BackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study ... Show moreBackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS).Results668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R-2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R-2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96-1.04, p = 0.84) or CYP polymorphisms.ConclusionSerum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients. Show less
Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided... Show moreObjectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treat-ment is superior to standard treatment for invasive aspergillosis.Methods: A multicentre ( n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged >= 18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treat-ment initiation of voriconazole and repeated during treatment in both groups. The TDM group had mea-sured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups ( P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) ( P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) Show less
This thesis was aimed at optimizing immunosuppressive therapy in kidney transplant recipients using pharmacometric models. Kidney transplantation comprises the preferred treatment strategy for... Show moreThis thesis was aimed at optimizing immunosuppressive therapy in kidney transplant recipients using pharmacometric models. Kidney transplantation comprises the preferred treatment strategy for patients with end-stage kidney disease. Its clinical success is challenged by graft rejection, necessitating lifelong immunosuppressive therapy to accommodate host-graft adaptation. Herein, achievement of balanced immunosuppression is vital for optimal outcomes, but is complicated by pharmacokinetic variability of the immunosuppressants. Currently, therapeutic drug monitoring (TDM)-guided dose individualization is conducted in an effort to achieve immunosuppressant exposure with adequate rejection prophylaxis and minimal toxicity. However, TDM target attainment rates are low and graft rejection and toxicity are observed in patients with on-target immunosuppressant exposure, indicating a need for further improvement. Pharmacometrics harnesses options to modernize this endeavor, allowing for model-based prediction of individual pharmacokinetic behavior and dosage requirements from patient characteristics and pharmacokinetic observations. We reviewed the current state of pharmacometrics in kidney transplantation, developed pharmacometric models for alemtuzumab and iohexol, externally evaluated a model-based dosing tool for everolimus, and combined pharmacometrics with microsampling to enable remote monitoring of immunosuppressant exposure and kidney function, simultaneously. Our research underlines the broad applicability of pharmacometrics and provides an impulse for future research to further optimize immunosuppressive therapy in kidney transplantation. Show less
Francke, M.I.; Andrews, L.M.; H.L. le; Velde, D. van de; Dieterich, M.; Udomkarnjananun, S.; ... ; Hesselink, D.A. 2022
Introduction: After kidney transplantation, rejection and drug-related toxicity occur despite tacrolimus whole blood pre-dose concentrations ([Tac](blood)) being within the target range. The... Show moreIntroduction: After kidney transplantation, rejection and drug-related toxicity occur despite tacrolimus whole blood pre-dose concentrations ([Tac](blood)) being within the target range. The tacrolimus concentration within peripheral blood mononuclear cells ([Tac](cells)) might correlate better with clinical outcomes. The aim of this study was to investigate the correlation between [Tac](blood) and [Tac](cells), the evolution of [Tac](cells) and the [Tac](cells)/[Tac](blood) ratio, and to assess the relationship between tacrolimus concentrations and the occurrence of rejection. Methods: In this prospective study, samples for the measurement of [Tac](blood) and [Tac](cells) were collected on days 3 and 10 after kidney transplantation, and on the morning of a for-cause kidney transplant biopsy. Biopsies were reviewed according to the Banff 2019 update. Results: Eighty-three [Tac](cells) samples were measured of 44 kidney transplant recipients. The correlation between [Tac](cells) and [Tac](blood) was poor (Pearson's r = 0.56 (day 3); r = 0.20 (day 10)). Both the dose-corrected [Tac](cells) and the [Tac](cells)/[Tac](blood) ratio were not significantly different between days 3 and 10, and the median inter-occasion variability of the dose-corrected [Tac](cells) and the [Tac](cells)/[Tac](blood) ratio were 19.4% and 23.4%, respectively (n = 24). Neither [Tac](cells), [Tac](blood), nor the [Tac](cells)/[Tac](blood) ratio were significantly different between patients with biopsy-proven acute rejection (n = 4) and patients with acute tubular necrosis (n = 4) or a cancelled biopsy (n = 9; p > 0.05). Conclusion: Tacrolimus exposure and distribution appeared stable in the early phase after transplantation. [Tac](cells) was not significantly associated with the occurrence of rejection. A possible explanation for these results might be related to the low number of patients included in this study and also due to the fact that PBMCs are not a specific enough matrix to monitor tacrolimus concentrations. Show less
Kleinherenbrink, W.; Baas, M.; Nakhsbandi, G.; Hesselink, D.A.; Roodnat, J.I.; Winter, B.C. de; ... ; Gelder, T. van 2021
Breakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the... Show moreBreakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the incidence of CMV disease was studied in a large population of renal transplant recipients who underwent a kidney transplantation in the Radboud University Medical Center between 2004 and 2015 (n = 1300). CMV disease occurred in 31/1300 patients. Multivariate binary linear regression analysis showed that delayed graft function (DGF) (p = 0.018) and rejection (p = 0.001) significantly and independently increased the risk of CMV disease, whereas CMV status did not. Valganciclovir prophylaxis was prescribed to 281/1300 (21.6%) high-risk patients (defined as CMV IgGseronegative recipients receiving a kidney from a CMV IgG-seropositive donor (D+/R-)). Of these 281 patients, 51 suffered from DGF (18%). The incidence of breakthrough CMV disease in D + /R- patients with DGF was much higher than in those with immediate function (6/51 (11.8%) vs 2/230, (0.9%), p = 0.0006 Fisher's exact test), despite valganciclovir prophylaxis. This higher incidence of CMV disease could not be explained by a higher incidence of rejection (and associated anti-rejection treatment) in patients with DGF. D + /R- patients with DGF are at increased risk of developing CMV disease despite valganciclovir prophylaxis. These findings suggest that underexposure to ganciclovir occurs in patients with DGF. Prospective studies evaluating the added value of therapeutic drug monitoring to achieve target ganciclovir concentrations in patients with DGF are needed. Show less
For more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide... Show moreFor more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide variability in response to therapy is still observed since disease recurrence happens in nearly 30 % of breast cancer patients. Tamoxifen has a complex metabolism and it is mainly metabolized by CYP2D6 enzyme, among others, into endoxifen, the most active metabolite of tamoxifen.In the search of a manner in order to individualize endocrine therapy with tamoxifen, CYP2D6 genotyping and therapeutic drug monitoring based on endoxifen serum concentrations were proposed as potential manners to individualize tamoxifen efficacy. Both approaches have been an ongoing discussion and many studies have been published claiming both negative and positive associations. This thesis mainly focusses on CYP2D6 genotyping and endoxifen concentrations and their impact on clinical survival outcome in early breast cancer patients treated with tamoxifen. Show less
Nuland, M. van; Janssen, J.M.; Hoek, B. van; Rosing, H.; Beijnen, J.H.; Bergman, A.M. 2019
Calcineurin inhibitor (CNI)-based therapy is associated with nephrotoxicity and cardiovascular adverse effects in renal transplant recipients. Early CNI withdrawal with mycophenolate mofetil (MMF)... Show moreCalcineurin inhibitor (CNI)-based therapy is associated with nephrotoxicity and cardiovascular adverse effects in renal transplant recipients. Early CNI withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about acute rejection. Therapeutic drug monitoring (TDM) may be advantageous when a CNI or MMF is withdrawn. The impact of late concentration-controlled CNI withdrawal with MMF on renal function, the incidence of acute rejection and markers of cardiovascular disease was evaluated in a randomised trial. In 158 stable renal transplant recipients on a CNI-based regimen with prednisone and MMF either the CNI or MMF was withdrawn. A total of 119 patients participated in the cardiovascular substudy. Late concentration-controlled CNI withdrawal resulted in improved renal function, especially in patients with an estimated glomerular filtration rate of less than 50 ml/min/1.73 m2, with a low acute rejection rate. The progression of left ventricular diastolic dysfunction was prevented by CNI elimination. CNI withdrawal decreased ambulatory blood pressures, but had no specific impact on carotid IMT. In conclusion, late CNI withdrawal with TDM of MMF may result in improved outcome by beneficial effects on renal function and cardiovascular risk, with a low risk of rejection in the majority of stable renal transplant recipients. Show less
After using C0-monitoring as the tool for therapeutic drug monitoring of cyclosporine for many years, studies suggested that C2-monitoring might be better. After switching 31 liver transplant... Show moreAfter using C0-monitoring as the tool for therapeutic drug monitoring of cyclosporine for many years, studies suggested that C2-monitoring might be better. After switching 31 liver transplant patients using cyclosporine from C0 via C2 to flexible limited sampling models (LSM), combinations of blood sampling time points 0+2h (r_=0.94); 0+1+2h (r_=0.94); 0+1+3h (r_=0.92); 0+2+3h (r_=0.92) and 0+1+2+3h (r_=0.96) showed excellent correlation with AUC0-12h with acceptable precision and bias. When evaluating the LSM0+1+2+3h model in the 18 months after introduction there was no significant change in average cyclosporine dose and creatinine clearance, compared to previous C2-monitoring. Especially LSM0+2h was optimal in terms of accuracy, ease-of-use and intrapatient variability. When optimizing tacrolimus monitoring after calculating limited sampling formulas (LSF) and LSM single and multiple-point combinations showed good correlations with AUC0-12h. The best single point calculation in terms of estimating systemic tacrolimus exposure using LSM were LSM 4h (r_=0.97) and LSM 6h (r_=0.97). During the study of the pharmacokinetic behaviour of MMF we found a wide range in MPA clearance in the population (8.08__57.47 L/h). Looking at possible sources of this variability in MPA clearance we divided our group, based on clinical selection, into two groups (with and without calcineurin inhibitors). These groups were used for further development of LSM for monitoring MPA. The combination 0-_-1-2h showed very good correlations with trapezoidal AUC0-12h for both models, with acceptable bias and precision. Show less
