Background: Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model... Show moreBackground: Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model-based follow-up dosing, which considers patient characteristics and pharmacological data, may further personalize treatment. This study investigated whether model-based follow-up dosing could lead to more accurate tacrolimus exposure than standard therapeutic drug monitoring (TDM) in kidney transplant recipients after an initial algorithm-based dose. Methods: This simulation trial included patients from a prospective trial that received an algorithm-based tacrolimus starting dose followed by TDM. For every measured tacrolimus predose concentration (C-0,C-obs), model-based dosing advice was simulated using the InsightRX software. Based on previous tacrolimus doses and C-0, age, body surface area, CYP3A4 and CYP3A5 genotypes, hematocrit, albumin, and creatinine, the optimal next dose, and corresponding tacrolimus concentration (C-0,C-pred) were predicted. Results: Of 190 tacrolimus C-0 values measured in 59 patients, 121 (63.7%; 95% CI 56.8-70.5) C-0,C-obs were within the therapeutic range (7.5-12.5 ng/mL) versus 126 (66.3%, 95% CI 59.6-73.0) for C-0,C-pred (P = 0.89). The median absolute difference between the tacrolimus C-0 and the target tacrolimus concentration (10.0 ng/mL) was 1.9 ng/mL for C-0,C-obs versus 1.6 ng/mL for C-0,C-pred. In a historical cohort of 114 kidney transplant recipients who received a body weight-based starting dose followed by TDM, 172 of 335 tacrolimus C-0 (51.3%) were within the therapeutic range (10.0-15.0 ng/mL). Conclusions: The combination of an algorithm-based tacrolimus starting dose with model-based follow-up dosing has the potential to minimize under- and overexposure to tacrolimus in the early posttransplant phase, although the additional effect of model-based follow-up dosing on initial algorithm-based dosing seems small. Show less
When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has... Show moreWhen mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted. Show less
Gelder, T. van; Huizinga, R.B.; Lisk, L.; Solomons, N. 2021
Background An open-label phase 1 study was conducted to evaluate the effect of voclosporin following dosing with mycophenolate mofetil (MMF) on blood levels of mycophenolic acid (MPA, the active... Show moreBackground An open-label phase 1 study was conducted to evaluate the effect of voclosporin following dosing with mycophenolate mofetil (MMF) on blood levels of mycophenolic acid (MPA, the active moiety of MMF) and MPA glucuronide (MPAG, the pharmacologically inactive metabolite of MMF) in subjects with systemic lupus erythematosus (SLE) and to assess the safety and tolerability of the combination. Methods MMF was orally administered at a dose of 1 g twice a day for at least 28 days prior to the study and continued at the same dose throughout the study. Voclosporin was orally administered at a dose of 23.7 mg twice a day for 7 consecutive days (Days 1-7), starting on the evening of Day 1 and ending with the morning dose on Day 7. Dense pharmacokinetic blood samples were collected pre-dose in the morning and from 0.25 to 12 h after the morning doses. Analyses were derived by non-compartmental methods. Results In 24 patients, MPA exposure [maximum serum concentration (C-max) and area under the concentration curve from time 0 to 12 h (AUC(0-12))] was similar in the presence and absence of voclosporin, with treatment ratios of 0.94 and 1.09, respectively [C-max 16.5 mu g/mL (Day 1) versus 15.8 (Day 7), AUC(0-12) 39.1 mu g/h/mL (Day 1) versus 40.8 (Day 7)]. MPAG exposure showed a small increase in the presence of voclosporin (12% for C-max and 27% for AUC(0-12)). Combination therapy was well tolerated. Conclusions There is no clinically meaningful interaction between voclosporin and MMF. As changes in exposure to MPA may affect efficacy and safety, these data confirm that voclosporin and MMF can be administered concomitantly without the need for dose adjustment. Show less
Gelder, T. van; Etsouli, O.; Moes, D.J.; Swen, J.J. 2020
Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one... Show moreTacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure are larger in patients who express the CYP3A5 enzyme (CYP3A5 *1/*3 or *1/*1) compared to nonexpressers (CYP3A5*3/*3). Possibly, these differences are due to the fact that in the upper region of the small intestine CYP3A activity is higher, and that this expression of CYP3A decreases towards the more distal parts of the gut. Modified release formulations may therefore be subject to a less presystemic metabolism. However, the full implications of pharmacogenetic variants affecting the expression and function of drug transporters in the gut wall and of enzymes involved in phase I and phase II metabolism on the different formulations are incompletely understood, and additional studies are required. Conclusions: In all patients in whom the formulation of tacrolimus is changed, drug levels need to be checked to avoid clinically relevant under- or overexposure. In patients with the CYP3A5 expresser genotype, this recommendation is even more important, as changes in drug exposure can be expected. Show less
Meziyerh, S.; Zwart, T.C.; Etten, R.W. van; Janson, J.A.; Gelder, T. van; Alwayn, I.P.J.; ... ; Vries, A.P.J. de 2020
The current coronavirus disease 2019 (COVID-19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35-year-old... Show moreThe current coronavirus disease 2019 (COVID-19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35-year-old renal transplant recipient who suffered from a severe COVID-19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence-based COVID-19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk-benefit balance of experimental or off-label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID-19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug-drug interactions associated with the various treatment options for COVID-19 in renal transplant patients. Show less
Brunet, M.; Gelder, T. van; Asberg, A.; Haufroid, V.; Hesselink, D.A.; Langman, L.; ... ; Bergan, S. 2019
