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.</p

Quantitative modeling of tumor dynamics and development of drug resistance in non-small cell lung cancer patients treated with erlotinib

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 tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics’ parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance.</p

High Treosulfan Exposure is Associated with Early Toxicity in Pediatric Hematopoietic Stem Cell Transplantation: A Prospective Multicenter Study

n/

Quantitative modeling of tumor dynamics and development of drug resistance in non-small cell lung cancer patients treated with erlotinib

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 tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics’ parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance.</p

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

International audienceBackground - 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

Mycophenolic Acid Exposure Determines Antibody Formation Following SARS-CoV-2 Vaccination in Kidney Transplant Recipients:A Nested Cohort Study

Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID-19 since a substantial number of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure–response relationship between mycophenolic acid 12-hour area under the curve (AUC0–12h) exposure and seroconversion including antibody titers after vaccination using mRNA-1273 SARS-CoV-2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID-19 vaccination – long term efficacy and safety of SARS-CoV-2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P &lt; 0.001). The mean mycophenolic acid AUC0–12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P &lt; 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC0–12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79–0.97; P = 0.010) and 0.89 (95% CI, 0.85–0.93; P &lt; 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC0–12h correlated with lower antibody titers (R = 0.44, P &lt; 0.001). This study demonstrates the exposure–response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting.</p

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

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. Graphical Abstract: A higher resolution version of the Graphical abstract is available as Supplementary information [Figure not available: see fulltext.

A comparison of the effectiveness of different doses of tocilizumab and sarilumab in the treatment of severe COVID-19: a natural experiment due to drug shortages

Objectives: Interleukin (IL)-6 inhibitors are administered to treat patients hospitalized with COVID-19. 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 patients with COVID-19, treated with IL-6 inhibitors, were included in this natural experiment study. Sixty-day survival, hospital- and intensive care unit (ICU) length of stay, and progression to ICU or death were compared between 8 mg/kg tocilizumab, fixed-dose tocilizumab, low-dose tocilizumab, and fixed-dose sarilumab treatment groups. Results: A total of 5485 patients from 49 hospitals were included. After correction for confounding, increased hazard ratios (HRs) for 60-day mortality were observed for fixed-dose tocilizumab (HR 1.20, 95% confidence interval [CI] 1.04-1.39), low-dose tocilizumab (HR 1.12, 95% CI 0.97-1.31), and sarilumab (HR 1.24, 95% CI 1.08-1.42), all relative to 8 mg/kg. The 8 mg/kg dosing regimen had lower odds of progression to ICU or death. Both hospital- and ICU length of stay were shorter for low-dose tocilizumab than for the 8 mg/kg group. Conclusion: We found differences in the probability of 60-day survival and the incidence of the combined outcome of mortality or ICU admission, mostly favoring 8 mg/kg tocilizumab. Because of potential time-associated residual confounding, further clinical studies are warranted