columns. Donors should be informed about the potential risks.

Comparison and development of machine learning for thalidomide-induced peripheral neuropathy prediction of refractory Crohn's disease in Chinese population.

BACKGROUND: Thalidomide is an effective treatment for refractory Crohn's disease (CD). However, thalidomide-induced peripheral neuropathy (TiPN), which has a large individual variation, is a major cause of treatment failure. TiPN is rarely predictable and recognized, especially in CD. It is necessary to develop a risk model to predict TiPN occurrence. AIM: To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables. METHODS: A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model. The National Cancer Institute Common Toxicity Criteria Sensory Scale (version 4.0) was used to assess TiPN. With 18 clinical features and 150 genetic variables, five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), specificity, sensitivity (recall rate), precision, accuracy, and F1 score. RESULTS: The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248 [P = 0.0004, odds ratio (OR): 8.983, 95% confidence interval (CI): 2.497-30.90], dose (mg/d, P = 0.002), brain-derived neurotrophic factor (BDNF) rs2030324 (P = 0.001, OR: 3.164, 95%CI: 1.561-6.434), BDNF rs6265 (P = 0.001, OR: 3.150, 95%CI: 1.546-6.073) and BDNF rs11030104 (P = 0.001, OR: 3.091, 95%CI: 1.525-5.960). In the training set, gradient boosting decision tree (GBDT), extremely random trees (ET), random forest, logistic regression and extreme gradient boosting (XGBoost) obtained AUROC values > 0.90 and AUPRC > 0.87. Among these models, XGBoost and GBDT obtained the first two highest AUROC (0.90 and 1), AUPRC (0.98 and 1), accuracy (0.96 and 0.98), precision (0.90 and 0.95), F1 score (0.95 and 0.98), specificity (0.94 and 0.97), and sensitivity (1). In the validation set, XGBoost algorithm exhibited the best predictive performance with the highest specificity (0.857), accuracy (0.818), AUPRC (0.86) and AUROC (0.89). ET and GBDT obtained the highest sensitivity (1) and F1 score (0.8). Overall, compared with other state-of-the-art classifiers such as ET, GBDT and RF, XGBoost algorithm not only showed a more stable performance, but also yielded higher ROC-AUC and PRC-AUC scores, demonstrating its high accuracy in prediction of TiPN occurrence. CONCLUSION: The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables. With the ability to identify high-risk patients using single nucleotide polymorphisms, it offers a feasible option for improving thalidomide efficacy in CD patients.

Distinct genotype distribution and haplotype profiles in MDR1 gene among Chinese Han, Bai, Wa and Tibetan ethnic groups.

P-Glycoprotein (P-gp, encoded by MDR1 gene) plays an important role in determining bioavailability and pharmacologic effects of many drugs. There is increasing evidence that P-gp activity may be genetically determined. In this study, we investigated the genotype distribution and the haplotype profiles of MDR1 gene in Chinese Han, Bai, Wa and Tibetan subjects. Much lower frequencies of the 1236T allele and the 2677T allele were found in Wa subjects than those in other three ethnic groups, while the 2677A allele was found about 6-fold more frequently in Han subjects than in subjects of other three ethnic groups. The Han, Bai and Tibetan subjects share the same three predominant haplotypes (T-T-T, T-G-C and C-G-C), and T-T-T is the highest and accounts for more than one third of the number of haplotypes in the subjects from each ethnic group. However, T-T-T was less common than T-G-C, T-G-T and C-G-C and occurring at only 13.8% in Wa subjects, furthermore, higher frequencies of T-G-T, C-T-C, C-G-T and C-T-T were observed in Wa subjects compared to those in other three ethnic groups. Frequencies of C-A-C and T-A-C in Han subjects were higher than those in other three ethnic groups. The findings of this study will be of some relevance in predicting MDR1 phenotype and pharmacokinetics as well as pharmacodynamic effects of many commonly used drugs that are P-gp substrates in these four Chinese ethnic groups.

DNA-Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD.

Thiopurine dose optimization by thiopurine-S-methyltransferase (TPMT) or nudix hydrolase-15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although laboratory monitoring of 6-thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA-thioguanine nucleotides (DNA-TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA-TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells < 3.5 × 109 /L) were observed in 43 patients (14.0%), who had significantly higher DNA-TG concentration than those without leucopenia (P = 4.1 × 10-9 , 423.3 (~ 342.2 to 565.7) vs. 270.5 (~ 188.1 to 394.3) fmol/µg DNA). No difference in 6TGN concentrations between leucopenia and non-leucopenia was found. With a DNA-TG threshold of 340.1 fmol/µg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed that DNA-TG was an independent risk factor for late leucopenia. Quantification of DNA-TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.