Dirk Jan A R Moes

Leiden University Medical Centre | LUMC · Department of Clinical Pharmacy and Toxicology

Vancomycin is a glycopeptide antibiotic used for the treatment of severe gram-positive infections. Despite decades of clinical experience, optimized dosing for vancomycin in pediatric populations still warrants further investigation. Patients admitted to the pediatric intensive care unit (PICU) after cardiac surgery are often treated with vancomyci...

High-dose methotrexate (HD-MTX)-based polychemotherapy is widely used for patients with central nervous system (CNS) lymphoma. The pharmacokinetic (PK) variability and unpredictable occurrence of toxicity remain major concerns in HD-MTX treatment. This study aimed to characterize the population PK of HD-MTX in patients with CNS lymphoma and to iden...

BK polyomavirus‐associated nephropathy (BKPyVAN) is a well‐known complication of kidney transplantation (KTx). The mainstay of prevention is the reduction of immunosuppression upon detection of BK polyomavirus (BKPyV) DNAemia, which precedes BKPyVAN. However, this reduction may inadvertently increase the risk of alloimmunity particularly in patient...

The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide Therapeutic Drug Monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version p...

PURPOSE In overweight patients, the Cockcroft-Gault (CG) formula is more likely to overestimate renal function and carboplatin dosing. In this prospective pharmacokinetic study, we evaluated the use of an adjusted Cockcroft-Gault formula (aCG) correcting, amongst other things, for overweight. METHODS aCG adjusted in patients with BMI > 25 kg/m² us...

The goal of the study was to describe the population pharmacokinetics of trimethoprim, sulfamethoxazole, and N ‐acetyl sulfamethoxazole in hospitalized patients. Furthermore, this study used the model to optimize dosing regimens of cotrimoxazole for Pneumocystis jirovecii pneumonia and in patients with renal insufficiency or with continuous renal r...

Atezolizumab is a programmed death-ligand 1 (PD-L1) checkpoint inhibitor for the treatment of different forms of cancer. The subcutaneous formulation of atezolizumab has recently received approval. However, treatment with atezolizumab continues to be expensive, and the number of patients needing treatment with this drug continues to increase. We pr...

Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survi...

Background Therapeutic drug monitoring (TDM) – performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets – could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which...

Introduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoanti...

The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low‐dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal...

The antibody–drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality. The purpose of this study was to develop an evidence-based rational dosing regimen that results in...

Cabozantinib is one of the preferred treatment options in the latest metastatic renal cell carcinoma (mRCC) guidelines. Cabozantinib is also associated with high drug expenses irrespective of the used dose, because a flat-prizing model has been implemented. In addition, concomitant intake with a high-fat meal increases its bioavailability on averag...

Measurement of pre‐dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is...

Background Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure–response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug mon...

Anti T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GvHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM® and the i...

Background Infliximab, an anti–tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide o...

Insight into the development of treatment resistance can support the optimization of anticancer treatments. This study aims to characterize the tumor dynamics and development of drug resistance in patients with non‐small cell lung cancer treated with erlotinib, and investigate the relationship between baseline circulating tumor DNA (ctDNA) data and...

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%–80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis‐specific Y‐encoded‐like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes incl...

Background Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemic...

Background: Meltdose tacrolimus (Envarsus®) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose individualization is essential. Relaxation of the upper age limits for kidney transplantations has resulted in larger numbers of elderly patients receiving tacrolimu...

Introduction Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus in vitro. We investigated the potential antiviral effects of voclosporin on SARS-CoV-2 in immunoc...

• Background: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. Treatment goal is reaching complete biochemical response (CR), defined as normalization of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical re...

Aims There are limited pharmacokinetic data on the use of irinotecan in patients with reduced glomerular filtration rate (GFR) and no haemodialysis. In this case report, we present 2 cases and review the current literature. Methods The dose of irinotecan in both patients was reduced pre‐emptively due to reduced GFR. The first patient had her irino...

Alemtuzumab (anti-CD52 antibody) is frequently prescribed to children with non-malignant diseases undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft failure (GF) and acute graft-versus-host disease (aGvHD). This multicenter study aimed at the characterization of alemtuzumab population pharmacokinetics to perform a...

Introduction: A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22...

Alemtuzumab (anti-CD52 antibody) is frequently prescribed to children with non-malignant diseases undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft failure (GF) and acute graft-versus-host disease (aGvHD). This multicenter study aimed at the characterization of alemtuzumab population pharmacokinetics to perform a...

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 drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune...

The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) and is therefore recommended for use in clinical drug-drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P-gp, it is susceptible to DDIs involving these proteins. Physiologically based pharmacokinetic...

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies...

Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at one year (1Y) and repeated measurements of real-world Tac-trough levels (C0 ) and abbreviated area-under-the-curves (AUC0-12h ) of Tac and MPA with b...

Background We aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer. Methods Data 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-des...

Objective It is unknown whether ustekinumab (UST) levels can predict clinical outcomes in Crohn’s disease (CD) patients. We assessed the exposure–response relationship of UST trough concentrations with biochemical outcomes at week 24 in a prospective, real-world setting. Methods We performed a prospective study in patients with CD starting UST in...

The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 and CYP3A5. For its pharmacokinetics (PK), a high inter‐ and intra‐individual variability can be observed. Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the CYP3A5 g...

Tailoring antiplatelet therapy based on CYP2C19 pharmacogenetic (PGx) testing can improve cardiovascular outcomes and potentially reduce healthcare costs in patients on a P2Y12-inhibitor regime with prasugrel or ticagrelor. However, ubiquitous adoption—particularly in an outpatient setting—remains limited. We conducted a proof-of-concept study to e...

Aim: to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP) treated COVID-19 patients with cytokine storm syndrome (CSS). Methods: MP pre-treated patients with COVID-19 associated CSS, defined as at least two elevations of C-reactive protein (CRP) > 100mg/L, ferritin...

Despite (repeated) boostering, kidney transplant recipients (KTR) may remain at increased risk of severe COVID-19 since a substantial amount of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid (MPA) use has been shown to affect antibody formation negatively and may be an important modifiable risk factor....

Personalized medicine is currently hampered by the lack of flexible drug formulations. Especially for pediatric patients, manual compounding of personalized drug formulations by pharmacists is required. 3D printing of medicines, which enables small-scale manufacturing at the point-of-care, can fulfil this unmet clinical need. This study investigate...

Objectives: IL-6 inhibitors are administered to treat hospitalized COVID-19 patients. In 2021, due to shortages, different dosing regimens of tocilizumab, and a switch to sarilumab, were consecutively implemented. Using real world data, we compare the effectiveness of these IL-6 inhibitors. Methods: Hospitalized COVID-19 patients, treated with I...

Purpose Machine Learning (ML) algorithms represent an interesting alternative to maximum a posteriori Bayesian estimators (MAP-BE) for tacrolimus AUC estimation, but it is not known if training an ML model using a lower number of full pharmacokinetic (PK) profiles (= “true” reference AUC) provides better performances than using a larger dataset of...

Aim Alemtuzumab is a monoclonal antibody used as induction immunosuppressive therapy in kidney transplantation. It targets CD52 on lymphocytes, inducing profound immune cell depletion upon administration. Owing to its off‐label status in kidney transplantation, its pharmacokinetic characteristics are largely unknown in this setting, and its current...

Background: After liver transplantation (LT), tacrolimus and ciclosporin treatment can lead to, partially concentration-dependent, chronic kidney disease. Monitoring ciclosporin with two-hour levels reduced overexposure and led to better renal function than trough-monitoring (C0). For tacrolimus, a four-hour level (C4) can give a reasonable approx...

Background: Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on most lymphocytes, subsequently inducing complement- and antibody-mediated cytotoxicity. Owing to its ability to induce profound immune depletion, alemtuzumab is frequently used in patients prior to allogeneic hematopoietic stem cell transplan...

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 strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer s...

Nirmatrelvir/ritonavir (Paxlovid®) consists of a peptidomimetic inhibitor (Nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (Ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primaril...

Background Acute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and ARC prevalence estimates are based on estimation of GFR (eGFR) using serum creatinine (SCr), which is known to be inaccurate. We aimed to test our hypothes...

Background: Oral targeted therapies show a high pharmacokinetic interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leadin...

Aims Immunosuppressant and kidney function monitoring are crucial for kidney transplant recipient follow‐up. Microsamples enable remote sampling and minimise patient burden as compared to conventional venous sampling at the clinic. We developed a liquid chromatography–tandem mass spectrometry assay to quantify tacrolimus, mycophenolic acid (MPA), c...

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remd...

Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcin...

Kidney transplant recipients (KTRs) are at increased risk of severe COVID-19 disease compared to the general population. This is partly driven by their use of immunosuppressive therapy, which influences inflammatory responses and viral loads. Current guidelines suggest to withdraw mycophenolate while calcineurin inhibitors are often continued durin...

Quantitative characterization of evolving tumor resistance under targeted treatment could help identify novel treatment schedules, which may improve the outcome of anti-cancer treatment. In this study, a mathematical model which considers various clonal populations and evolving treatment resistance was developed. With parameter values fitted to the...

Allogeneic 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...

Background Eculizumab is a lifesaving yet expensive drug for atypical hemolytic uremic syndrome. Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. Methods We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) (classical pathway (CP) activity levels) of eculizumab in 48 patie...

Aim In the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure–response relations...

Background Ustekinumab (UST) is a monoclonal antibody which binds to the p40 subunit of interleukins-12/23 and is an effective and safe treatment for patients with Crohn’s disease (CD). An association between serum drug concentrations and therapeutic outcomes is required to justify Therapeutic Drug Monitoring (TDM). However, it is currently unknown...

Background and objective: In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatm...

Background : Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long...

In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the course of AαVal541 plasma...

Background The cytokine storm syndrome (CSS) associated with COVID-19 pneumonia occurs in up to 20% of the admitted patients causing high morbidity and mortality [1] . In the COVID High-intensity Immunosuppression in Cytokine storm syndrome (CHIC) study [1] we reported that CSS patients, who despite high-dose methylprednisolone (MP) treatment still...

Immunosuppressive therapy is pivotal for sustained allograft and patient survival after renal transplantation. However, optimally balanced immunosuppressive therapy is challenged by between-patient and within-patient pharmacokinetic (PK) variability. This could warrant the application of personalised dosing strategies to optimise individual patient...