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 (CFS 1-3), mildly frail (CFS 4-5), or frail (CFS 6-9). 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: CFS 6-9 vs CFS 1-3 odds ratio [OR] 2•71 [95% CI 2•04-3•60], p<0•0001 and CFS 4-5 vs CFS 1-3 OR 1•54 [1•16-2•06], p=0•0030; age ≥65 years: CFS 6-9 vs CFS 1-3 OR 2•90 [2•12-3•97], p<0•0001 and CFS 4-5 vs CFS 1-3 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 (CFS 6-9 vs CFS 1-3 OR 2•22 [1•08-4•57], p=0•030; CFS 4-5 vs CFS 1-3 OR 1•08 [0•48-2•39], p=0•86). Frail patients had a higher incidence of admission to intensive care than fit patients (CFS 6-9 vs CFS 1-3 OR 1•54 [1•21-1•97], p=0•0010), whereas mildly frail patients had a lower incidence than fit patients (CFS 4-5 vs CFS 1-3 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 (CFS 6-9 vs CFS 1-3 OR 2•96 [1•98-4•43], p<0•0001), whereas mildly frail patients had no significant difference in incidence compared with fit patients (CFS 4-5 vs CFS 1-3 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 (CFS 6-9 vs CFS 1-3 OR 1•27 [0•92-1•75], p=0•14), whereas mildly frail patients had a lower incide...

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 123J Pharmacokinet Pharmacodyn (2009) 36:541-564 DOI 10.1007 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.

Mycophenolic acid (MPA) inhibits the enzyme inosine 5'-monophosphate dehydrogenase (IMPDH). Thus, the measurement of IMPDH activity could serve as a specific pharmacodynamic (PD) tool for monitoring MPA therapy. At present, however, monitoring of pharmacokinetic parameters is preferred over that of PD parameters because, in general, PD assays are labor-intensive and poorly reproducible. Currently, cell count or protein concentration is widely accepted as methods to normalize enzyme activity. In the present study, we have attempted to further improve a method for the determination of IMPDH activity to increase the robustness and reproducibility of the IMPDH activity assay itself, without making the assay more labor-intensive. Therefore, several aspects of the IMPDH method were investigated regarding their influence on the reproducibility and also modified to increase the feasibility and consistency of the assay. The isolation of peripheral blood mononuclear cells (PBMCs) of whole blood samples was found to be the most variable step. Normalization on cell count is labor-intensive and at the same time has a poor reproducibility. Determination of the protein content in cell extracts is impaired by contamination with extracellular proteins and non-PBMCs. Alternatively, the intracellular substance adenosine monophosphate (AMP) was investigated to normalize the newly generated xanthosine monophosphate. Among various subject groups, no significant differences in mean AMP concentration were found. To simplify the procedure, PBMCs were diluted to a fixed volume after isolation from sample of whole blood, and the IMPDH activity was normalized to the AMP concentration quantified in the same high-performance liquid chromatography run as xanthosine monophosphate was quantified. The within-run and total imprecision (coefficient of variation) ranged from 4.2% to 10.6% and from 6.6% to 11.9%, respectively. In conclusion, the modified method described here for the measurement of IMPDH activity can be used reliably in multicenter trials and in longitudinal studies to evaluate the additional value of any PD monitoring among a diversity of patients treated with MPA.

SummaryBackground and objectives Mycophenolate mofetil (MMF) is an immunosuppressive drug used in renal transplant patients. Upon oral administration it is hydrolyzed to the active agent mycophenolic acid (MPA). In renal transplant recipients, MMF therapy is optimal when the area under the curve of MPA is 30 to 60 mg⅐h/L. When MMF doses are adjusted, a linear relationship between dose and MPA exposure is assumed. In this study, the linearity of MMF pharmacokinetics was investigated.Design, setting, participants, & measurements MPA concentration-time profiles from renal transplant recipients cotreated with cyclosporine (n ϭ 140) or tacrolimus (n ϭ 101) were analyzed retrospectively using nonlinear mixed-effects modeling. The correlation between the MMF dose and the pharmacokinetics parameters was evaluated. ResultsIn the developed population pharmacokinetics model MPA clearance and the central volume of distribution were correlated with cyclosporine coadministration and time posttransplantation. The pharmacokinetics of MPA were not linear. Bioavailability decreased with increasing MMF doses. Compared with an MMF dose of 1000 mg (ϭ100%), relative bioavailability was 123%, 111%, 94%, and 90% in patients receiving MMF doses of 250, 500, 1500, and 2000 mg in combination with cyclosporine (P Ͻ 0.001); respective values in tacrolimus-cotreated patients were 176%, 133%, 85%, and 76% (P Ͻ 0.001). Because of the decreasing relative bioavailability, MPA exposure will increase less than proportionally with increasing MMF doses.Conclusions MMF exhibits nonlinear pharmacokinetics. This should be taken into account when performing therapeutic drug monitoring.

We report that the IMPDH type II 3757T > C polymorphism is associated with an increased IMPDH activity in MMF-treated renal transplant patients. This polymorphism explains 8.0% of the interpatient variability in IMPDH activity.