Background:The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma... Show moreBackground:The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively.Methods:A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with +/- 15% for busulfan concentrations and +/- 10% for busulfan plasma exposure. The dose recommendations were deemed accurate.Results:Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values.Conclusions:The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan. Show less
Giraud, E.L.; Brake, L.M.H. te; Hombergh, E.C.A. van den; Desar, I.M.E.; Kweekel, D.M.; Erp, N.P. van 2023
Aims: With the rising number of oral targeted oncolytics and growing awareness of the benefits of therapeutic drug monitoring (TDM) within the field of oncology, it is expected that the requests... Show moreAims: With the rising number of oral targeted oncolytics and growing awareness of the benefits of therapeutic drug monitoring (TDM) within the field of oncology, it is expected that the requests for quantifying concentrations of these drugs will increase. It is important to (cross-)validate available assays and ensure its quality, as results may lead to altered dosing recommendations. Therefore, we aimed to evaluate the performance of laboratories measuring concentrations of targeted oral oncolytics in a one-time international quality control (QC) programme.Methods: Participating laboratories received a set of plasma samples containing low, medium and high concentrations of imatinib, sunitinib, desethylsunitinib, pazopanib, cabozantinib, olaparib, enzalutamide, desmethy lenzalutamide and abiraterone, with the request to report their results back within five weeks after shipment. Accuracy was defined acceptable if measurements where within 85%-115% from the weighed-in reference concentrations. Besides descriptive statistics, an exploratory ANOVA was performed.Results: Seventeen laboratories from six countries reported 243 results. Overall, 80.7% of all measurements were within the predefined range of acceptable accuracy. Laboratories performed best in quantifying imatinib and poorest in quantifying desethylsunitinib (median absolute inaccuracy respectively 4.0% (interquartile range (IQR) 1.8%-6.5%) and 15.5% (IQR 8.8%-34.9%)). The poorest performance of desethylsunitinib might be caused by using the stable-isotope-labelled sunitinib instead of desethylsunitinib as an internal standard, or due to the light-induced cis(Z)/trans(E) isomerization of (desethyl)sunitinib. Overall, drug substance and performing laboratory seemed to influence the absolute inaccuracy (F = 16.4; p < 0.001 and F = 35.5; p < 0.001, respectively).Conclusion: Considering this is the first evaluation of an international QC programme for oral targeted oncolytics, an impressive high percentage of measurements were within the predefined range of accuracy. Cross-validation of assays that are used for dose optimization of oncolytics will secure the performance and will protect patients from incorrect advices. Show less
BackgroundBrain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic-ischemic reperfusion injury. The aim of this... Show moreBackgroundBrain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic-ischemic reperfusion injury. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics (PK) of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase. MethodsSingle-center, open-label dose-escalation study in adult OHCA patients, investigating three 2-IB dosing schedules (targeting an AUC(0-24h) of 600-1,200 ng*h/m in cohort A, of 2,100-3,300 ng*h/mL in cohort B, and 7,200-8,400 of ng*h/mL in cohort C). Safety was investigated by monitoring vital signs until 15 min after study drug administration and adverse events up to 30 days after admission. Blood sampling for PK analysis was performed. Brain biomarkers and patient outcomes were collected 30 days after OHCA. ResultsA total of 21 patients was included, eight in cohort A and B and five in cohort C. No changes in vital signs were observed, and no adverse events related to 2-IB were reported. A two-compartment PK model described data the best. Exposure in group A (dosed on bodyweight) was three times higher than targeted (median AUC(0-24h) 2,398 ng*h/mL). Renal function was an important covariate; therefore, in cohort B, dosing was performed on eGFR on admission. In cohort B and C, the targeted exposure was met (median AUC(0-24h) 2,917 and 7,323 ng*h/mL, respectively). ConclusionThe administration of 2-IB to adults after OHCA is feasible and safe. PK can be well predicted with correction for renal function on admission. Efficacy studies with 2-IB after OHCA are needed. Show less
Meertens, M.; Muntinghe-Wagenaar, M.B.; Sikkema, B.J.; Lopez-Yurda, M.; Retél, V.P.; Paats, M.S.; ... ; Wekken, A.J. van der 2023
Background: Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free... Show moreBackground: Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (C-min,C-SS) were below 435 ng/mL. This may suggest that patients should have an alectinib C-min,C-SS=435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM.Methods: ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged = 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib C-min,C-SS < 435 ng/mL, arm A will receive increased doses of alectinib till C-min,C-SS = 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition.Discussion: The ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib. Show less
Erreni, M.; D'Autilia, F.; Avigni, R.; Bolli, E.; Arnouk, S.M.; Movahedi, K.; ... ; Ginderachter, J.A. van 2023
Rationale: Nanobodies (Nbs) have emerged as an elegant alternative to the use of conventional monoclonal antibodies in cancer therapy, but a detailed microscopic insight into the in vivo... Show moreRationale: Nanobodies (Nbs) have emerged as an elegant alternative to the use of conventional monoclonal antibodies in cancer therapy, but a detailed microscopic insight into the in vivo pharmacokinetics of different Nb formats in tumor-bearers is lacking. This is especially relevant for the recognition and targeting of pro-tumoral tumor-associated macrophages (TAMs), which may be located in less penetrable tumor regions.Methods: We employed anti-Macrophage Mannose Receptor (MMR) Nbs, in a monovalent (m) or bivalent (biv) format, to assess in vivo TAM targeting. Intravital and confocal microscopy were used to analyse the blood clearance rate and targeting kinetics of anti-MMR Nbs in tumor tissue, healthy muscle tissue and liver. Fluorescence Molecular Tomography was applied to confirm anti-MMR Nb accumulation in the primary tumor and in metastatic lesions.Results: Intravital microscopy demonstrated significant differences in the blood clearance rate and macrophage targeting kinetics of (m) and (biv)anti-MMR Nbs, both in tumoral and extra-tumoral tissue. Importantly, (m)anti-MMR Nbs are superior in reaching tissue macrophages, an advantage that is especially prominent in tumor tissue. The administration of a molar excess of unlabelled (biv)anti-MMR Nbs increased the (m)anti-MMR Nb bioavailability and impacted on its macrophage targeting kinetics, preventing their accumulation in extra-tumoral tissue (especially in the liver) but only partially influencing their interaction with TAMs. Finally, anti-MMR Nb administration not only allowed the visualization of TAMs in primary tumors, but also at a distant metastatic site.Conclusions: These data describe, for the first time, a microscopic analysis of (m) and (biv)anti-MMR Nb pharmacokinetics in tumor and healthy tissues. The concepts proposed in this study provide important knowledge for the future use of Nbs as diagnostic and therapeutic agents, especially for the targeting of tumor-infiltrating immune cells. Show less
Prins, M.L.M.; Plas, J.L. van der; Vissers, M.F.J.M.; Berends, C.L.; Tresch, G.; Soergel, M.; ... ; Kamerling, I.M.C. 2022
AimTo assess viral clearance, pharmacokinetics, tolerability and symptom evolution following ensovibep administration in symptomatic COVID-19 outpatients.MethodsIn this open-label, first-in-patient... Show moreAimTo assess viral clearance, pharmacokinetics, tolerability and symptom evolution following ensovibep administration in symptomatic COVID-19 outpatients.MethodsIn this open-label, first-in-patient study a single dose of either 225 mg (n = 6) or 600 mg (n = 6) of ensovibep was administered intravenously in outpatients with mild-to-moderate COVID-19 symptoms. Pharmacokinetic profiles were determined (90-day period). Pharmacodynamic assessments consisted of viral load (qPCR and cultures) and symptom questionnaires. Immunogenicity against ensovibep and SARS-CoV-2-neutralizing activity were determined. Safety and tolerability were assessed throughout a 13-week follow-up.ResultsBoth doses showed similar pharmacokinetics (first-order) with mean half-lives of 14 (SD 5.0) and 13 days (SD 5.7) for the 225- and 600-mg groups, respectively. Pharmacologically relevant serum concentrations were maintained in all subjects for at least 2 weeks postdose, regardless of possible immunogenicity against ensovibep. Viral load changes from baseline at day 15 were 5.1 (SD 0.86) and 5.3 (SD 2.2) log10 copies/mL for the 225- and 600-mg doses, respectively. COVID-19 symptom scores decreased from 10.0 (SD 4.1) and 11.3 (SD 4.0) to 1.6 (SD 3.1) and 3.3 (SD 2.4) in the first week for the 225- and 600-mg groups, respectively. No anti-SARS-CoV-2 neutralizing activity was present predose and all patients had SARS-CoV-2 antibodies at day 91. Adverse events were of mild-to-moderate severity, transient and self-limiting.ConclusionSingle-dose intravenous administration of 225 or 600 mg of ensovibep appeared safe and well tolerated in patients with mild-to-moderate COVID-19. Ensovibep showed favourable pharmacokinetics in patients and the pharmacodynamic results warrant further research in a larger phase 2/3 randomized-controlled trail. Show less
Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath... Show moreConcentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol. Show less
Wijk, R.C. van; Krekels, E.H.J.; Kantae, V.; Ordas, A.; Kreling, T.; Harms, A.C.; ... ; Graaf, P.H. van der 2019
Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of... Show moreZebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically study and quantify pharmacokinetics in zebrafish larvae, and compare this to higher vertebrates, using paracetamol (acetaminophen) as paradigm compound. A method was developed to sample blood from zebrafish larvae at five days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulphate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analysed through non-linear mixed effects modelling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein with median volume (interquartile range) of 1.12 (0.676-1.66) nL per blood sample. Samples were pooled (n=15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulphate was the major metabolite and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well to reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development. Show less
Smit, C.; Hoogd, S. de; Bruggemann, R.J.M.; Knibbe, C.A.J. 2018
