Tacrolimus Personalized Therapy based on CYP3A5 Genotype in Chinese Patients with Idiopathic Inflammatory Myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous and life-threatening group of diseases, especially anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is reportedly strongly associated with high mortality rate. Tacrolimus (TAC) provides an excellent therapeutic option, but the trough concentration (Cmin) -outcome relationship remains unexplored. This study was undertaken to identify optimal Cmin and individualized dose based on CYP3A5 genotype for IIM patients. METHODS: 134 IIM patients with 467 Cmin were enrolled. We examined the relationship between TAC Cmin and relapses. The receiver operating characteristic analysis was used to confirm the optimal Cmin. Analyses of factors influencing Cmin were conducted. The dose requirement based on CYP3A5 genotype was confirmed. RESULTS: TAC Cmin is strongly associated with relapses. The optimal cutoff values were 5.30, 5.85, 4.85 and 5.35 ng/ml for acute, subacute, chronic and all phase IIM patients (p = 0.001, 0.013, 0.002, and < 0.001, respectively), as well as 5.35, 5.85, 5.55 and 5.85 ng/ml for acute, subacute, chronic and all phase MDA5+ DM patients (p = 0.007, 0.001, 0.036, and < 0.001, respectively). CYP3A5 genotype was one of the significant factors influencing TAC Cmin. CYP3A5 expressers required 0.059 mg/kg/d to attain the target Cmin, while nonexpressers required 0.046 mg/kg/d (p = 0.019). CONCLUSION: TAC treatment may elicit favorable outcome in patients with IIM and MDA5+ DM when Cmin exceeded 5.35 and 5.85 ng/ml, which is crucial to lower relapse rate. The individualized dose based on the CYP3A5 genotype provides a reference for TAC personalized therapy in IIM.

Chinese pregnant women's knowledge, attitude, and practice of self-protection against coronavirus disease 2019 during the post-pandemic period: A structural equation modeling-based survey.

This study aimed to investigate the Chinese pregnant women's levels of knowledge, attitude, and practice (KAP) of self-protection against coronavirus disease 2019 (COVID-19) during the post-pandemic period, to aid the development of targeted health education. An online questionnaire was conducted for 2156 Chinese pregnant women from October 1, 2021, to December 31, 2021, to collect socio-demographic and KAP information. Structural equation modeling (SEM) was used to determine self-protection-related factors. The mean age of the participants was 30 ± 4.1 years. SEM indicated that pregnant women's level of knowledge can directly and indirectly affect the practice of self-protection (r = 0.23) through their belief, with a correlation coefficient of 0.56 and 0.46 between knowledge and belief and belief and practice, respectively. The "basic protection" and "hospital visits after infection" exerted the greatest impact on knowledge formation, with correlation coefficients of 0.85 and 0.89, respectively. Attitude had a direct effect on practice with a correlation coefficient of 0.46. "Awareness of prevention and control" and "family and social support" had the greatest impact on belief formation, with correlation coefficients of 0.77 and 0.73, respectively. Pregnant Chinese women were generally familiar with COVID-19 knowledge, and their levels of knowledge and beliefs particularly affect the practice of self-protection. Health education aimed at improving pregnant women's knowledge and belief toward self-protection against COVID-19 may be an effective way to guide them toward positive practices and promote their health and that of their babies.

Central Nervous System Toxicity of Voriconazole: Risk Factors and Threshold - A Retrospective Cohort Study.

Purpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C min) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C min threshold for CNS toxicity. Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2-19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C min significantly affects the occurrence of CNS toxicity and the threshold of C min for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C min >4.85 mg/L and ≤4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. Conclusion: Voriconazole trough concentration of C min is an independent risk factor for CNS toxicity, and the threshold of C min for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.

Impact of CYP2C19 Phenotype and Drug-Drug Interactions on Voriconazole Concentration in Pediatric Patients.

Voriconazole (VRC), a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by human cytochrome P450 (CYP) 2C19. In this study, a retrospective analysis was performed to investigate the key factors that influence the plasma trough concentration (Cmin) of VRC, and an appropriate dosing regimen for pediatric patients was drafted subsequently. Overall, factors such as age, CYP2C19 phenotype, and combination medication with proton pump inhibitors accounted for 23.4% of variability in dose-normalized Cmin values of VRC by a multiple linear regression analysis. Dose-normalized Cmin values in the poor metabolizers (PMs) and intermediate metabolizers (IMs) were significantly higher than those in extensive metabolizers (EMs) (P < 0.001). To achieve therapeutic Cmin for CYP2C19 ultrarapid metabolizers (UMs) or EMs, patients aged no more than 12 and more than 12 years required doses of 6.53 ± 2.08 and 3.95 ± 0.85 mg/kg of body weight twice daily (P = 0.007). For CYP2C19 PMs or IMs, patients aged under 12 and over 12 years required doses of 5.75 ± 1.73 and 4.23 ± 0.76 mg/kg twice daily, respectively (P = 0.019). Furthermore, coadministration of rifamycin sodium or omeprazole exhibited significant effects on VRC Cmin. Taken together, it is necessary to pay attention to the impact of CYP2C19 phenotype and drug-drug interactions to achieve optimal therapy.

Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors.

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured Cmin values. In total 2241 blood samples were analyzed. The estimated Ctrough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after Tmax. The calculated Ctrough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology.

The potential of Atorvastatin for chronic lung diseases therapy.

Atorvastatin (ATO) is of the statin class and is used as an orally administered lipid-lowering drug. ATO is a reversible synthetic competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase thus leading to a reduction in cholesterol synthesis. It has recently been demonstrated that ATO has different pharmacological actions, which are unrelated to its lipid-lowering effects and has the ability to treat chronic airway diseases. This paper reviews the potential of ATO as an anti-inflammatory, antioxidant, and anti-proliferative agent after oral or inhaled administration. This paper discusses the advantages and disadvantages of using ATO under conditions associated with those found in the airways. This treatment could potentially be used to support the formulating of ATO as an inhaler for the treatment of chronic respiratory diseases.

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients.

Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9-22). Blood samples were investigated for pharmacokinetic parameters before and 7-14 days after the conversion. Fifteen patients were included and provided AUC0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p = 0.41). Mean trough blood concentration (Cmin) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p = 0.01). Correlation coefficient (r) between Cmin and AUC0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of Cmin > 30% had a significant lower AUC0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of Cmin > 30% after conversion to TAC-OD will require additional dose adjustment.

The Influence of Proinflammatory Cytokines on Voriconazole Trough Concentration in Patients With Different Forms of Hematologic Disorders.

Even though multiple factors are involved in the high fluctuation of voriconazole (VCZ) plasma concentration, little is known regarding the influence of proinflammatory cytokines on VCZ concentration. The aim of this study was to investigate the influence of proinflammatory cytokines, namely, interleukin (IL)-1ß, IL-6, IL-18, interferon-γ, tumor necrosis factor-α, and transforming growth factor (TGF)-ß1 on VCZ trough concentration (VCZ-Cmin ) in Chinese patients with different forms of hematologic disorders. A total of 250 plasma samples from 113 patients were analyzed for VCZ-Cmin and proinflammatory cytokines using a validated liquid chromatography-tandem mass spectrometry and enzyme-linked immunosorbent assay methods, respectively. Patient demographics and clinical characteristics were obtained from hospital records. VCZ-Cmin was significantly correlated with IL-18 in acute myeloid leukemia (r = 0.456; P ˂ .0001), acute lymphoblastic leukemia (r = 0.317; P = .019), and chronic myeloid leukemia (r = 0.737; P = .004) while VCZ-Cmin and TGF-ß1 were correlated (r = 0.436; P ˂ .001) in acute myeloid leukemia patients only. VCZ-Cmin at different concentration range showed significant inhibitory effect of IL-6. A backward multiple linear regression model revealed patient age (coefficient [ß] = 0.025; P = .04), gamma-glutamyl transferase (ß = 0.003; P = .023), IL-6 (ß = -0.001; P = .024), proton pump inhibitor coadministration (ß = 1.518; P = .002), and cytochrome P450 (CYP) 2C19 polymorphism as predictors of VCZ-Cmin ; however, these factors explained only 29% of VCZ-Cmin variation. In conclusion, IL-18 and TGF-ß1 have correlation with VCZ-Cmin in Chinese patients with leukemia. Apparently, VCZ may have an inhibitory effect on IL-6 levels. Furthermore, patient age, gamma-glutamyl transferase, IL-6, PPI coadministration, and cytochrome P450 2C19 polymormorphism partially predicted the VCZ-Cmin . Therapeutic drug monitoring of VCZ in Chinese patients is highly encouraged.

Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens.

Enzalutamide is a nonsteroidal antiandrogen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) both before and after chemotherapy. Enzalutamide is more effective than its predecessor bicalutamide, which was analyzed in head-to-head studies of patients with CRPC. This family of nonsteroidal antiandrogens is now comprised of four drugs approved by the US Food and Drug Administration with two investigational drugs in clinical trials. Antiandrogens have been employed clinically for more than five decades to provide a rich resource of information. Steady-state concentration minimums (Cmin or trough) in the range of ~1-13 µg/mL are measured in patients at therapeutic doses. Interestingly, enzalutamide which is considered to have strong affinity for the androgen receptor (AR) requires Cmin levels >10 µg/mL. The sequence of antiandrogens and the clinical order of application in regard to other drugs that target the androgen axis remain of high interest. One novel first-in-class drug, called ralaniten, which binds to a unique region in the N-terminus domain of both the full-length and the truncated constitutively active splice variants of the AR, is currently in clinical trials for patients who previously received abiraterone, enzalutamide, or both. This highlights the trend to develop drugs with novel mechanisms of action and potentially differing mechanisms of resistance compared with antiandrogens. Better and more complete inhibition of the transcriptional activity of the AR appears to continue to provide improvements in the clinical management of mCRPC.

Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin.

Evidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximum a posteriori probability Bayesian estimation. Vancomycin AUC and minimum-concentration (Cmin) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC0-48) of ≥1,218 mg · h/liter, AUC0-24 of ≥677 mg · h/liter, AUC24-48 of ≥683 mg · h/liter, and day 1 Cmin (Cmin24) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.

Optimization of voriconazole dosage regimen to improve the efficacy in patients with invasive fungal disease by pharmacokinetic/pharmacodynamic analysis.

Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in hospitalized patients. To maximize the efficacy of voriconazole treatment, the study established the relationship between voriconazole pharmacokinetic/pharmacodynamic (PK/PD) and probability of response and optimized voriconazole dosage regimen in patients with IFD based on Monte Carlo simulation. Forty-four patients proven with IFD were involved in this study. Among them, the overall cure rate was 75% (33/44) and there was a significant difference between Cmin /MIC values in patients with lack of response (n = 11) and those with successful response (n = 33) (mean value: 1.91 vs. 11.33; P < 0.05). Logistic regression model showed a high correlation between voriconazole Cmin /MIC ratio and clinical response (P = 0.044, OR = 1.349). According to Monte Carlo simulation results under different voriconazole dosing regimens, we could draw a conclusion that 200 mg voriconazole administered intravenously or orally twice daily for Candida infections and 300 mg administered orally or with 200 mg administered intravenously twice daily for Aspergillus infections were rational, which could achieve a value of the cumulative fraction of response >90%. This study built the relationship between voriconazole PK/PD and clinical response and obtained the reasonable empirical dosage regimen, which can be used to customize individual dosage regimen and improve the efficacy of voriconazole treatment.

Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein.

Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRV-Env) protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin, expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk. Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in 10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.

Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). Combination therapy targeting multiple signaling pathways may improve outcomes. This phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus given with sorafenib 400mg twice daily in patients with advanced HCC of Child-Pugh class A liver function who were naive to systemic therapy. METHODS: Everolimus was initiated at 2.5mg once daily and increased per a Bayesian sequential dose-escalation scheme based on the dose-limiting toxicities experienced within the first 28 days of treatment. Adverse events were assessed continuously. Efficacy was evaluated using the best overall response rate per RECIST. RESULTS: Thirty patients were enrolled; 25 were evaluable for MTD determination. One out of 12 patients treated with everolimus 2.5mg once daily and 6 out of 13 patients treated with everolimus 5.0mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n=5). All patients experienced 1 adverse event, most commonly diarrhea (66.7%), hand-foot skin reaction (66.7%), and thrombocytopenia (50.0%). Best overall response was stable disease (62.5% and 42.9% in the 2.5-mg and 5.0-mg cohorts, respectively). Median time to progression and overall survival in the 2.5-mg cohort were 4.5 months and 7.4 months, respectively, and 1.8 months and 11.7 months, respectively, in the 5.0-mg cohort. CONCLUSIONS: In patients with advanced HCC, the everolimus MTD in combination with standard-dose sorafenib was 2.5mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination.