Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although... Show moreMycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune suppression. We therefore aimed to identify biomarkers that reflect the overall immune status of the patient and might support individualized dosing. We previously studied immune biomarkers for CNIs and aimed to investigate whether these are also suitable to monitor MMF activity. Healthy volunteers received a single dose of MMF or placebo, after which IMPDH enzymatic activity, T cell proliferation, and cytokine production were measured and compared to MPA (MMF's active metabolite) concentration in three different matrices (plasma, peripheral blood mononuclear cells, and T cells). MPA concentrations in T cells exceeded those in PBMCs, but all intracellular concentrations correlated strongly with plasma concentrations. At clinically relevant MPA concentrations, IL-2 and IFN-& gamma; production was mildly suppressed, while MPA T cell proliferation was strongly inhibited. Based on these data, it is expected that monitoring of T cell proliferation in MMF-treated transplantation patients may be a valid strategy to avoid excessive immune suppression. Show less
Veld, A.E.I. 't; Jansen, M.A.A.; Huisman, B.W.; Schoonakker, M.; Kam, M.L. de; Moes, D.J.A.R.; ... ; Moerland, M. 2022
Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has... Show moreTherapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer study we therefore aimed to identify biomarkers to move from a pharmacokinetic-based towards a pharmacodynamic-based monitoring approach for calcineurin inhibitor treatment. Healthy volunteers received a single dose of cyclosporine A (CsA) or placebo, after which whole blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine production, and activation marker expression. The highest whole blood concentration of CsA was found at 2 h post-dose, which resulted in a strong inhibition of interferon gamma (IFNy) and interleukin-2 (IL-2) production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied by incubation of pre-dose whole blood samples with a concentration range of CsA. The average in vitro and ex vivo CsA activity overlapped, making the in vitro dose-effect relationship an interesting method for prediction of post-dose drug effect. The clinical relevance of the results is to be explored in transplantation patients on calcineurin inhibitor treatment. Show less
Stoep, M.Y.E.C. van der; Oostenbrink, L.V.E.; Bredius, R.G.M.; Moes, D.J.A.R.; Guchelaar, H.J.; Zwaveling, J.; Lankester, A.C. 2022
Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non... Show moreAllogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT. Show less
Purpose Tamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy.... Show morePurpose Tamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy. Three endoxifen thresholds have been suggested (5.9 ng/ml, 5.2 ng/ml and 3.3 ng/ml) for therapeutic drug monitoring (TDM). Our aim was to validate these thresholds and to examine endoxifen exposure with clinical outcome in early-breast cancer patients using tamoxifen. Methods Data from 667 patients from the CYPTAM study (NTR1509) were available. Patients were stratified (above or below), according to the endoxifen threshold values for tamoxifen efficacy and tested by Cox regression. Logistic regressions to estimate the probability of relapse and tamoxifen discontinuation were performed. Results None of the thresholds showed a statistically significant difference in relapse-free survival: 5.2 ng/ml threshold: hazard ratio (HR): 2.545, 95% confidence interval (CI) 0.912-7.096,pvalue: 0.074; 3.3 ng/ml threshold: HR: 0.728; 95% CI 0.421-1.258,pvalue: 0.255. Logistic regression did not show a statistically significant association between the risk of relapse (odds ratio (OR): 0.971 (95% CI 0.923-1.021,pvalue: 0.248) and the risk for tamoxifen discontinuation (OR: 1.006 95% CI 0.961-1.053,pvalue: 0.798) with endoxifen concentrations. Conclusion Our findings do not confirm the endoxifen threshold values for TDM nor does it allow definition of a novel threshold. These findings indicate a limited value of TDM to guide tamoxifen efficacy. Show less
Background: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to... Show moreBackground: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes.Methods: In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (C-min) will be calculated. In cases where C-min, falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase.Discussion: Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs. Show less
Wit, D. de; Hartigh, J. den; Gelderblom, H.; Qian, Y.W.; Hollander, M. den; Verheul, H.; ... ; Erp, N.P. van 2015
Over the last decades, restoration of renal function by renal allograft transplantation has evolved into the preferred treatment option for patients with end stage renal disease. The introduction... Show moreOver the last decades, restoration of renal function by renal allograft transplantation has evolved into the preferred treatment option for patients with end stage renal disease. The introduction of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus have significantly contributed to this success. Adverse drug effects, together with the large inter-individual variation in pharmacokinetics of both drugs necessitates therapeutic drug monitoring (TDM). Nowadays, TDM is routinely performed by drug concentration measurement in blood. Unfortunately, the incidence of acute allograft rejection episodes is still 10-20% within first year after transplantation. A strategy to improve clinical immunesuppresion early after transplantation is improved monitoring. Next to advanced pharmacokinetic monitoring, such as estimated AUC monitoring, the development of pharmacodynamic markers could theoretically contribute to improve CNI therapy. Pharmacodynamic monitoring strategies, however, are still in an experimental phase and have not proven clinical benefit yet. They carry the theoretical advantage of monitoring the true effectiveness of immunosuppressive therapy. This led us to investigate pharmacodynamic monitoring as potential tool to guide drug dosing. We choose calcineurin activity as pharmacodynamic marker for monitoring and in this thesis, the analytical aspects, fundamental characteristics and insights in clinical usefulness of calcineurin activity measurement as a pharmacodynamic marker for CNI were investigated. Show less
