Genotype and Phenotype Influence the Personal Response to Prostaglandin Analogues and Beta-Blockers in Spanish Glaucoma and Ocular Hypertension Patients.

Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). The MD values presented significant differences between wildtype rs3766355 (-2 ± 2.2 dB), HT (-3.87 ± 4 dB), and HM carriers (-9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (-6.1 ± 8.67 dB), HT (-9.02 ± 8.63 dB), and HM carriers (-9.51 ± 7.44 dB) (p = 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.

Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. RESULTS: Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. CONCLUSIONS: Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients.

BACKGROUND & AIMS: Nuclear factor of activated T cell-regulated gene expression (NFAT-RGE) has been proposed as a pharmacodynamic biomarker for tacrolimus (Tac) and cyclosporine (CsA). Our aim was to evaluate the role of NFAT-RGE in modulating intralymphocytary IL-2 and IFN-γ expression and its clinical utility as an early non-invasive predictive biomarker for the risk of acute rejection (AR) and infection in de novo liver transplant (LT) recipients. METHODS: Fifty-six LT recipients treated with Tac or CsA [with and without mycophenolate mofetil (MMF)] were included: 30 free of rejection or infection, 11 rejectors (T cell-mediated acute rejection), 5 with subclinical rejection (SCR) and 10 with cytomegalovirus (CMV) infection. Within the first 3 months after transplantation, NFAT-RGE of IL-2, IFN-γ and GM-CSF and intralymphocytary synthesis of IL-2 and IFN-γ were evaluated by real-time PCR and flow cytometry respectively. RESULTS: A significant increase in NFAT-RGE was observed in patients who experienced TCMAR (75% [42-100%]) or SCR (41% [18-78%]) compared with patients without rejection or infection (14% [2-23%]). Positive correlations between the %NFAT-RGE-IFN and both the %CD8CD69IFN-γ and %CD4CD69IFN-γ and between the %NFAT-RGE-IL2 and the %CD8CD69IL2 were observed. NFAT-RGE was significantly lower in CMV+ patients than in non-infected patients. Finally, an inverse correlation between the Tac or CsA concentration and inhibition of NFAT-RGE were observed. CONCLUSIONS: Sequential post-transplantation NFAT-RGE monitoring combined with intralymphocytary IL-2 and IFN-γ before transplantation and at the first and third month post-transplantation may be key predictive and diagnostic biomarkers for the risk of TCMAR and SCR and better guide CNi therapy in LT patients.

Effects of CYP3A5 Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation.

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.

Early prognostic performance of miR155-5p monitoring for the risk of rejection: Logistic regression with a population pharmacokinetic approach in adult kidney transplant patients.

Previous results from our group and others have shown that urinary pellet expression of miR155-5p and urinary CXCL-10 production could play a key role in the prognosis and diagnosis of acute rejection (AR) in kidney transplantation patients. Here, a logistic regression model was developed using NONMEM to quantify the relationships of miR155-5p urinary expression, CXCL-10 urinary concentration and tacrolimus and mycophenolic acid (MPA) exposure with the probability of AR in adult kidney transplant patients during the early post-transplant period. Owing to the contribution of therapeutic drug monitoring to achieving target exposure, neither tacrolimus nor MPA cumulative exposure was identified as a predictor of AR in the studied population. Even though CXCL-10 urinary concentration showed a trend, its effect on AR was not significant. In contrast, urinary miR155-5p expression was prognostic of clinical outcome. Monitoring miR155-5p urinary pellet expression together with immunosuppressive drug exposure could be very useful during routine clinical practice to identify patients with a potential high risk of rejection at the early stages of the post-transplant period. This early risk assessment would allow for the optimization of treatment and improved prevention of AR.

Monitoring of miR-181a-5p and miR-155-5p Plasmatic Expression as Prognostic Biomarkers for Acute and Subclinical Rejection in de novo Adult Liver Transplant Recipients.

Background and Aims: News strategies for the accurate assessment of the state of immunosuppression (IS) in liver transplant recipients are needed to prevent rejection and minimize drug-related side effects. miRNAs can potentially be used as diagnostic or prognostic biomarkers in transplant patients. This study evaluated the capacity of a plasmatic miRNA panel (miR-155-5p, miR-122-5p, miR-181a-5p, and miR148-3p) as an early non-invasive prognostic and diagnostic biomarker for T cell-mediated acute rejection (TCMAR) and subclinical rejection (SCR) in adult liver recipients. Methods: A total of 145 liver recipients were included. All patients received a calcineurin inhibitor with or without mycophenolate mofetil and methylprednisolone. Plasmatic miRNA expression was assessed by qPCR before and at different time-points after liver transplantation. Results: Seventeen patients experienced TCMAR, and eight were diagnosed with SCR during the protocol biopsy at the 3rd month post-transplantation. Pre-transplantation, miR-155-5p expression was significantly higher in TCMAR patients and in SCR patients than in non-rejectors, and miR-181a-5p expression was also significantly higher in SCR patients than in non-rejectors. Post-transplantation, before transaminase-level modification, significantly increased miR-181a-5p, miR-155-5p, and miR-122-5p expression was observed in TCMAR and SCR patients. Binary logistic regression analyses showed, post-transplantation, that TCMAR risk was better predicted by individual expression of miR-181a-5p (LOGIT = -6.35 + 3.87*miR-181a-5p), and SCR risk was better predicted by the combination of miR-181a-5p and miR-155-5p expression (LOGIT = -5.18 + 2.27*miR-181a-5p+1.74*miR-155-5p). Conclusions: Pre-transplantation plasmatic miR-155-5p expression may be useful for stratifying low-immunologic-risk patients, and post-transplantation miR-181a-5p and miR-155-5p may be candidates for inclusion in early, non-invasive prognostic biomarker panels to prevent TCMAR or SCR and better identify patient candidates for IS minimization. Large prospective randomized multicenter trials are needed to refine the cut-off values and algorithms and validate the clinical usefulness of these biomarkers.

High expression of CD38, CD69, CD95 and CD154 biomarkers in cultured peripheral T lymphocytes correlates with an increased risk of acute rejection in liver allograft recipients.

The mayor goal still outstanding into the solid organ transplantation field involves the search of surrogate biomarkers able to predict several clinical events, such as acute rejection (AR) or opportunistic infection. In the present multicenter study, a series of interesting surface antigens with important activator or inhibitory immune functions on cultured peripheral T cells were monitored in liver transplant recipients drawn at baseline and up to one year after transplantation. Sixty-four patients were included in the multicenter study during 3 years. Pre- and post-transplantation surface antigens levels displayed significant differences between AR and non acute rejection (NAR) groups, and also this differential expression was used to construct a risk predictive model based on a composite panel of outcome biomarkers (CD38, CD69, CD95 and CD154). The model was able to stratify these patients at high risk of AR. These preliminary results could provide basic information to improve the immunosuppressive treatment and it might better help to predict AR episodes.

Development and validation of a UHPLC diode array detector method for meropenem quantification in human plasma.

OBJECTIVES: Meropenem is a ß-lactam antibiotic frequently used to treat serious infections in intensive care unit patients. The main objective was to develop and validate a sensitive and specific ultra high performance liquid chromatography method with photodiode array detection for the quantitation of meropenem in human plasma. The applicability of the method for meropenem monitoring was also examined. DESIGN AND METHODS: The validation of the method was performed following the FDA's guidelines for bioanalytical methods. In parallel, the method was applied for monitoring meropenem in forty plasma samples from ten critically ill patients treated intravenously at a total dose of 1 g. Drug levels were measured in each patient at 0 h, 2 h, 4 h and 8 h after meropenem infusion. RESULTS: With this method, intraday and day-to-day variation was below 10%; intraday and day-to-day accuracy was between 94% and 114%; the limit of quantification was 0.5 µg/mL and recovery was above 70%. The method was successfully applied to quantitate meropenem concentrations and the results showed significant pharmacokinetic interindividual variability. Of special interest is that 50% of treated patients had meropenem plasma levels below the minimum inhibitory concentration at 8h after the start of infusion, which was strongly related to creatinine clearance >60 mL/min. CONCLUSIONS: The method meets the requirements to be applied for meropenem concentration measurements in pharmacokinetics studies and clinical routine. The results suggest the need for therapeutic drug monitoring of meropenem in treated critically-ill patients.

Tratamiento antipsicótico en metabolizadores lentos CYP2D6 en la práctica clínica: a propósito de un caso / Antipsychotic therapy amongst Cytochrome P450 2D6 poor metabolizers in the clinical practice: A case report

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