Mycophenolic Acid Levels Research Articles

Determination of mycotoxin content, microbiological and physicochemical properties and sensory quality during ripening of Erzincan Tulum cheese produced with strain Penicillium roqueforti 41

Erzincan Tulum cheeses were produced from raw sheep milk with traditional homemade rennet as the uninoculated (control) and inoculated with Penicillium roqueforti 41. The cheese was ripened at 4 ± 1 °C for 120 days. All the cheese samples were drilled to achieve oxygenation during the last two stages of the ripening period. The microbiological and physicochemical properties, presence of mycotoxins and sensory characteristics of the Tulum cheeses, which were filled by pressing into the goat skin bags (called tulums) and plastic barrels, were investigated during the ripening period. The coliform bacteria count of the cheeses decreased, and Staphylococcus aureus was not detected (< 2 log CFU/g) in the cheeses. The lowest and highest levels of penicillic acid (PA), roquefortine C and mycophenolic acid (MPA) in the cheeses during ripening ranged from 0.01–0.08, 0.01–0.06 and ND–0.06 mg/kg, respectively. Patulin was not detected. It was concluded that the Tulum cheeses were safer in terms of the amount of patulin, PA, roquefortine C, and MPA than those previously reported in the literature. P. roqueforti counts considerably increased during the last two stages of ripening. A new variety of credible mouldy cheese can be manufactured using the P. roqueforti 41 strain. However, a drilling process is needed to provide oxygen for P. roqueforti 41 growth during ripening.

Layered double hydroxide nanozyme (LDHzyme)-assisted high-performance electrochemical analysis of organ transplant therapeutic drug concentration

The variability in mycophenolic acid (MPA) exposure levels among organ transplant patients is substantial and directly influences the drug’s therapeutic efficacy. Therefore, precise monitoring of MPA blood concentrations is imperative to devise personalized diagnostic and treatment plans tailored to individual patient profiles. In this study, we developed a screen-printed carbon electrode (SPCE) incorporating Layered Double Hydroxide-based nanozymes (LDHzymes) and multi-walled carbon nanotubes (MWCNT) to achieve high-sensitivity and stable determination of MPA in blood samples. We synthesized three distinct LDHzymes via a straightforward co-precipitation method, selecting CuMn-LDHzyme for its superior electrochemical properties and laccase activity in the context of MPA detection. The sensor’s performance was enhanced by the amalgamation of CuMn-LDHzyme with MWCNT, leveraging the laccase-like activity of CuMn-LDHzyme and the exceptional conductivity of MWCNT to amplify the oxidation current response to MPA. This integration significantly bolstered the sensor’s detection capabilities. The developed electrochemical sensor exhibited remarkable characteristics, including high selectivity, stability, repeatability, and reproducibility. It demonstrated a notable sensitivity with a detection range of 0.5 µM to 200 µM for MPA, and a detection limit of 0.1 µM, effectively detecting MPA in mouse blood samples. These attributes underscore the sensors as promising tool for clinical drug detection, ensuring fast and precise monitoring of MPA levels in organ transplant patients. This innovative approach holds significant promise for advancing personalized medical care and improving therapeutic outcomes.

Development of an HPLC method using relative molar sensitivity for the measurement of blood concentrations of nine pharmaceutical compounds

We developed a reliable high-performance liquid chromatographic analysis method using a relative molar sensitivity (RMS) technique that does not require an authentic, identical reference analyte material to quantify blood serum carbamazepine, phenytoin, voriconazole, lamotrigine, meropenem, mycophenolic acid, linezolid, vancomycin, and caffeine levels for routine blood concentration measurements. Carbamazepine and caffeine were also used as non-analyte reference materials to calculate the RMS of each analyte. The RMS was calculated from the ratio of the slope of the calibration equation (analyte/non-analyte reference material), then used to quantify analytes in control serum samples spiked with carbamazepine, phenytoin, voriconazole, meropenem, mycophenolic acid, linezolid or vancomycin. In addition, the concentrations of these six drugs in control serum samples determined by the proposed RMS method agreed well with that obtained using a conventional method. The proposed RMS method is a promising tool for the clinical determination of nine drugs, given the accuracy, precision, and efficiency of quantifying these analytes.

Therapeutic drug monitoring of mycophenolic acid and azole antifungals on two distinct LC-MS/MS instruments

BackgroundAs an active metabolite of a commonly prescribed immunosuppressant, mycophenolic acid (MPA) levels are often monitored to prevent organ rejection following a transplant. Triazoles are often prescribed for treatment of invasive fungal infections in immunocompromised patients. Due to the variability in individual pharmacokinetics and drug-drug interactions, therapeutic drug monitoring is recommended for triazole antifungals. A multiplex LC-MS/MS assay has been developed that can quantify both MPA and triazole drugs in serum. MethodsA sample preparation procedure was established to spike in internal standard compounds and precipitate proteins. Reversed-phase chromatographic separation was performed on a C18 column with an analysis time of five minutes per sample. The mass spectrometer was operated in multiple reaction monitoring mode. The method was validated on two HPLC systems interfaced with either a Triple Quad 6500 or an API 4000 instrument. ResultsThe multiplex assay was linear over a wide dynamic range with analyte measurable ranges of 0.4–48 μg/mL for MPA, 0.1–12 μg/mL for posaconazole, and 0.2–24 μg/mL for voriconazole, itraconazole, hydroxyitraconazole, and isavuconazole. The between-day and intraday imprecisions were less than 10 %. Limits of detection were below 0.04 ug/mL with limits of quantitation below 0.2 μg/mL. Method comparison studies against the current in-house method met acceptance criteria. The instrument comparison study demonstrated a strong correlation between data collected from the two systems. ConclusionA robust multiplex LC-MS/MS assay was developed and validated for monitoring MPA and triazoles drug levels in a clinical laboratory. The assay performance on two distinct instruments was acceptable and comparable.

#2047 Trough-level guided dosing is reliable for mycophenolate mofetil but not for enteric-coated mycophenolic sodium

Abstract Background and Aims While trough level (TL) guided dosing is usus for calcineurin inhibitors, mycophenolic acid (MPA) was marketed as a one-size-fits-all drug. TL has been reported to be a poor surrogate marker of MPA exposure by reason of complex pharmacokinetics. Measurement of area under the curve (AUC) remains the gold-standard for MPA dosing. Method We measured MPA TL and AUC in 299 KTRs at the University Hospital of Zurich. KTRs with agreement between TL and AUC target range of 40-60 mg/Lxh were compared to KTRs with missing agreement between TL and AUC for differences regarding baseline characteristics and co-medication. Results For mycophenolate mofetil (MMF, n = 218) a high correlation between TL and AUC was observed, p &amp;lt; 0.0001, r = 0.85, while correlation was only low for enteric-coated mycophenolate sodium (EC-MPS, n = 81), p = 0.002, r = 0.34, Fig. 1. However, a high correlation between MPA level 4 hours after EC-MPS intake (C4L) and AUC was found, p &amp;lt; 0.0001, r = 0.94. ROC analysis defined an MMF-TL range of &amp;gt;2.05 mg/l (sensitivity 68%, specificity 89%) and &amp;lt;3.05 mg/l (sensitivity 70%, specificity 81%) correlating with an AUC of 40-60 mg/Lxh. Lack of proton pump inhibitors (PPI) use was significantly associated with incorrect classification (n = 71/218). For EC-MPS C4L a range of &amp;gt;1.25 mg/l (sensitivity 98, specificity 100) and &amp;lt;4.4 mg/l (sensitivity 93, specificity 91) was defined for an AUC of 40-60 mg/Lxh. Here, non-tacrolimus-based immunosuppression was significantly associated with incorrect classification (n = 7/81). Conclusion MMF dosing according to TL highly correlates with AUC especially in KTRs treated with PPI. In contrast, EC-MPS dosing according to C4L is preferred especially in context of tacrolimus-based immunosuppression.

Efficacy and Safety of Mycophenolate Mofetil In De Novo Renal Transplantation in a Retrospective Cohort of Transplant Recipients in Colombia—Esmitren Study

To describe and establish the efficacy and safety of Mycophenolate Mofetil (Micoflavin) in patients with de novo renal transplantation during one-year post-transplant follow-up. As secondary objectives, the behavior of mycophenolic acid (MPA) C0 levels in this population, the relationship between MPA levels and renal function of the grafts, the incidence of acute rejection, and the incidence of adverse effects were evaluated. A prospective cohort study was conducted on patients who received a first kidney transplant from a deceased donor between March 1, 2021, and February 28, 2022, at the Alma Mater of Antioquia Hospital of the Antioquia's University, in Medellín, Colombia. MPA C0 levels were taken from the patients on days 15, 30, 90, 180, and 360 after the kidney transplantation. Patients presented MPA therapeutic levels in the study. The average of the MPA levels in the population was 2.5 µg/mL, with an IQR of 2.13 to 3.32. There were 5 acute rejections (27%), but none of the patients with acute rejection presented subtherapeutic levels of mycophenolate. No significant relationship was observed between mycophenolic acid levels and rejection (P = .255). The patients who completed the study had no gastrointestinal intolerance to mycophenolate, cytomegalovirus infections, or significant hematological complications. MMF (Micoflavin) maintained mycophenolic acid levels C0 within the therapeutic range, was well tolerated and without the presence of significant adverse events, and maintained stable renal function throughout the follow-up period in the population studied.

Co prescription of anti-acid therapy reduces the bioavailability of mycophenolate mofetil in systemic sclerosis patients: A crossover trial

ObjectiveMycophenolate mofetil (MMF) is an effective treatment option for interstitial lung disease (ILD) in systemic sclerosis (SSc). Many patients require co-administration of proton pump inhibitors (PPI) or H2 receptor blockers (HRB) because of various gastrointestinal (GI) manifestations in SSc. Co-treatment with PPI or HRB have shown to reduce serum drug levels in post-transplant patients. We wanted to see if there is a similar phenomenon for Mycophenolate in SSc. MethodsTwenty SSc patients, who were on a stable dose of MMF (1.5-3 g) underwent a sequential cross over study with MMF alone in the first month, followed by co-treatment with Ranitidine and then Esomeprazole in the second and third month respectively. Estimation of 12-hour area under curve (AUC) of Mycophenolic Acid (MPA) levels and total GI score were calculated at the end of each month and compared between the treatment arms. [Trial registration: CTRI/2020/06/025,939] ResultsCo-administration of esomeprazole was associated with 32.7% (mean difference = 22.28 μg h ml–1) reduction in mean AUC MPA, whereas ranitidine caused a reduction of 21.97% (mean difference = 14.93 μg h ml–1) in MPA AUC when compared to MMF without anti-acid therapies. The addition of ranitidine or esomeprazole resulted in significant reduction in the total GI score. ConclusionCo-administration of PPI or HRB can significantly reduce the bioavailability of MMF in patients with SSc. To avoid therapeutic failure of MMF drug level monitoring is essential when these agents are co-prescribed with MMF.

B-329 Comparison Between Trough and AUC Monitoring of MPA in Patients With and Without Organ Transplantation. Influence of the Co-administered Immunosuppressant

Abstract Background Monitoring of mycophenolic acid (MPA) could be performed by measurement of trough concentrations with target therapeutic range of 1.3 to 3.5 mg/L, or by calculation of area under the drug concentration vs time curve (AUC) utilizing 3 or 4 samples within a dosing interval, with a target range of 30 to 60 mg*h/L. AUC is considered more reliable compared to trough levels, and MPA kinetics are dependent on the type of the co-administered calcineurine inhibitor. This study compares trough vs AUC MPA monitoring received alone or in co-administration with Cyclosporine (CsA) or with Tacrolimus (TAC). Methods 77 transplanted patients receiving MPA, 25 of them on CsA, 49 on TAC, and 20 non-transplanted patients on MPA alone, were evaluated more than once, yielding 260 monitoring consults included for assessment: 45 for MPA alone, 108 for MPA combined with CsA, and 117 consults for the MPA combined with TAC. MPA, CsA, and TAC levels were measured by validated LC/MS/MS methods. Validated pharmacokinetic programs for the calculation of MPA AUC were used, adapted to the type of calcineurine inhibitor. Assessment was made by comparison of the distribution and coincidence between trough levels and AUC with respect to the above therapeutic ranges. Results Transplanted patents: when combined with CsA, MPA AUC was in the target range in 61% of cases, under it—in 31%, and in 8%—over it, while trough levels were 52% under, 42.5% within, and 5.5% over the therapeutic range; agreement between trough MPA and MPA AUC was poor—there was coincidence in 37.5% of sub-therapeutic, 63% of therapeutic and 0% of supra-therapeutic ranges, 3 cases were identified with sub-therapeutic trough and supra-therapeutic AUC; when combined with TAC, MPA AUC was in the target range in 63% of cases, under it—in 13%, and in 24%—over it; trough levels being 23% under, 60% within and 17% over the therapeutic range; agreement between trough MPA and MPA AUC was much better, compared to the combination with CsA: there was coincidence in 56% of sub-therapeutic, 84% of therapeutic and 80% of supra-therapeutic ranges. Nevertheless, 1 case was found with sub-therapeutic trough and supra-therapeutic AUC. In non-transplanted patients MPA AUC was in the target range in 47% of cases, under it—in 13%, and in 40%—over it; trough levels being 18% under, 53% within and 29% over the therapeutic range; agreement between trough MPA and MPA AUC showed coincidence in 75% of sub-therapeutic, 75% of therapeutic and 92% of supra-therapeutic ranges. Conclusion This study confirms that MPA AUC is more relevant than trough monitoring for dose individualization. It also shows that MPA trough levels are much more concordant with MPA AUC in non-transplanted patients and in transplanted patients on TAC, while in combination with CsA, discordance remains significant.

Torque Teno Virus Load Predicts Opportunistic Infections after Kidney Transplantation but Is Not Associated with Maintenance Immunosuppression Exposure.

Measuring the non-pathogenic Torque Teno Virus (TTV) load allows assessing the net immunosuppressive state after kidney transplantation (KTx). Currently, it is not known how exposure to maintenance immunosuppression affects TTV load. We hypothesized that TTV load is associated with the exposure to mycophenolic acid (MPA) and tacrolimus. We performed a prospective study including 54 consecutive KTx. Blood TTV load was measured by an in-house PCR at months 1 and 3. Together with doses and trough blood levels of tacrolimus and MPA, we calculated the coefficient of variability (CV), time in therapeutic range (TTR) and concentration/dose ratio (C/D) of tacrolimus, and the MPA-area under the curve (AUC-MPA) at the third month. TTV load at the first and third month discriminated those patients at risk of developing opportunistic infections between months 1 and 3 (AUC-ROC 0.723, 95%CI 0.559-0.905, p = 0.023) and between months 3 and 6 (AUC-ROC 0.778, 95%CI 0.599-0.957, p = 0.028), respectively, but not those at risk of acute rejection. TTV load did not relate to mean tacrolimus blood level, CV, TTR, C/D and AUC-MPA. To conclude, although TTV is a useful marker of net immunosuppressive status after KTx, it is not related to exposure to maintenance immunosuppression.

Quantitation of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Serum or Plasma by LC-MS/MS.

Mycophenolic acid (MPA) is an immunosuppressant that is used as an adjunct therapy in renal, liver, and heart transplantation. Due to its narrow therapeutic range, monitoring MPA levels is essential to avoid toxicity and organ rejection. Although immunoassays are available for the determination of MPA, mass spectrometry methods are preferred due to their higher specificity. Herein, we describe a liquid chromatography tandem mass spectrometry (LC-MS/MS) method utilizing positive ionization electrospray and multiple reaction monitoring (MRM) for the quantification of MPA levels and its conjugate, MPA glucuronide (MPAG). Blood collected in a plain, EDTA, or heparin-containing tube is centrifuged to separate the serum or plasma. Proteins are precipitated using a zinc sulfate solution and acetonitrile containing deuterated internal standards (MPA-d3 and MPAG-d3). The resulting protein-free supernatant is injected into the LC-MS/MS system for analysis. The chromatography involves the use of a C18 column and ammonium acetate/water/formic acid and ammonium acetate/methanol/formic acid mobile phases. Quantification of MPA and MPAG levels is achieved by comparing the MRM peak area ratios of analytes and internal standards, consisting of specific precursor/product pairs, with those of calibrators at various concentrations. Calibration curves are constructed from the MRM peak area ratios of calibrators and internal standards versus concentration. © 2023 Wiley Periodicals LLC. Basic Protocol: Quantitation of mycophenolic acid and mycophenolic acid glucuronide in serum or plasma by LC-MS/MS.

Immunosuppressant and SARS-CoV-2 Vaccine Antibody Response After Lung Transplantation

There are insufficient reports on the immunogenicity and safety of the COVID-19 vaccination after lung transplantation in Korea. Between April and September 2021, lung transplant recipients (n=52) and healthy controls (n=22) underwent vaccination. The levels of antibodies were assessed prospectively at 4 weeks after priming and second dose. Of a total of 52 lung transplant recipients, there were 84.6% nonresponders, 15.4% second-dose responders, and 0% primary dose responders. Among healthy controls, 63.6% were priming responders, and 18.2% were second-dose responders, and 18.2% were nonresponders. Compared with the control group, lung recipients were less likely to develop antibodies (P < .001). Antibody formation tended to be higher in recipients more than 1 year after transplantation (0 vs 20.5%, P=.076). No major safety events were reported, and the adverse symptoms were mild and consistent with those of the general population. In a multivariate regression analysis, mycophenolic acid levels (µg/mL) (odds ratio 0.25, P=.005) and tacrolimus level (ng/mL) (odds ratio 0.65, P=.035) were significantly associated with antibody formation. The immunogenicity of the second dose of COVID-19 vaccination with various combinations was substantially low in lung transplants. A booster of the COVID-19 vaccine is warranted in lung transplants, especially a year later.

Adherence to medication by adolescents and young adults with childhood-onset systemic lupus erythematosus.

Background: Approximately 20% of all cases systemic lupus erythematous (SLE) are juvenile onset. Children and adolescents with SLE usually present with more severe illness and have a higher mortality rate compared to adults with SLE. Adherence to medications in children and adolescents has a major impact on disease control as well as short- and long-term outcomes. Improved understanding of adherence rates, risk factors for non-adherence, and barriers to adherence are essential in order to increase patient adherence with medication regimens. The aim of our study was to evaluate adherence to medications among children and young adults with pediatric-onset SLE and identify barriers for non-adherence by utilizing several adherence evaluation methods.Methods: Adherence to medications of patients aged 12-25, with childhood-onset SLE was assessed as follows: (1). The brief medication questionnaire (BMQ): self-report tool for screening adherence and barriers to adherence. (2). Mycophenolic acid (MPA) serum level. (3). Medication possession ratio (MPR): data assessing 90-day refills and dispense prior to patient's enrollment was collected.Results: Of the 38 patients who were enrolled in the study, 65% were found to be non-adherent according to at least 1 measurement method. Forty-four percent of patients were found to be non-adherent based on the self-reported questionnaire (BMQ). Of those taking MMF, 33% had an MPA level < 1mcg/mL and were defined as non-adherent. Seventeen percent of patients were found to be non-adherent according to pharmacy refills rate. Forty-six percent of patients stated that their medications caused side effects, 33% of patients indicated difficulty remembering to take the medications, and 25% reported difficulty paying for medications. The disease activity index (SLEDAI) score of the "adherent group" at diagnosis was significantly lower compared to the "non-adherent" group. Patients with private insurance had more access barriers to obtaining medications compared to patients with public insurance.Conclusion: Non-adherence to medications is highly prevalent among cSLE patients. Higher SLEDAI score is a risk factor for non-adherence. Adherence to medications should be routinely evaluated among adolescence and young adults with cSLE and barriers to adherence need to be addressed to decrease morbidity and improve patient outcomes.

Prescribing Nirmatrelvir/Ritonavir for COVID-19 in Advanced CKD.

Prescribing Nirmatrelvir/Ritonavir for COVID-19 in Advanced CKD.

Quantitation of mycophenolic acid and metabolites by UPLC-MS/MS in renal transplant patients

Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), specific inhibitors of lymphocyte proliferation, are commonly used as adjuvant therapy with calcineurin inhibitor agents after kidney transplantation. After administration, MMF and EC-MPS are hydrolyzed to mycophenolic acid (MPA), the active form of the drug, which must be monitored due to its narrow therapeutic window, drug–drug interactions, and large intra-and inter-individual pharmacokinetic variability despite a fixed dose. Monitoring plasma MPA level is recommended to maintain the drug within the therapeutic window, optimize its efficacy, and minimize side effects. This study aims to develop a method for quantifying MPA and its major metabolites (mycophenolic acid glucuronide [MPAG]) using on-line solid phase extraction (SPE) coupled with an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in kidney transplant patients. The linearity of MPA and MPAG were 0.3–13.6 μg/mL and 2.6–232.9 μg/mL, respectively (r2 > 0.999). The relative error of accuracy was < 15%. The within-run and between-run imprecision was < 5.8%. No carryover, ion suppression, or ion enhancement were observed. This method was used to analysis of 351 plasma samples from renal transplant patients after MMF or EC-MPS using this method showed large pharmacokinetic variability between patients. Analysis of the same samples by

Antibody Response to mRNA Vaccines against SARS-CoV-2 with Chronic Kidney Disease, Hemodialysis, and after Kidney Transplantation.

Most trials on mRNA vaccines against SARS-CoV-2 did not include patients with chronic kidney disease (CKD), hemodialysis (HD) patients, or kidney transplant recipients (KTR). However, those patients have a higher risk for a severe course of COVID-19 disease and mortality. Available literature has demonstrated a reduced efficacy of mRNA vaccines in HD patients and KTR, while data on CKD patients is scarce. Additionally, factors associated with non-response are poorly understood and not well characterized. We assessed antibody (AB) response (n = 582, 160 CKD patients, 206 patients on HD, 216 KTR) after the administration of two doses of a mRNA-vaccine with either BNT162b2 or mRNA-1273. AB measurements were carried out after a median of 91 days after first vaccinations, demonstrating non-response in 12.5% of CKD patients, 12.1% of HD patients, and 50% of KTR. AB titers were significantly higher in CKD patients than in HD patients or KTR. Factors associated with non-response were treated with rituximab in CKD patients, the use of calcineurin inhibitors in HD patients and older age, and the use of BNT162b2, mycophenolic acid, or glucocorticoids and lower hemoglobin levels in KTR. This study contributes to the understanding of the extent and conditions that predispose for non-response in patients with impaired kidney function.

Long-Term Results of Triple Immunosuppression With Tacrolimus Added to Mycophenolate and Corticosteroids in the Treatment of Lupus Nephritis

IntroductionAddition of a calcineurin inhibitor (CNI) to corticosteroids and mycophenolate increased the renal response rate in lupus nephritis (LN) because of proteinuria reduction, but there is little long-term efficacy and safety data on this triple immunosuppressive regimen.MethodsThis is a cohort study of patients with class III/IV/V LN whose proteinuria persisted despite initial standard therapy with mycophenolate mofetil (MMF) and prednisolone (PRED), in whom tacrolimus (TAC) was added (target 12-hour trough TAC plasma levels of 4–6 μg/l).ResultsA total of 22 patients with LN treated with triple immunosuppression were included, with follow-up of 61.1 ± 28.1 months. Achieved trough levels of TAC and mycophenolic acid (MPA) were 3.8 to 5.7 μg/l and 1.3 to 2.1 mg/l respectively. Significant proteinuria reduction occurred after 6 months and was sustained up to 5 years. Complete response (CR) and partial response (PR) rates at 12, 24, and 36 months was 59.1%, 72.7%, and 77.3% respectively. The slope of estimated glomerular filtration rate (eGFR) over time did not change after TAC was added. A total of 7 patients (31.8%) showed progressive chronic kidney disease (CKD). Two patients reached end-stage kidney disease during follow-up. Renal survival rate at -, 3, and 5 years was 100.0%, 95.0%, and 88.7% respectively. Two patients (9.1%) had renal relapse after 8.5 ± 0.7 months. A total of 5 patients (22.7%) showed worsening of hypertension, and 3 (13.6%) had worsened hyperlipidemia. Other key adverse events included infection (n = 16, 1 in 7 patient-years) and gastrointestinal upset (n = 6).ConclusionTriple immunosuppression with the addition of TAC to mycophenolate and PRED resulted in further proteinuria reduction and sustained disease quiescence in patients with LN whose proteinuria did not respond optimally to standard therapy.

Serum albumin level is associated with mycophenolic acid concentration in children with idiopathic nephrotic syndrome.

Mycophenolate mofetil is effective for the treatment of pediatric idiopathic nephrotic syndrome (INS). The dosage of mycophenolate mofetil is adjusted according to the serum concentration of mycophenolic acid (MPA). Kidney function or cyclosporine (CsA) concentrations affect serum MPA levels. However, few studies have focused on the association between serum concentrations of MPA and albumin. This retrospective observational study aimed to evaluate the relationship between the serum concentrations of MPA and albumin in INS children. Subjects were children with INS who underwent the therapeutic drug monitoring of CsA and MPA. We obtained the serum albumin (sAlb) concentration, estimated glomerular filtration rate (eGFR), age, and MPA and CsA areas under concentration-time curves from 0 to 12h (AUC0-12). Multiple linear regression analysis and generalized estimating equations were performed to predict values for MPA AUC0-12. We obtained information for 51 INS children with 261 MPA AUC0-12 measurements. The standardized regression coefficients of sAlb, eGFR, CsA AUC0-12, and age were 0.54, - 0.21, - 0.07, and 0.04, respectively. Furthermore, MPA AUC0-12 levels positively correlated with sAlb concentrations (p < 0.001) and were inversely correlated with eGFR values (p = 0.005) but not with CsA AUC0-12 (p = 0.24) and age (p = 0.65).Conclusion: Serum albumin concentration was strongly associated with total MPA concentration compared with kidney function or CsA values. Although patients with INS may have a low serum concentration of total MPA in the presence of low sAlb concentration, close attention should be paid to the interpretation of the low MPA values. What is Known: • The dosage of mycophenolate mofetil is adjusted according to the serum concentration of total mycophenolic acid. • Kidney function, cyclosporin concentrations, or serum albumin concentrations influence serum mycophenolic acid levels. What is New: • Serum albumin concentration is more strongly associated with total mycophenolic acid concentration than kidney function or cyclosporin values. • In children with nephrotic syndrome, the total mycophenolic acid concentration may not increase in the presence of severe hypoalbuminemia.

Exposure levels of mycophenolic acid are associated with comorbidities in children with systemic lupus erythematosus.

Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0-24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0-24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982-0.999), SLE duration (OR 1.012, 95% CI 1.002-1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925-0.991), plasma albumin levels (OR 0.891, 95% CI 0.843-0.940), use of aspirin (OR 0.292, 95% CI 0.126-0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184-0.906). The random forest model showed that albumin and AUC0-24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0-24h of 73.63 mg · h/L, while the control group had a mean AUC0-24h of 100.39 mg · h/L. Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0-24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.

Influence of SLCO1B1 521T&gt;C, UGT2B7 802C&gt;T and IMPDH1 −106G&gt;A Genetic Polymorphisms on Mycophenolic Acid Levels and Adverse Reactions in Chinese Autoimmune Disease Patients

IntroductionMycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.MethodsThis study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 −118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 −106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.ResultsSLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 −106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).ConclusionFor Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 −106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.

Impact of Colectomy with Ileostomy in Immunosuppression Management after Heart Transplantation Mycophenolate Mofetil Levels Secondary to Ileostomy

<h3>Introduction</h3> The management of immunosuppressants constitutes a challenge in clinical practice to maintain drug exposure within therapeutic target because of its variable pharmacokinetics. <h3>Case Report</h3> A 38 years-old male with an advanced non-compacted cardiomyopathy underwent orthotopic heart transplantation (OHT). On the 4^th day post-op he developed a paralytic ileum complicated with cecum perforation and faecaloid peritonitis that required emergent right hemicolectomy and terminal ileostomy. At discharge, his treatment was tacrolimus, mycophenolate mofetil (MMF) and prednisone.During follow-up pre-dose mycophenolic acid (MPA) levels were undetectable despite ensuring good adherence and increased MMF dose. Meanwhile, tacrolimus levels were on target. A pharmacokinetic study with area under concentration-time (AUC) evidenced absence of MPA levels after 4h from oral administration. Everolimus was introduced in substitution of MMF because of this, achieving adequate pre-dose concentration levels. After per-protocol intestine reconstruction with ileocolonic anastomosis, a new MPA pharmacokinetic curve was obtained. MPA dose adjusted AUC was 51% higher post correction. Concentration curves pre and post corrective surgery are presented (<b>figure 1</b>). <h3>Discusion</h3> MMF and its active metabolite MPA are rapidly absorbed resulting in a high oral bioavailability. Yet, because of enterohepatic circulation (EHC), a second rise in MPA plasmatic concentrations appears after 4-8h of its administration, contributing to 10-60% of the total AUC exposure. In patients with ileostomy, the lack of EHC causes a complete absence of MPA levels after 4h of oral administration and thus, an ulterior undetectable Cmin. <h3>Summary</h3> Patients with ileostomy and OHT may be at risk of rejection given the lack of EHC of MPM. Therapeutic monitoring of MPA with AUC or conversion to other immunosuppressants should be considered in this population.