Anti-T-lymphocyte globulin exposure is associated with acute graft-versus-host disease and relapse in pediatric acute lymphoblastic leukemia patients undergoing hematopoietic stem cell transplantation: a multinational prospective study.

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 impact of ATLG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing. Based on 121 patients and 812 samples for POPPK analysis, a two-compartmental model with parallel linear and non-linear clearance and bodyweight as covariate, best described the ATLG concentrationtime data. The level of ATLG exposure (day active ATLG day 16 8.2%, p.

Therapeutic drug monitoring of tacrolimus after kidney transplantation: trough concentration or area under curve-based monitoring?

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 convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration-time curve (AUC). However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long-term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed. In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients.

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

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 on implementing TDM in current clinical practices and outlines priority areas for future research. METHODS: The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. RESULTS: Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. CONCLUSIONS: Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

Pharmacokinetic profile of irinotecan in patients with chronic kidney disease: Two cases and literature review.

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 irinotecan dose reduced to 50%, but was nevertheless admitted to hospital because of irinotecan-induced toxicity, including gastrointestinal toxicity and neutropenic fever. The dose was reduced further to 40% for the second cycle; however, the patient was again admitted to the hospital, and irinotecan was stopped indefinitely. The second patient also had his irinotecan dose reduced to 50% and was admitted to the emergency department for gastrointestinal toxicity after the first cycle. However, irinotecan could be administered in the same dose in later cycles. RESULTS: The area under the curve to infinity of irinotecan and SN-38 in the first patient were comparable to those of an individual receiving 100% dose intensity. The area under the curve to infinity of irinotecan and SN-38 in patient 2 in both cycles were slightly less than reference values. Furthermore, clearance values of irinotecan and SN-38 in our patients were comparable to those without renal impairment. CONCLUSION: Our case report suggests that reduced GFR may not significantly affect the clearance of irinotecan and SN-38, but can still result in clinical toxicity. Reduced initial dosing seems indicated in this patient population. Further research is needed to fully understand the relationship between reduced GFR, pharmacokinetics, and toxicity of irinotecan and SN-38.

Population pharmacokinetics of subcutaneous alemtuzumab in kidney transplantation.

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 fixed dosing algorithm originates from other populations. We developed a population pharmacokinetic model for alemtuzumab in kidney transplant recipients and investigated the potential of personalized alemtuzumab therapy. METHODS: In total, 362 pharmacokinetic observations drawn 0-165 days after transplantation were available from 61 adult kidney transplant recipients who received two consecutive doses of 15 mg alemtuzumab subcutaneously. A population pharmacokinetic model was developed using nonlinear mixed-effects modelling and applied to simulate various dosing regimens. RESULTS: The alemtuzumab concentration-time data were best described by a two-compartmental model with first-order absorption and parallel first-order and time-varying concentration-dependent elimination, with between-subject variability on the first-order elimination (39.6%) and central distribution volume (39.6%). Alemtuzumab pharmacokinetics varied with body size, rendering lighter individuals exposed to lympholytic alemtuzumab concentrations (>0.1 mg/L) for prolonged durations as compared to their heavier peers. This between-subject variability could be reduced through lean bodyweight-adjusted dosing, showing a twofold to threefold reduction in the slope of the median alemtuzumab exposure over the bodyweight range. CONCLUSION: Alemtuzumab displays substantial pharmacokinetic variability in kidney transplant recipients, which may warrant a personalized treatment strategy. Lean bodyweight-adjusted dosing poses an option for individualized dosing, but further evaluation of its potential clinical benefit is warranted.

Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We 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) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

Development and Validation of an Efficient and Highly Sensitive Enzyme-Linked Immunosorbent Assay for Alemtuzumab Quantification in Human Serum and Plasma.

BACKGROUND: Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on most lymphocytes, subsequently inducing complement-mediated and antibody-mediated cytotoxicity. Owing to its ability to induce profound immune depletion, alemtuzumab is frequently used in patients before allogeneic hematopoietic stem cell transplantation to prevent graft rejection and acute graft-versus-host disease. In this clinical context, a stable immunoassay with high sensitivity and specificity to determine alemtuzumab levels is essential for performing pharmacokinetic and pharmacodynamic analyses; however, the available methods have several limitations. Here, we report the successful development and validation of an efficient and highly sensitive enzyme-linked immunosorbent assay technique based on commercially available reagents to quantify alemtuzumab in human serum or plasma. METHODS: This enzyme-linked immunosorbent assay technique was developed and validated in accordance with the European Medicines Agency guidelines on bioanalytical method validation. RESULTS: The assay sensitivity (lower limit of quantification) is 0.5 ng·mL -1 , and the dynamic range is 0.78-25 ng·mL -1 . To accommodate quantification of peak concentration and concentrations below the lympholytic level (<0.1 mcg·mL -1 ), patients' serum samples were prediluted 20-400 times according to the expected alemtuzumab concentration. The overall within-run accuracy was between 96% and 105%, whereas overall within-run precision (coefficient of variation) was between 3% and 9%. The between-run assessment provided an overall accuracy between 86% and 95% and an overall coefficient of variation between 5% and 14%. CONCLUSIONS: The developed assay provides accurate insight into alemtuzumab exposure and its effects on the clinical response to treatment, which is key to optimizing treatment strategies.

Therapeutic Drug Monitoring and Dosage Adjustments of Immunosuppressive Drugs When Combined With Nirmatrelvir/Ritonavir in Patients With COVID-19.

ABSTRACT: 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), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Coadministration of nirmatrelvir/ritonavir with immunosuppressive drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. Although a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here, we provide some general recommendations for therapeutic drug monitoring of ISDs and dosing recommendations when coadministered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day 1, whereas cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.

Application of machine learning to predict tacrolimus exposure in liver and kidney transplant patients given the MeltDose formulation.

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 less accurate AUC estimates. The objectives of this study were: to develop and benchmark ML algorithms trained using full PK profiles to estimate MeltDose®-tacrolimus individual AUCs using 2 or 3 blood concentrations; and to compare their performance to MAP-BE. METHODS: Data from liver (n = 113) and kidney (n = 97) transplant recipients involved in MeltDose-tacrolimus PK studies were used for the training and evaluation of ML algorithms. "True" AUC0-24 h was calculated for each patient using the trapezoidal rule on the full PK profile. ML algorithms were trained to estimate tacrolimus true AUC using 2 or 3 blood concentrations. Performances were evaluated in 2 external sets of 16 (renal) and 48 (liver) transplant patients. RESULTS: Best estimation performances were obtained with the MARS algorithm and the following limited sampling strategies (LSS): predose (0), 8, and 12 h post-dose (rMPE = - 1.28%, rRMSE = 7.57%), or 0 and 12 h (rMPE = - 1.9%, rRMSE = 10.06%). In the external dataset, the performances of the final ML algorithms based on two samples in kidney (rMPE = - 3.1%, rRMSE = 11.1%) or liver transplant recipients (rMPE = - 3.4%, rRMSE = 9.86%) were as good as or better than those of MAP-BEs based on three time points. CONCLUSION: The MARS ML models developed using "true" MeltDose®-tacrolimus AUCs yielded accurate individual estimations using only two blood concentrations.

Glomerular filtration rate in critically ill neonates and children: creatinine-based estimations versus iohexol-based measurements.

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 hypothesis that AKI prevalence will be higher and ARC prevalence will be lower in critically ill children when using iohexol-based measured GFR (mGFR), rather than using eGFR. Additionally, we aimed to investigate the performance of different SCr-based eGFR methods. METHODS: In this single-center prospective study, critically ill term-born neonates and children were included. mGFR was calculated using a plasma disappearance curve after parenteral administration of iohexol. AKI diagnosis was based on the KDIGO criteria, SCr-based eGFR, and creatinine clearance (CrCL). Differences between eGFR and mGFR were determined using Wilcoxon signed-rank tests and by calculating bias and accuracy (percentage of eGFR values within 30% of mGFR values). RESULTS: One hundred five children, including 43 neonates, were included. AKI prevalence was higher based on mGFR (48%), than with KDIGO or eGFR (11-40%). ARC prevalence was lower with mGFR (24%) compared to eGFR (38-51%). eGFR equations significantly overestimated mGFR (60-71 versus 41 ml/min/1.73 m2, p < 0.001-0.002). Accuracy was highest with eGFR equations based on age- and sex-dependent equations (up to 59%). CONCLUSION: Iohexol-based AKI prevalence was higher and ARC prevalence lower compared to standard SCr-based eGFR methods. Age- and sex-dependent equations for eGFR (eGFR-Smeets for neonates and eGFR-Pierce for children) best approached measured GFR and should preferably be used to optimize diagnosis of AKI and ARC in this population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Ustekinumab Trough Concentrations Are Associated with Biochemical Outcomes in Patients with Crohn's Disease.

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 four academic centres in the Netherlands. All patients received a weight-adjusted intravenous (IV) UST induction dose, followed by one subcutaneous (SC) dose of 90 mg UST at 8 weeks. Maintenance therapy consisted of 90 mg subcutaneous UST every 8 or 12 weeks. Individual UST concentration time course during treatment were estimated using a population pharmacokinetic (PK) model. Quartile analysis and logistic regression were performed to analyse if UST concentrations at week 8 were associated with biochemical remission rates at week 24 (C-reactive protein (CRP) ≤ 5 mg/L and / or faecal calprotectin (FC) ≤ 250 mg/kg). RESULTS: In total, 124 patients with CD were included. Patients achieving biochemical remission at week 12 and 24 had significantly higher UST levels at week 8 compared to patients without biochemical remission (6.6 µg/mL versus 3.9 µg/mL, P < 0.01 and 6.3 µg/mL versus 3.9 µg/mL, P < 0.01, respectively). In quartile analysis, patients with UST levels in the highest quartile (≥ 6.3 µg/mL at week 8) had higher biochemical remission rates at week 12 and week 24. There was no association between UST levels at and corticosteroid-free clinical remission rates. CONCLUSION: In this real-world cohort of patients with CD, UST levels in the highest quartile (≥ 6.3 µg/mL) at week 8 were associated with higher biochemical remission rates at week 24.

Exposure-response analyses of cabozantinib in patients with metastatic renal cell cancer.

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 relationship in patients with mRCC treated in routine care. METHODS: Cabozantinib trough concentrations (Cmin) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of Cmin > 750 ng/mL and median Cmin. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. RESULTS: In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0-5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median Cmin was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average Cmin ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with Cmin ≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14-0.70, p = .004). CONCLUSION: In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.

Volumetric microsampling for simultaneous remote immunosuppressant and kidney function monitoring in outpatient kidney transplant recipients.

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), creatinine and iohexol in dried blood spot (DBS), and volumetric absorptive microsample (VAMS) samples. METHODS: The assay was successfully validated analytically for all analytes. Clinical validation was conducted by direct comparison of paired DBS, VAMS and venous reference samples from 25 kidney transplant recipients. Patients received iohexol 5-15 minutes before immunosuppressant intake and were sampled 0, 1, 2 and 3 hours thereafter, enabling tacrolimus and MPA area under the concentration-time curve (AUC) and creatinine-based and iohexol-based glomerular filtration rate (GFR) estimation. Method agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and the percentages of values within 15-30% of the reference (P15 -P30 ) with a P20 acceptance threshold of 80%. RESULTS: For DBS samples, method agreement was excellent for tacrolimus trough concentrations (n = 25, P15  = 92.0%) and AUCs (n = 25; P20  = 95.8%) and adequate for creatinine-based GFR trend monitoring (n = 25; P20  = 80%). DBS-based MPA AUC assessment showed suboptimal agreement (n = 16; P20  = 68.8%), but was considered acceptable given its P30 of 100%. The assay performed inadequately for DBS-based iohexol GFR determination (n = 24; P20  = 75%). The VAMS technique generally showed inferior performance, but can be considered for certain situations. CONCLUSION: The assay was successfully validated for tacrolimus, MPA and creatinine quantification in DBS samples, enabling simultaneous remote kidney function trend monitoring and immunosuppressant therapeutic drug monitoring in kidney transplant recipients.

The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture.

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. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI's in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.

Systemic Pharmacokinetics of Oxaliplatin After Intraperitoneal Administration by Electrostatic Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC) in Patients with Unresectable Colorectal Peritoneal Metastases in the CRC-PIPAC Trial.

BACKGROUND: Electrostatic pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a palliative treatment for unresectable peritoneal metastases from various primary cancers. However, little is known about the systemic pharmacokinetics of oxaliplatin after ePIPAC. METHODS: Twenty patients with unresectable colorectal peritoneal metastases were treated with repetitive ePIPAC monotherapy with oxaliplatin (92 mg/m2) and a simultaneous intravenous bolus of leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Samples were collected during each ePIPAC: whole blood at t = 0, t = 5, t = 10, t = 20, t = 30, t = 60, t = 120, t = 240, t = 360 and t = 1080 min for plasma and plasma ultrafiltrate concentrations; urine at t = 0, t = 1, t = 3, t = 5 and t = 7 days. Samples were analyzed using atomic absorption spectrometry. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling. RESULTS: Four patients received one ePIPAC, three patients received two ePIPAC, and thirteen patients received ≥ 3 ePIPAC. The population pharmacokinetic models adequately described the pharmacokinetics of oxaliplatin after ePIPAC. The plasma ultrafiltrate Cmax of oxaliplatin reached 1.36-1.90 µg/mL after 30 min with an AUC0-24 h of 9.6-11.7 µg/mL * h. The plasma Cmax reached 2.67-3.28 µg/mL after 90 min with an AUC0-24 h of 49.0-59.5 µg/mL * h. The absorption rate constant (Ka) was 1.13/h. Urine concentrations of oxaliplatin rapidly decreased to less than 3.60 µg/mL in 90% of the samples at day 7. DISCUSSION: Systemic exposure to oxaliplatin after ePIPAC seemed comparable to that after systemic chemotherapy, as described in other literature. Since this is an indirect comparison, future research should focus on the direct comparison between the systemic exposure to oxaliplatin after ePIPAC and after systemic chemotherapy. TRIAL REGISTRATION: NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.

Population pharmacokinetics and genetics of oral meltdose tacrolimus (Envarsus) in stable adult liver transplant recipients.

AIMS: Meltdose tacrolimus (Envarsus) is marketed as a formulation with a more consistent exposure. Due to the narrow therapeutic window, therapeutic drug monitoring is essential to maintain adequate exposure. The primary objective of this study was to develop a population pharmacokinetic (PK) model of Envarsus among liver transplant patients and select a limited sampling strategy (LSS) for AUC estimation. The secondary objective was to investigate potential covariates including CYP3A/IL genotype suitable for initial dose optimization when converting to Envarsus. METHODS: Adult liver transplant patients were converted from prolonged release tacrolimus (Advagraf) to Envarsus and blood samples were obtained using whole blood and dried blood spot sampling. Subsequently the population PK parameters were estimated using nonlinear-mixed effect modelling. Demographic factors, and recipient and donor CYP3A4, CYP3A5, IL-6, -10 and -18 genotype were tested as potential covariates to explain interindividual variability. RESULTS: Fifty-five patients were included. A 2-compartment model with delayed absorption was the most suitable to describe population PK parameters. The population PK parameters were as follows: clearance, 3.27 L/h; intercompartmental clearance, 9.6 L/h; volume of distribution of compartments 1 and 2, 95 and 500 L, respectively. No covariates were found to significantly decrease interindividual variability. The best 3-point LSS was t = 0,4,8 with a median bias of 1.8% (-12.5-12.5). CONCLUSIONS: The LSS can be used to adequately predict the AUC. No clinically relevant covariates known to influence the PK of Envarsus, including CYP3A status, were identified and therefore do not seem useful for initial dose optimization.

Comprehensive evaluation of microneedle-based intradermal adalimumab delivery vs. subcutaneous administration: results of a randomized controlled clinical trial.

AIMS: To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle. METHODS: In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography, clinical photography, thermal imaging, and laser speckle contrast imaging to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device. RESULTS: While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 100-point visual analogue scale). Initial absorption rate and relative bioavailability were higher after i.d. adalimumab (time to maximum plasma concentration = 95 h [47-120]; Frel = 129% [6.46%]) compared to s.c. adalimumab (time to maximum plasma concentration = 120 h [96-221]). Anti-adalimumab antibodies were detected in 50% and 83% of the subjects after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (P < .0001). Cytokine secretion after whole blood lipopolysaccharide challenge was comparable between administration routes. CONCLUSIONS: Intradermal injection of adalimumab using hollowing microneedles was perceived as more painful and less accepted than s.c. administration, but yields a higher relative bioavailability with similar safety and pharmacodynamic effects.

The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients.

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 levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure AαVal541 in plasma and applied population pharmacokinetic modeling for AAT. The median AαVal541 plasma level before treatment was 140.2 nM (IQR 51.5-234.8 nM)). In five patients who received AAT for the first time, AαVal541 levels decreased to 20.6 nM (IQR 5.8-88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31-35.0 nM). In 9 of 10 patients, AαVal541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7-30.1 nM). At 7-14 days after treatment, AαVal541 levels started to increase again in all patients. Our results show that fibrinopeptide AαVal541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy.

Human leukocyte antigen selected allogeneic mesenchymal stromal cell therapy in renal transplantation: The Neptune study, a phase I single-center study.

Mesenchymal stromal cells (MSC) hold promise as a novel immune-modulatory therapy in organ transplantation. First clinical studies have used autologous MSCs; however, the use of allogeneic "off-the-shelf" MSCs is more sustainable for broad clinical implementation, although with the risk of causing sensitization. We investigated safety and feasibility of allogeneic MSCs in renal transplantation, using a matching strategy that prevented repeated mismatches. Ten patients received two doses of 1.5 × 106 /kg allogeneic MSCs 6 months after transplantation in a single-center nonrandomized phase Ib trial, followed by lowering of tacrolimus (trough level 3 ng/mL) in combination with everolimus and prednisone. Primary end point was safety, measured by biopsy proven acute rejection (BPAR) and graft loss 12 months after transplantation. Immune monitoring was performed before and after infusion. No BPAR or graft loss occurred and renal function remained stable. One patient retrospectively had DSAs against MSCs, formed before infusion. No major alterations in T and B cell populations or plasma cytokines were observed upon MSC infusion. Administration of HLA selected allogeneic MSCs combined with low-dose tacrolimus 6 months after transplantation is safe at least in the first year after renal transplantation. This sets the stage to further explore the efficacy of third-party MSCs in renal transplantation.

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug-Drug Interactions.

BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. CONCLUSIONS: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.