Hydration Methods for Cisplatin Containing Chemotherapy: A Systematic Review.

INTRODUCTION: Cisplatin-induced nephrotoxicity (CIN) can be prevented by fluid hydration, electrolyte supplementation, or forced diuresis; however, the best way to prevent CIN is still unknown. The aim of this study was to provide objective evidence on the optimal design of hydration schemes to prevent CIN based on an update of the literature. METHODS: A Pubmed and Embase search were conducted in December 2021 and repeated in April 2022 and March 2023. Two independent reviewers screened the articles. The included articles were categorized and reviewed per category. RESULTS: Twenty-seven articles met the inclusion criteria. The included studies varied widely. Four out of seven studies investigating diuretics found a protective effect of adding mannitol to the hydration scheme. All six studies investigating duration and amount of volume of hydration found that a short-hydration scheme resulted in less CIN than a longer hydration scheme. Seven out of nine articles evaluating the role of electrolytes found that magnesium supplementation reduced the risk of nephrotoxicity. Three studies investigated the safety of oral hydration and concluded that nephrotoxicity did not occur more frequently after oral hydration. CONCLUSION: The hydration scheme of cisplatin should be short and consist of a relatively small amount of volume. The scheme should include mannitol and magnesium supplementation. Head-to-head studies are needed to investigate the safety of furosemide compared with mannitol and the dose of mannitol and magnesium.

Varying concentrations of tyrosine kinase inhibitors in chronic myeloid leukemia patients following bariatric surgery: a case series.

Bariatric surgery is increasingly performed to treat severe obesity. As a result of anatomical and physiological changes in the gastrointestinal tract, the pharmacokinetics (PK) of oral drugs can be altered, affecting their efficacy and safety. This includes the class of tyrosine kinase inhibitors (TKIs) which are used to treat chronic myeloid leukemia (CML). This case series describes the clinical course of four CML cases with a history of bariatric surgery. The patients used various TKIs (nilotinib, dasatinib, bosutinib, ponatinib, and imatinib) for which 15 drug levels were measured. The measured TKI concentrations were in part subtherapeutic, and highly variable when compared to mean levels measured in the general population. Multiple drug levels were measured in these patients, as the clinicians were aware of the possible impact of bariatric surgery. The drug levels were used as additional input for clinical decision-making. All four patients required TKI switches and/or dose modifications to achieve an effective and tolerable treatment. Eventually, adequate clinical and molecular remissions were achieved in all cases. In summary, TKI concentrations of patients undergoing bariatric surgery may be subtherapeutic. Moreover, there is substantial interindividual and intraindividual variation, which may be explained by the complex interference of bariatric surgery and associated weight loss. For clinical practice, therapeutic drug monitoring is advised in patients with a history of bariatric surgery in case of suboptimal response or loss of response.

Patients with bariatric surgery: Urgent need for accurate registration of the contraindication to enable safe pharmacotherapy in hospital and primary care.

PURPOSE: To enable the use of automatic clinical decision support for pharmacotherapy in patients with bariatric surgery, it is necessary to register the contraindication "bariatric surgery" in the hospital, general practitioner (GP), and community pharmacy electronic health record systems. The aim of this research was to quantify the correct registration of this contraindication in hospital, GP, and community pharmacy records. Furthermore, we investigated whether the registration status in primary care was dependent on the registration status in the hospital. METHODS: From patients who underwent bariatric procedures performed in the Albert Schweitzer Hospital (Dordrecht, the Netherlands) between 2018 and 2021, the percentage of registered contraindications in hospital medical records was assessed. Due to feasibility reasons, a subset of the patients' data was created for assessing the percentage of registered contraindications in GP and community pharmacy records. RESULTS: Out of 664 patients who underwent bariatric surgery, the contraindication bariatric surgery was registered in 69.1% of the cases. Out of 552 patients, 28.3% and 25.1% were correctly registered in GP and community pharmacy records, respectively. There was no correlation between registration status in the hospital EHR and registration status in GP practices or community pharmacies. CONCLUSIONS: The percentage of correct registration of bariatric surgery in hospital, GP, and community pharmacies is low. To avoid doctors prescribing and pharmacists dispensing drugs to post-bariatric patients without knowing that they have undergone this procedure, better registration of the contraindication is required to enable optimal use of clinical decision support systems for the pharmacotherapy of patients after bariatric surgery.

A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance.

AIM: To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. METHODS: Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. RESULTS: In both models, a similar clearance decrease of 7% (range -82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. CONCLUSION: These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.

Difference in decline in renal function due to cisplatin after a short or long hydration scheme in non-small-cell lung cancer: A retrospective cohort study (HYCIS-XL).

WHAT IS KNOWN AND OBJECTIVE: Nephrotoxicity is a frequently occurring side effect of cisplatin, which may be reduced by applying ample hydration. The aim of this study was to determine whether there is a difference in decline in renal function due to cisplatin between a short hydration (SH) and long hydration scheme (LH). METHODS: A retrospective, observational, cohort study was conducted in two hospitals. Patients in one hospital received an SH scheme (SH group), whereas patients in the other hospital received an LH scheme (LH group). Other aspects of treatment and hydration were comparable between both patient groups. Consecutive patients (≥18 years) treated for non-small-cell lung cancer with cisplatin-pemetrexed with ≥1 cisplatin dose were included. Patients were excluded when serum creatinine at baseline was <40 µmol/L. Primary outcome was the difference in estimated glomerular filtration rate (eGFR) between baseline and after the last cisplatin cycle for the SH and LH patients, regardless of the number of administered cisplatin courses. RESULTS: Fifty patients were included in the SH and LH group. There were no significant differences in baseline characteristics between the two groups. None of the patients had renal failure at baseline. After two cisplatin cycles, the median differences between the baseline eGFR and the eGFR after the last cisplatin dose were 1 (-6 to 5) and -9 (-22 to -2) mL/min/1.73 m2 (interquartile range) for the SH and LH group, respectively (P = .000). Less patients completed the four cycles in the LH group (16%) compared to the SH group (64%), mainly because more LH patients were switched to another treatment and due to nephrotoxicity. However, the difference in eGFR remained statistically significant (P = .027). WHAT IS NEW AND CONCLUSION: In this retrospective study, the SH scheme resulted in less decrease in renal function compared with the LH scheme, with a significant and clinically relevant difference. Additionally, more LH patients had to stop this effective treatment prematurely due to nephrotoxicity. Therefore, a short hydration scheme provides adequate and safe hydration, with a lower risk of nephrotoxic side effects and therefore better outcomes for patients and a reduction of healthcare costs.

Innate Immune Recovery Predicts CD4+ T Cell Reconstitution after Hematopoietic Cell Transplantation.

Innate immune cells are the first to recover after allogeneic hematopoietic cell transplantation (HCT). Nevertheless, reports of innate immune cell recovery and their relation to adaptive recovery after HCT are largely lacking. Especially predicting CD4+ T cell reconstitution is of clinical interest, because this parameter directly associates with survival chances after HCT. We evaluated whether innate recovery relates to CD4+ T cell reconstitution probability and investigated differences between innate recovery after cord blood transplantation (CBT) and bone marrow transplantation (BMT). We developed a multivariate, combined nonlinear mixed-effects model for monocytes, neutrophils, and natural killer (NK) cell recovery after transplantation. A total of 205 patients undergoing a first HCT (76 BMT, 129 CBT) between 2007 and 2016 were included. The median age was 7.3years (range, .16 to 23). Innate recovery was highly associated with CD4+ T cell reconstitution probability (P < .001) in multivariate analysis correcting for covariates. Monocyte (P < .001), neutrophil (P < .001), and NK cell (P < .001) recovery reached higher levels during the first 200days after CBT compared with BMT. The higher innate recovery after CBT may be explained by increased proliferation capacity (measured by Ki-67 expression) of innate cells in CB grafts compared with BM grafts (P = .041) and of innate cells in vivo after CBT compared with BMT (P = .048). At an individual level, patients with increased innate recovery after either CBT or BMT had received grafts with higher proliferating innate cells (CB; P = .004, BM; P = .01, respectively). Our findings implicate the use of early innate immune monitoring to predict the chance of CD4+ T cell reconstitution after HCT, with respect to higher innate recovery after CBT compared with BMT.

Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation.

Successful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti-thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host disease and graft failure, negatively influences T-cell IR. We studied the relationships among ATG exposure, IR, and clinical outcomes. All pediatric patients receiving a first CBT between 2004 and 2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated pharmacokinetics model. Main outcome of interest was early CD4+ IR, defined as CD4+ T-cell counts >50 × 106/L twice within 100 days after CBT. Other outcomes of interest included event-free survival (EFS). Cox proportional-hazard and Fine-Gray competing-risk models were used. A total of 137 patients, with a median age of 7.4 years (range, 0.2-22.7), were included, of whom 82% received ATG. Area under the curve (AUC) of ATG after infusion of the cord blood transplant predicted successful CD4+ IR. Adjusted probability on CD4+ IR was reduced by 26% for every 10-point increase in AUC after CBT (hazard ratio [HR], 0.974; P < .0001). The chance of EFS was higher in patients with successful CD4+ IR (HR, 0.26; P < .0001) and lower ATG exposure after CBT (HR, 1.005; P = .0071). This study stresses the importance of early CD4+ IR after CBT, which can be achieved by reducing the exposure to ATG after CBT. Individualized dosing of ATG to reach optimal exposure or, in selected patients, omission of ATG may contribute to improved outcomes in pediatric CBT.

Impact of serotherapy on immune reconstitution and survival outcomes after stem cell transplantations in children: thymoglobulin versus alemtuzumab.

The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is strongly affected by the kinetics of reconstitution of the immune system. This study compared the effects of antithymocyte globulin (ATG) and alemtuzumab on various outcome parameters after HSCT. The study cohort consisted of 148 children, with a median age of 9.6 years (range, .4 to 19.0), who underwent HSCT for malignant and benign hematological disorders in a single HSCT unit. Conditioning included ATG (n = 110) or alemtuzumab (n = 38). Cox proportional hazard regression analysis showed that alemtuzumab significantly delayed the recovery of CD3(+) T cells and CD4(+)as well as CD8(+) T cell subsets (P ≤ .001) and natural killer (NK) cells (P = .008) compared with ATG. In both ATG- and alemtuzumab-treated patients, shorter drug exposure lead to significantly faster recovery of T cells. Alemtuzumab was associated with lower donor chimerism 3 and 6 months after transplantation and a higher risk of disease relapse (P = .001). The overall survival and event-free survival risks were significantly lower for alemtuzumab-treated patients (P = .020 and P < .001, respectively). Patients who received alemtuzumab showed a trend to lower risk of acute graft-versus-host disease, more human adenovirus, and less Epstein-Barr virus reactivations compared with patients who received ATG. These data indicate that children treated with alemtuzumab as part of the conditioning regimen have a slower T cell and NK cell reconstitution compared with those treated with ATG, which compromises the overall and event-free survival. Prolonged length of lympholytic drug exposure delayed the T cell recovery in both ATG- and alemtuzumab-treated patients. Therefore, we recommend detailed pharmacokinetic/pharmacodynamic (PK/PD) analyses in a larger cohort of patients to develop an algorithm aiming at optimization of the serotherapy containing conditioning regimen.

A Dutch Survey on Medication Adjustments after Metabolic and Bariatric Surgery: Experiences of Bariatric Surgeons, Internists, Pharmacists, and General Practitioners.

BACKGROUND: As metabolic and bariatric surgery (MBS) can alter the pharmacokinetics of drugs, post-bariatric surgery patients may require medication adjustments and monitoring. To improve pharmacotherapy in these patients, we aimed to understand the beliefs, attitudes, knowledge, and concerns of healthcare professionals who treat these patients. METHODS: A survey by means of an online questionnaire was divided into six sections. It was sent to bariatric surgeons, internists, pharmacists, and general practitioners in the Netherlands. RESULTS: Out of 229 returned surveys, 222 were included. Virtually all respondents (98%) expected MBS to influence the effect of medication. Both reduced efficacy (23%) and more adverse events or medication-related complications (21%) were recognized. Two-thirds of the respondents felt competent to prescribe or to provide advice regarding medication in post-bariatric surgery patients. Most of the respondents (95%) believed that other healthcare professionals should be aware of the contraindication "bariatric surgery". Of the respondents, 37% indicated that they were not aware of the medication advice incorporated in the electronic health record systems. Almost half of the respondents (48%) indicated that they documented changes in drug effects. Most respondents answered that these ought to be registered in the pharmacovigilance database or national registry. CONCLUSIONS: The majority of prescribers and pharmacists believe that patients will receive better pharmacotherapy if healthcare professionals take MBS into account. However, not all prescribers think they are competent to act adequately. To improve this, information on changed drug effects after MBS should be more widely shared among healthcare professionals via resources that are easily accessible.

Impact of Bariatric Surgery in the Short and Long Term: A Need for Time-Dependent Dosing of Drugs.

Sparse information is available on pharmacokinetic changes of drugs over time after bariatric surgery. By reviewing the literature on the short- and long-term pharmacokinetic changes of drugs, several patterns were identified for 39 drugs. No relevant pharmacokinetic changes were identified for roughly a third of the drugs. Of the remaining drugs, levels were variable and partly unpredictable shortly after the surgery. In the long term, most of the drug levels remain altered, but in some cases they returned to preoperative values. Based on the changes and the efficacy-safety balance of each drug, clinicians may need to perform additional clinical monitoring for specific drugs, including measuring drug levels. This review provides suggestions for clinicians and pharmacists for specific time-dependent drug dosing advice.

Predictive performance of a busulfan pharmacokinetic model in children and young adults.

BACKGROUND: Recently a pediatric pharmacokinetic (PK) model was developed for busulfan to explain the wide variability in PK of busulfan in children, as this variability is known to influence the outcome of hematopoietic stem cell transplantation in terms of toxicity and event free survival. This study assesses the predictive performance of this busulfan PK model in a new, more diverse pediatric population, including data from patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices, from 5 international pediatric transplant centers. PATIENTS AND METHODS: The previously published (original) busulfan PK model was developed from data of 245 patients (0.1-26 years of age). To externally validate this model, data were collected from another 158 patients (0.1-35 years) who underwent hematopoietic stem cell transplantation in 5 international transplant centers. Observed versus predicted plots, normalized prediction distribution error analysis, refit of the model on the external (n = 158) and combined datasets (n = 403), and subpopulation analyses were evaluated. RESULTS: The original busulfan PK model was found to be stable and parameter estimates precise. Concentrations predicted by this model were in good agreement with the observed concentrations from the 5 external datasets. Plasma concentrations in patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices were adequately predicted. CONCLUSIONS: Our pediatric busulfan PK model has been externally validated. This model predicts busulfan concentrations in pediatric and young adult patients ranging between 3 and 86 kg without bias and with good precision, regardless of transplant center, underlying disease, ethnicity, body weight age, or body mass index. This busulfan PK model forms the basis for individualized busulfan dosing.

Clozapine Treatment During Pregnancy and the Postpartum Period: A Systematic Literature Review.

Objective: The objective of this systematic review was to provide a critical appraisal of the evidence related to the safety of clozapine for schizophrenia during pregnancy and lactation.Data Sources: PubMed/MEDLINE, Embase, and the Cochrane Library were searched from inception through December 2020. Reference lists of included studies were hand-searched. The International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for unpublished trials, and PROSPERO was searched for unpublished reviews. The current marketing authorization holder of the originator brands Clozaril and Leponex was also contacted for pharmacovigilance data.Study Selection: Original reports published in English, German, French, or Dutch containing clinical and preclinical data were included if they provided data on maternal, fetal, and neonatal outcomes after clozapine exposure during pregnancy or lactation.Data Extraction: Two reviewers independently extracted relevant data.Results: A total of 860 records were identified, and the full texts of 117 articles were reviewed. Forty-two studies met the inclusion criteria. Data on perinatal clozapine exposure are of limited quality and quantity. Although clozapine demonstrates partial placental passage, data thus far do not support that clozapine is teratogenic; that it increases the risk of stillbirth, abortion, or fetal disorders; or that it increases the risk of delivery complications or premature birth. Information about clozapine exposure through breast milk is scarce, but based on its chemical properties, it is likely that clozapine enters the breast milk of nursing mothers taking clozapine.Conclusions: When weighing the risks and benefits of clozapine continuation during pregnancy and lactation versus switching to another antipsychotic, one should include severity of illness and treatment history but also be aware of the limitations of the available safety data regarding perinatal clozapine use, including the fact that there are few studies.

The Influence of Body Composition on the Systemic Exposure of Paclitaxel in Esophageal Cancer Patients.

Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with esophageal cancer. Skeletal muscle index (SMI), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were measured at the third lumbar vertebra on computed tomography (CT) scans performed before treatment. Paclitaxel PK data were collected from a prospective study performed between May 2004 and January 2014. Non-linear mixed-effects modeling was used to fit paclitaxel PK profiles and evaluate the covariates body surface area (BSA), SMI, VAT, and SMD using a significance threshold of p < 0.001. Paclitaxel was administered to 184 patients in a dose range of 50 to 175 mg/m2. Median BSA was 1.98 m2 (range of 1.4 to 2.8 m2). SMI, VAT, and SMD were not superior to BSA in predicting paclitaxel PK. The additive value of SMI, VAT, and SMD to BSA was also negligible. We did not find evidence that paclitaxel dosing could be further optimized by correcting for SMI, VAT, or SMD.

Clinical Trial Simulation To Optimize Trial Design for Fludarabine Dosing Strategies in Allogeneic Hematopoietic Cell Transplantation.

Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m2 ) to either covariate-based or therapeutic drug monitoring (TDM)-guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of end points and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM-guided dosing to current practice with NRM as primary outcome (n = 70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible.

No Differences in Weight Gain Between Risperidone and Aripiprazole in Children and Adolescents After 12 Months.

BACKGROUND: Weight gain due to the use of second-generation antipsychotics is a major health care issue for adult and paediatric psychiatric patients. Little is known about long-term weight gain effects of aripiprazole compared to risperidone in children and adolescents. OBJECTIVE: The primary aim of this study is to assess whether risperidone and aripiprazole are associated with different weight changes in children and adolescents during the first 12 months of treatment. Secondary aim was to assess the influence of the covariates co-medication, gender and indication on weight change. METHODS: This study was a retrospective observational cohort study of in- and outpatients of a Dutch mental health organization aged ≤19 years on long-term treatment with risperidone or aripiprazole. Primary outcome measure was body-mass index (BMI) z-score change. Data were extracted from medical charts and analysed using linear mixed models. RESULTS: In total, 89 risperidone patients and 42 aripiprazole patients were included in the study. At baseline, the BMI z-score of aripiprazole subjects was significantly higher than risperidone subjects (p = 0.003). In both treatment groups BMI z-score significantly increased during 12 months of follow-up. This weight change was not significantly different in risperidone and aripiprazole users after 12 months (p = 0.943). Covariates did not significantly influence weight change. CONCLUSION: This study demonstrated that there was no significant difference in weight gain between risperidone and aripiprazole users during the first year of treatment. Based on this study, aripiprazole should not be favoured over risperidone in children and adolescents because of the degree of weight gain.

Population Pharmacokinetics of Fludarabine in Children and Adults during Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Fludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used. OBJECTIVE: We sought to describe the population PK of fludarabine in HCT recipients of all ages. METHODS: From 258 HCT recipients aged 0.3-74 years, 2605 samples were acquired on days 1 (42%), 2 (17%), 3 (4%) and 4 (37%) of conditioning. Herein, the circulating metabolite of fludarabine was quantified, and derived concentration-time data were used to build a population PK model using non-linear mixed-effects modelling. RESULTS: Variability was extensive where area under the curve ranged from 10 to 66 mg h/L. A three-compartment model with first-order kinetics best described the data. Actual body weight (BW) with standard allometric scaling was found to be the best body-size descriptor for all PK parameters. Estimated glomerular filtration rate (eGFR) was included as a descriptor of renal function. Thus, clearance was differentiated into a non-renal (3.24 ± 20% L/h/70 kg) and renal (eGFR × 0.782 ± 11% L/h/70 kg) component. The typical volumes of distribution of the central (V1), peripheral (V2), and second peripheral (V3) compartments were 39 ± 8%, 20 ± 11%, and 50 ± 9% L/70 kg respectively. Intercompartmental clearances between V1 and V2, and V1 and V3, were 8.6 ± 8% and 3.8 ± 13% L/h/70 kg, respectively. CONCLUSION: BW and eGFR are important predictors of fludarabine PK. Therefore, current linear BSA-based dosing leads to highly variable exposure, which may lead to variable treatment outcome.

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome.

BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing. METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers. RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance. CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.

Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation.

Because of intra- and interindividual variability, bioavailability, and pharmacokinetics of busulfan (Bu) in children, oral busulfan without therapeutic drug monitoring (TDM) is assumed to be associated with higher graft failure rates as well as higher toxicity (eg, veno-occlusive disease [VOD]). This study compares the outcome of hematopoietic stem cell transplantation (HSCT) of 2 groups: 1) 30 patients who received myeloablation with once-daily intravenous (i.v.) dose-targeted busulfan (BUdtIV) based on TDM and 2) 30 patients who received the current practice of untargeted oral busulfan (BUPO). Patients received a 3-hour infusion of Bu at a first dose of 120 mg/m(2) (age >or=1 year) or 80 mg/m(2) (<1 year), or BUPO 1 mg/kg 4 times daily. Both regimens were continued for 4 days. The target area under the curve (AUC) was defined as 17,500 microg *h/l. BUdtIV resulted in higher event-free survival (EFS) and survival rates compared to BUPO (EFS: 30% versus 83%, P < .001, survival: 53% versus 83%, P = .016). BUdtIV was associated with more cases of VOD. TDM was feasible in routine clinical practice. The results show that i.v. Bu using TDM is preferable over oral Bu in children undergoing allogeneic stem cell transplantation, especially in those at high risk for graft failure/relapse.

Simultaneous quantification of busulfan, clofarabine and F-ARA-A using isotope labelled standards and standard addition in plasma by LC-MS/MS for exposure monitoring in hematopoietic cell transplantation conditioning.

In allogeneic hematopoietic cell transplantation (HCT) it has been shown that over- or underexposure to conditioning agents have an impact on patient outcomes. Conditioning regimens combining busulfan (Bu) and fludarabine (Flu) with or without clofarabine (Clo) are gaining interest worldwide in HCT. To evaluate and possibly adjust full conditioning exposure a simultaneous analysis of Bu, F-ARA-A (active metabolite of Flu) and Clo in one analytical run would be of great interest. However, this is a chromatographical challenge due to the large structural differences of Bu compared to F-ARA-A and Clo. Furthermore, for the bioanalysis of drugs it is common to use stable isotope labelled standards (SILS). However, when SILS are unavailable (in case of Clo and F-ARA-A) or very expensive, standard addition may serve as an alternative to correct for recovery and matrix effects. This study describes a fast analytical method for the simultaneous analysing of Bu, Clo and F-ARA-A with liquid chromatography-tandem mass spectrometry (LC-MS/MS) including standard addition methodology using 604 spiked samples. First, the analytical method was validated in accordance with European Medicines Agency guidelines. The lower limits of quantification (LLOQ) were for Bu 10µg/L and for Clo and F-ARA-A 1µg/L, respectively. Variation coefficients of LLOQ were within 20% and for low medium and high controls were all within 15%. Comparison of Bu, Clo and F-ARA-A standard addition results correspond with those obtained with calibration standards in calf serum. In addition for Bu, results obtained by this study were compared with historical data analysed within TDM. In conclusion, an efficient method for the simultaneous quantification of Bu, Clo and F-ARA-A in plasma was developed. In addition, a robust and cost-effective method to correct for matrix interference by standard addition was established.