Pharmacodynamic Monitoring of Inosine Monophosphate Dehydrogenase Activity: A Basis For Optimized and Individualized Mycophenolate Mofe

In 1896 Gosic isolated for the first time mycophenolic acid (MPA) from Penicillium glaucum.It was subsequently isolated from Penicillium stoloniferum Thom (synonym P. brevi-compactum Dierckx) by Alsberg and Black in 1913 who gave the acid phenolic substance its name mycophenolic acid (MPA).From 1931 to 1933 a series of studies in the biochemistry of micro-organisms was published by Clutterbuck, Raistrick and Oxford of the division of biochemistry from the University of London. These series described in detail the isolation and characterization of MPA. The structure of MPA was finally established in 1952. In the first decades, MPA was eventually found to have antineoplastic, antibacterial, antifungal and antiviral properties and was investigated by a few groups.In 1969, Planterose et al described an effect of MPA most likely to an immunosuppressive effect, and Mitsui et al reported in the same year for the first time the immunosuppressive effect of MPA in mice, at the cellular and humoral levels of antibody formation. In the following years, more and more research was done on the efficacy of MPA as an immunosuppressant. Mycophenolate mofetil (MMF) was developed at Syntex Corporation to be a more bioavailable form of MPA. The first human trials of MMF in kidney recipients were conducted by Sollinger et al, leading to the registration of the pharmaceutical compound as immunosuppressant in 1995

Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration–time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected

Outcome effects of antiretroviral drug combinations in HIV-positive patients with chemotherapy for lymphoma: a retrospective analysis

Background The combination of combined active antiretroviral therapy (cART) with chemotherapy in the treatment of lymphoma in human immunodeficiency virus (HIV)-positive patients has improved the overall survival of these patients. However, drug–drug interactions between antineoplastic agents and the antiretroviral agents non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) can occur by influencing the activity of the CYP3A4 enzyme. So far, little is known about the clinical relevance of this interaction: the effect on the efficacy and toxicity of the chemotherapy. Also, there is no general consensus which cART is preferable in combination with antineoplastic drugs. Objective To compare PI-based with NNRTI-based cART on the efficacy and toxicity of chemotherapy in lymphoma patients. Setting The Onze Lieve Vrouwe Gasthuis, located in Amsterdam, The Netherlands. Method A retrospective observational cohort study including all patients with HIV and lymphoma over a 10-year period. Clinical outcome (response to chemotherapy and survival) and toxicity of chemotherapy (renal, hepatic and bone marrow toxicity as well as dose reduction, treatment delay and discontinuation) was compared in patients with PI based and NNRTI-based cART. Main outcome measure: Response to chemotherapy and survival. Results Patients using PI-based cART (n = 22) had a significantly lower 1 year survival compared to NNRTI-based cART (n = 21). No significant differences were observed in reaching complete remission after chemotherapy. No overall significant differences in toxicity and discontinuation of the chemotherapy were observed. However, there was a trend towards more severe bone-marrow toxicity in patients with PI-based cART. In addition, patients with PI-based cART received earlier dose-reduction and treatment delay, indicating increased toxicity in PI-treated patients. Conclusion This retrospective study shows that PI-based cART is inferior in combination with chemotherapy to NNRTI-based cART: a lower 1 year survival is observed and dose-reduction and treatment delay occur earlier, possibly based on an earlier onset of toxicity

cART op basis van proteaseremmers vermindert respons en geeft meer bijwerkingen bij chemotherapie tegen lymfomen dan cART op basis van niet-nucleoside reversetranscriptaseremmers

OBJECTIVE: To investigate the incidence of dose adjustments, delays and discontinuation of chemotherapy and the incidence of antineoplastic drug related toxicity in patients treated for lymphoma combined with cART, as well as differences between patients with PI-based and NNRTI-based cART. DESIGN AND METHODS: A retrospective observational cohort study was conducted among HIV-infected adult patients with cART who have been diagnosed with lymphoma and treated with cyclophosphamide, doxorubicin and/or vinca alkoloids, which interact with CYP3A4. Toxic events were identified and classified as renal, hepatic or bone marrow toxicity. Time of administration and dosage of antineoplastic drugs were collected to determine dose adjustments, delay and discontinuation of the chemotherapy and the clinical outcome of chemotherapy was registered. RESULTS: 50 HIV-positive patients were included of which 22 patients used PI-based and 21 NNRTI-based cART. HIV-positive patients with cART had more toxicity than HIV-negative patients. No significant differences in toxicity were observed between patients with PI-based and NNRTI-based cART, apart from a trend that patients with PI-based cART suffered more severe or life-threatening bone marrow toxicity. Patients with PI-based cART applied significantly earlier dose reduction and treatment delay than with NNRTI-based cART. No significant differences in clinical outcome of the chemotherapy were found between PI-based and NNRTI-based cART, but cART achieved less complete remission compared to HIV-negative patients. CONCLUSION: Patients with PI-based cART applied earlier dose adjustments and delays due to toxicity than patients with NNRTI-based cART. A prospective study should enhance the knowledge of the clinical pharmacology of the drug-drug interaction between antineoplastic and antiretroviral agents

Differences in Clearance of Mycophenolic Acid Among Renal Transplant Recipients, Hematopoietic Stem Cell Transplant Recipients, and Patients With Autoimmune Disease

For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients

Association between Clinical Frailty Scale score and hospital mortality in adult patients with COVID-19 (COMET): an international, multicentre, retrospective, observational cohort study

Background: During the COVID-19 pandemic, the scarcity of resources has necessitated triage of critical care for patients with the disease. In patients aged 65 years and older, triage decisions are regularly based on degree of frailty measured by the Clinical Frailty Scale (CFS). However, the CFS could also be useful in patients younger than 65 years. We aimed to examine the association between CFS score and hospital mortality and between CFS score and admission to intensive care in adult patients of all ages with COVID-19 across Europe. Methods: This analysis was part of the COVID Medication (COMET) study, an international, multicentre, retrospective observational cohort study in 63 hospitals in 11 countries in Europe. Eligible patients were aged 18 years and older, had been admitted to hospital, and either tested positive by PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or were judged to have a high clinical likelihood of having SARS-CoV-2 infection by the local COVID-19 expert team. CFS was used to assess level of frailty: fit (CFS1–3), mildly frail (CFS4–5), or frail (CFS6–9). The primary outcome was hospital mortality. The secondary outcome was admission to intensive care. Data were analysed using a multivariable binary logistic regression model adjusted for covariates (age, sex, number of drugs prescribed, and type of drug class as a proxy for comorbidities). Findings: Between March 30 and July 15, 2020, 2434 patients (median age 68 years [IQR 55–77]; 1480 [61%] men, 954 [30%] women) had CFS scores available and were included in the analyses. In the total sample and in patients aged 65 years and older, frail patients and mildly frail patients had a significantly higher risk of hospital mortality than fit patients (total sample: CFS6–9 vs CFS1–3 odds ratio [OR] 2·71 [95% CI 2·04–3·60], p<0·0001 and CFS4–5 vs CFS1–3 OR 1·54 [1·16–2·06], p=0·0030; age ≥65 years: CFS6–9 vs CFS1–3 OR 2·90 [2·12–3·97], p<0·0001 and CFS4–5 vs CFS1–3 OR 1·64 [1·20–2·25], p=0·0020). In patients younger than 65 years, an increased hospital mortality risk was only observed in frail patients (CFS6–9 vs CFS1–3 OR 2·22 [1·08–4·57], p=0·030; CFS4–5 vs CFS1–3 OR 1·08 [0·48–2·39], p=0·86). Frail patients had a higher incidence of admission to intensive care than fit patients (CFS6–9 vs CFS1–3 OR 1·54 [1·21–1·97], p=0·0010), whereas mildly frail patients had a lower incidence than fit patients (CFS4–5 vs CFS1–3 OR 0·71 [0·55–0·92], p=0·0090). Among patients younger than 65 years, frail patients had an increased incidence of admission to intensive care (CFS6–9 vs CFS1–3 OR 2·96 [1·98–4·43], p<0·0001), whereas mildly frail patients had no significant difference in incidence compared with fit patients (CFS4–5 vs CFS1–3 OR 0·93 [0·63–1·38], p=0·72). Among patients aged 65 years and older, frail patients had no significant difference in the incidence of admission to intensive care compared with fit patients (CFS6–9 vs CFS1–3 OR 1·27 [0·92–1·75], p=0·14), whereas mildly frail patients had a lower incidence than fit patients (CFS4–5 vs CFS1–3 OR 0·66 [0·47–0·93], p=0·018). Interpretation: The results of this study suggest that CFS score is a suitable risk marker for hospital mortality in adult patients with COVID-19. However, treatment decisions based on the CFS in patients younger than 65 years should be made with caution. Funding: LOEY Foundation

Pharmacogenetics and immunosuppressive drugs in solid organ transplantation

The transplantation literature includes numerous papers that report associations between polymorphisms in genes encoding metabolizing enzymes and drug transporters, and pharmacokinetic data on immunosuppressive drugs. Most of these studies are retrospective in design, and although a substantial number report significant associations, pharmacogenetic tests are hardly used in clinical practice. One of the reasons for this poor implementation is the current lack of evidence of improved clinical outcome with pharmacogenetic testing. Furthermore, with efficient therapeutic drug monitoring it is possible to rapidly correct for the effect of genotypic deviations on pharmacokinetics, thereby decreasing the utility of genotype-based dosing. The future of pharmacogenetics will be in treatment models in which patient characteristics are combined with data on polymorphisms in multiple genes. These models should focus on pharmacodynamic parameters, variations in the expression of drug transporter proteins, and predictors of toxicity. Such models will provide more information than the relatively small candidate gene studies performed so far. For implementation of these models into clinical practice, linkage of genotype data to medication prescription systems within electronic health records will be crucial