Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan.

BACKGROUND: 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. OBJECTIVE: The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access. PATIENTS AND METHODS: Exposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9-1.11 boundaries for area under the concentration-time curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios. RESULTS: Dosing regimens of sacituzumab govitecan for the EU (< 50 kg: 400 mg, 50-80 kg: 600 mg, and > 80 kg: 800 mg) and US population (< 40 kg: 360 mg, 40-65 kg: 540 mg, 65-90 kg: 720 mg, and > 90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and 19.0% lower for the EU and US scenarios, respectively. CONCLUSIONS: With the alternative dosing proposal, an approximately 20% reduction in drug expenses for sacituzumab govitecan can be realized while maintaining an equivalent and more evenly distributed exposure throughout the body weight range, without notable increases in pharmacokinetic variability.

Effect of Busulfan and Treosulfan on Gonadal Function after Allogeneic Stem Cell Transplantation in Children and Adolescents with Nonmalignant Diseases Is Not Exposure-Dependent.

With an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant impact on quality of life. In this retrospective study, we evaluated the exposure of busulfan (Bu) and treosulfan (Treo) in relation to gonadal function in pediatric patients who underwent HSCT for a nonmalignant disease between 1997 and 2018. In the Bu group, 56 patients could be evaluated, and gonadal dysfunction was found in 35 (63%). Lower Bu exposure (ie, cumulative area under the curve [AUC] <70 mg*h/L) was not associated with a reduced risk of gonadal dysfunction (odds ratio [OR], .92; 95% confidence interval [CI], .25 to 3.49; P = .90). In the Treo cohort, 32 patients were evaluable and gonadal insufficiency occurred in 9 patients (28%). Lower Treo exposure (AUC <1750 mg*h/L on day 1) was not associated with a reduced risk of gonadal dysfunction (OR, 1.6; 95% CI, .16 to 36.6; P = .71). Our data do not support the premise that reduced-intensity Bu-based conditioning reduces the risk for gonadal toxicity, and it is unlikely that therapeutic drug monitoring-based reduced treosulfan exposure will further limit the risk of gonadal dysfunction.

A text-mining approach to study the real-world effectiveness and potentially fatal immune-related adverse events of PD-1 and PD-L1 inhibitors in older patients with stage III/IV non-small cell lung cancer.

BACKGROUND: This study was designed to investigate the impact of age on the effectiveness and immune-related adverse events (irAEs) of programmed death-(ligand)1 [PD-(L)1] inhibitors in patients with non-small cell lung cancer (NSCLC) using a novel text-mining technique. METHODS: This retrospective study included patients with stage III/IV NSCLC treated with a PD-(L)1 inhibitor (nivolumab, pembrolizumab, atezolizumab and durvalumab) at Leiden University Medical Centre and Haga Teaching hospital, (both in The Netherlands) from September 2016 to May 2021. All the relevant data was extracted from the structured and unstructured fields of the Electronic Health Records using a novel text-mining tool. Effectiveness [progression-free survival (PFS) and overall survival (OS)] and safety (the incidence of nine potentially fatal irAEs and systemic corticosteroid requirement) outcomes were compared across age subgroups (young: < 65 years, Middle-aged: 65-74 years, and old: ≥ 75 years) after adjustment for confounding. RESULTS: Of 689 patients, 310 patients (45.0%) were < 65 years, 275 patients (39.9%) were aged between 65 and 74 years, and 104 patients (15.1%) were ≥ 75 years. There was no significant difference between younger and older patients regarding PFS (median PFS 12, 8, 13 months respectively; Hazard ratio (HR)middle-aged = 1.14, 95% CI 0.92-1.41; HRold = 1.10, 95% CI 0.78-1.42). This was also the case for OS (median OS 19, 14, 18 months respectively; HRmiddle-aged = 1.22, 95% CI 0.96-1.53; HRold = 1.10, 95% CI 0.79-1.52). Safety analysis demonstrated a higher incidence of pneumonitis among patients aged 65-74. When all the investigated irAEs were pooled, there was no statistically significant difference found between age and the incidence of potentially fatal irAEs. CONCLUSIONS: The use of PD-(L)1 inhibitors is not associated with age related decrease of PFS and OS, nor with increased incidence of serious irAEs compared to younger patients receiving these treatments. Chronological age must therefore not be used as a predictor for the effectiveness or safety of ICIs.

Application of Electronic Health Record Text Mining: Real-World Tolerability, Safety, and Efficacy of Adjuvant Melanoma Treatments.

Introduction: Nivolumab (N), pembrolizumab (P), and dabrafenib plus trametinib (D + T) have been registered as adjuvant treatments for resected stage III and IV melanoma since 2018. Electronic health records (EHRs) are a real-world data source that can be used to review treatments in clinical practice. In this study, we applied EHR text-mining software to evaluate the real-world tolerability, safety, and efficacy of adjuvant melanoma treatments. Methods: Adult melanoma patients receiving adjuvant treatment between January 2019 and October 2021 at the Leiden University Medical Center, the Netherlands, were included. CTcue text-mining software (v3.1.0, CTcue B.V., Amsterdam, The Netherlands) was used to construct rule-based queries and perform context analysis for patient inclusion and data collection from structured and unstructured EHR data. Results: In total, 122 patients were included: 54 patients treated with nivolumab, 48 with pembrolizumab, and 20 with D + T. Significantly more patients discontinued treatment due to toxicity on D + T (N: 16%, P: 6%, D + T: 40%), and X2 (6, n = 122) = 14.6 and p = 0.024. Immune checkpoint inhibitors (ICIs) mainly showed immune-related treatment-limiting adverse events (AEs), and chronic thyroid-related AE occurred frequently (hyperthyroidism: N: 15%, P: 13%, hypothyroidism: N: 20%, P: 19%). Treatment-limiting toxicity from D + T was primarily a combination of reversible AEs, including pyrexia and fatigue. The 1-year recurrence-free survival was 70.3% after nivolumab, 72.4% after pembrolizumab, and 83.0% after D + T. Conclusions: Text-mining EHR is a valuable method to collect real-world data to evaluate adjuvant melanoma treatments. ICIs were better tolerated than D + T, in line with RCT results. For BRAF+ patients, physicians must weigh the higher risk of reversible treatment-limiting AEs of D + T against the risk of long-term immune-related AEs.

Real-world evaluation of supportive care using an electronic health record text-mining tool: G-CSF use in breast cancer patients.

PURPOSE: Chemotherapy-induced febrile neutropenia (FN) is a life-threatening and chemotherapy dose-limiting adverse event. FN can be prevented with granulocyte-colony stimulating factors (G-CSFs). Guidelines recommend primary G-CSF use for patients receiving either high (> 20%) FN risk (HR) chemotherapy, or intermediate (10-20%) FN risk (IR) chemotherapy if the overall risk with additional patient-related risk factors exceeds 20%. In this study, we applied an EHR text-mining tool for real-world G-CSF treatment evaluation in breast cancer patients. METHODS: Breast cancer patients receiving IR or HR chemotherapy treatments between January 2015 and February 2021 at LUMC, the Netherlands, were included. We retrospectively collected data from EHR with a text-mining tool and assessed G-CSF use, risk factors, and the FN and neutropenia (grades 3-4) and incidence. RESULTS: A total of 190 female patients were included, who received 77 HR and 113 IR treatments. In 88.3% of the HR regimens, G-CSF was administered; 7.3% of these patients developed FN vs. 33.3% without G-CSF. Although most IR regimen patients had ≥ 2 risk factors, only 4% received G-CSF, of which none developed neutropenia. However, without G-CSF, 11.9% developed FN and 31.2% severe neutropenia. CONCLUSIONS: Our text-mining study shows high G-CSF use among HR regimen patients, and low use among IR regimen patients, although most had ≥ 2 risk factors. Therefore, current practice is not completely in accordance with the guidelines. This shows the need for increased awareness and clarity regarding risk factors. Also, text-mining can effectively be implemented for the evaluation of patient care.

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

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 to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT.

Impact of Treosulfan Exposure on Early and Long-Term Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Prospective Multicenter Study.

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 relationships between systemic treosulfan exposure and early and long-term clinical outcomes in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases remain unclear. In this a multicenter, prospective observational study, we assessed the association between treosulfan exposure and early and, in particular, long-term clinical outcomes. Our study cohort comprised 110 pediatric patients with nonmalignant diseases who underwent HSCT between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected, and treosulfan area under the receiver operating characteristic curve (AUC0-∞) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationships between treosulfan exposure and overall survival (OS) and event-free survival (EFS). The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days was evaluated using a multivariable logistic regression analysis. In the overall cohort, OS and EFS at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children age <2 years. The occurrence of grade II-IV acute graft-versus-host disease, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.26-13.68; P = .02) and all-grade mucositis (OR, 4.43; 95% CI, 1.43-15.50; P = .02), but not grade ≥2 mucositis (OR, 1.51; 95% CI, 0.52 to 4.58; P = .46) was related to high treosulfan exposure (>1750 mg*h/L). Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with nonmalignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring, thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether deescalation of treosulfan doses is possible to minimize early and long-term toxicity without compromising efficacy.

Treosulfan-induced myalgia in pediatric hematopoietic stem cell transplantation identified by an electronic health record text mining tool.

Treosulfan is increasingly used as myeloablative agent in conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). In our pediatric HSCT program, myalgia was regularly observed after treosulfan-based conditioning, which is a relatively unknown side effect. Using a natural language processing and text-mining tool (CDC), we investigated whether treosulfan compared with busulfan was associated with an increased risk of myalgia. Furthermore, among treosulfan users, we studied the characteristics of given treatment of myalgia, and studied prognostic factors for developing myalgia during treosulfan use. Electronic Health Records (EHRs) until 28 days after HSCT were screened using the CDC for myalgia and 22 synonyms. Time to myalgia, location of pain, duration, severity and drug treatment were collected. Pain severity was classified according to the WHO pain relief ladder. Logistic regression was performed to assess prognostic factors. 114 patients received treosulfan and 92 busulfan. Myalgia was reported in 37 patients; 34 patients in the treosulfan group and 3 patients in the busulfan group (p = 0.01). In the treosulfan group, median time to myalgia was 7 days (0-12) and median duration of pain was 19 days (4-73). 44% of patients needed strong acting opiates and adjuvant medicines (e.g. ketamine). Hemoglobinopathy was a significant risk factor, as compared to other underlying diseases (OR 7.16 95% CI 2.09-30.03, p = 0.003). Myalgia appears to be a common adverse effect of treosulfan in pediatric HSCT, especially in hemoglobinopathy. Using the CDC, EHRs were easily screened to detect this previously unknown side effect, proving the effectiveness of the tool. Recognition of treosulfan-induced myalgia is important for adequate pain management strategies and thereby for improving the quality of hospital stay.

Liver and kidney function in patients with Covid-19 treated with remdesivir.

For the treatment of Covid-19 patients with remdesivir, poor renal and liver function were both exclusion criteria in randomized clinical trials and contraindication for treatment. Also, nephrotoxicity and hepatotoxicity are reported as adverse events. We retrospectively reviewed renal and liver functions of Covid-19 103 patients who received remdesivir in the 15 days after treatment initiation. Approximately 20% of the patient population met randomized clinical trial exclusion criteria. In total, 11% of the patients had a decrease in estimated glomerular filtration rate >10 mL/min/1.73m2 . Also, 25 and 35% had increased alanine transaminase and aspartate transaminase levels, respectively. However, serious adverse events were limited. Therefore, based on these preliminary results, contraindications based on kidney and liver function should not be absolute for remdesivir treatment in patients with Covid-19 if these functions are monitored regularly. A larger patient cohort is warranted to confirm our results.

No need for H2-antagonists in premedication regimens for paclitaxel infusions: less is more.

The theoretical basis for use of histamine 2 (H2)-receptor inhibitors to prevent hypersensitivity reactions for paclitaxel infusions is weak. This Editorial discusses a clinical study showing that ranitidine is not indicated any more in this setting and puts this in the context of other valuable efforts leaving non-evidence-based interventions behind us.

An Electronic Health Record Text Mining Tool to Collect Real-World Drug Treatment Outcomes: A Validation Study in Patients With Metastatic Renal Cell Carcinoma.

Real-world evidence can close the inferential gap between marketing authorization studies and clinical practice. However, the current standard for real-world data extraction from electronic health records (EHRs) for treatment evaluation is manual review (MR), which is time-consuming and laborious. Clinical Data Collector (CDC) is a novel natural language processing and text mining software tool for both structured and unstructured EHR data and only shows relevant EHR sections improving efficiency. We investigated CDC as a real-world data (RWD) collection method, through application of CDC queries for patient inclusion and information extraction on a cohort of patients with metastatic renal cell carcinoma (RCC) receiving systemic drug treatment. Baseline patient characteristics, disease characteristics, and treatment outcomes were extracted and these were compared with MR for validation. One hundred patients receiving 175 treatments were included using CDC, which corresponded to 99% with MR. Calculated median overall survival was 21.7 months (95% confidence interval (CI) 18.7-24.8) vs. 21.7 months (95% CI 18.6-24.8) and progression-free survival 8.9 months (95% CI 5.4-12.4) vs. 7.6 months (95% CI 5.7-9.4) for CDC vs. MR, respectively. Highest F1-score was found for cancer-related variables (88.1-100), followed by comorbidities (71.5-90.4) and adverse drug events (53.3-74.5), with most diverse scores on international metastatic RCC database criteria (51.4-100). Mean data collection time was 12 minutes (CDC) vs. 86 minutes (MR). In conclusion, CDC is a promising tool for retrieving RWD from EHRs because the correct patient population can be identified as well as relevant outcome data, such as overall survival and progression-free survival.

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study.

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m2 , administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m2 ) and 1561 ± 511 mg*h/l (14 g/m2 ), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19-16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07-18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity.

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.

BACKGROUND: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. METHODS: In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses. FINDINGS: 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37). INTERPRETATION: Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications. FUNDING: Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.

Pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation.

BACKGROUND: High-dose treosulfan is used in conditioning regimens before hematopoietic stem cell transplantation in children. Pharmacokinetic data to optimize treosulfan dosing are scarce in this patient population. The aims of this study were the development and validation of an analytical method for treosulfan in human serum and the development of a pharmacokinetic model for treosulfan in pediatric patients. Furthermore, we aimed to develop a limited sampling strategy to estimate treosulfan systemic exposure with a minimum of inconvenience and risk for the patient. METHODS: A reversed phase high-performance liquid chromatography method using ultraviolet detection to determine treosulfan in human serum samples was developed and validated according to food and drug administration guidelines. Serum pharmacokinetics after the first treosulfan administration was investigated in 20 children using nonlinear mixed-effect modeling, and a limited sampling strategy was developed and validated. RESULTS: The assay was validated in a 10-500 mg/L concentration range with a lower limit of quantification of 10 mg/L. Accuracies were within the 90%-110% limit. The coefficients of variation of the within-day imprecision and between-days imprecision were less than 5%. Pharmacokinetics was adequately described with a 1-compartment model. The population estimates for clearance (CL) and volume of distribution were 6.85 L/h and 13.2 L for a typical patient of 20 kg, respectively. Treosulfan exposure could be adequately quantified with 2 samples, at 4 and 7 hours after the start of a 3-hour treosulfan infusion, with a mean deviation of 3% of individual CL and area under the curve based on limited sampling in comparison with the full data set in a total cohort. CONCLUSIONS: In this study, a bioanalytical method, PK model, and limited sampling model were developed and validated. Furthermore, PK parameters of 20 pediatric patients were analyzed, demonstrating an interpatient variability in area under the curve of 14.5%. This study demonstrates the essential developments in the optimization of treosulfan therapy based on PK data.

Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation.

BACKGROUND: Busulfan is used in preparative regimens prior to stem cell transplantation in pediatric patients. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. To date, only polymorphisms in genes encoding for glutathione-S-transferases were studied, but could only explain a small portion of the variability in PK. AIM: To investigate the effect of seven genetic markers on busulfan clearance and the effect of ontogenesis on these genetic variants in a pediatric population. MATERIALS & METHODS: In an earlier study of our group seven genetic markers in GSTA1, CYP2C19, CYP39A1, ABCB4, SLC22A4 and SLC7A8 were associated with busulfan clearance in adult patients. Eighty four pediatric patients were genotyped for these markers and genotype was associated with busulfan clearance. RESULTS & CONCLUSION: GSTA1 and CYP39A1 were found to be associated with busulfan clearance. When combined, the two haplotypes explained 17% of the variability in busulfan clearance. Furthermore, the effect of GSTA1 haplotype on clearance was dependent on age.

Exploratory analysis of 1936 SNPs in ADME genes for association with busulfan clearance in adult hematopoietic stem cell recipients.

BACKGROUND: Busulfan is used in preparative regimens before stem cell transplantation. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. Polymorphisms in genes encoding glutathione-S-transferases have been associated with busulfan PK but only explain a limited portion of the observed variability. AIM: The aim of this study is to identify additional genetic variants associated with busulfan PK by interrogating 1936 variants in 225 genes involved in drug absorption, distribution, metabolism, and excretion (ADME). MATERIALS AND METHODS: In an exploratory cohort (n=65), patients who received busulfan were genotyped with the DMET array. Top SNPs and haplotypes associated with busulfan clearance were validated in an independent validation cohort (n=78). RESULTS: In the exploratory cohort, seven variants were identified to be associated with busulfan clearance (P<0.001). In the validation cohort, only GSTA5 (rs4715354 and rs7746993) remained significantly associated with busulfan clearance (P=0.025). CONCLUSION: This is the first study using an exploratory pharmacogenetic approach to explain the interindividual variability in busulfan PK. The role of glutathione-S-transferases was confirmed, but no additional genetic markers involved in drug ADME appear to be associated with busulfan PK.

Evaluation of rule effectiveness and positive predictive value of clinical rules in a Dutch clinical decision support system in daily hospital pharmacy practice.

INTRODUCTION: Our advanced clinical decision support (CDS) system, entitled 'adverse drug event alerting system' (ADEAS), is in daily use in our hospital pharmacy. It is used by hospital pharmacists to select patients at risk of possible adverse drug events (ADEs). The system retrieves data from several information systems, and uses clinical rules to select the patients at risk of ADEs. The clinical rules are all medication related and are formulated using seven risk categories. OBJECTIVE: This studies objectives are to 1) evaluate the use of the CDS system ADEAS in daily hospital pharmacy practice, and 2) assess the rule effectiveness and positive predictive value (PPV) of the clinical rules incorporated in the system. SETTING: Leiden University Medical Center, The Netherlands. All patients admitted on six different internal medicine and cardiology wards were included. MEASURES: Outcome measures were total number of alerts, number of patients with alerts and the outcome of these alerts: whether the hospital pharmacist gave advice to prevent a possible ADE or not. Both overall rule effectiveness and PPV and rule effectiveness and PPV per clinical rule risk category were scored. STUDY DESIGN: During a 5 month study period safety alerts were generated daily by means of ADEAS. All alerts were evaluated by a hospital pharmacist and if necessary, healthcare professionals were subsequently contacted and advice was given in order to prevent possible ADEs. RESULTS: During the study period ADEAS generated 2650 safety alerts in 931 patients. In 270 alerts (10%) the hospital pharmacist contacted the physician or nurse and in 204 (76%) cases this led to an advice to prevent a possible ADE. The remaining 2380 alerts (90%) were scored as non-relevant. Most alerts were generated with clinical rules linking pharmacy and laboratory data (1685 alerts). The overall rule effectiveness was 0.10 and the overall PPV was 0.08. Combination of rule effectiveness and PPV was highest for clinical rules based upon the risk category "basic computerized physician order entry (CPOE) medication safety alerts fine-tuned to high risk patients" (rule efficiency=0.17; PPV=0.14). CONCLUSION: ADEAS can effectively be used in daily hospital pharmacy practice to select patients at risk of potential ADEs, but to increase the benefits for routine patient care and to increase efficiency, both rule effectiveness and PPV for the clinical rules should be improved. Furthermore, clinical rules would have to be refined and restricted to those categories that are potentially most promising for clinical relevance, i.e. "clinical rules with a combination of pharmacy and laboratory data" and "clinical rules based upon the basic CPOE medication safety alerts fine-tuned to high risk patients".

Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing.

BACKGROUND AND OBJECTIVES: The wide variability in pharmacokinetics of busulfan in children is one factor influencing outcomes such as toxicity and event-free survival. A meta-analysis was conducted to describe the pharmacokinetics of busulfan in patients from 0.1 to 26 years of age, elucidate patient characteristics that explain the variability in exposure between patients and optimize dosing accordingly. PATIENTS AND METHODS: Data were collected from 245 consecutive patients (from 3 to 100 kg) who underwent haematopoietic stem cell transplantation (HSCT) in four participating centres. The inter-patient, inter-occasion and residual variability in the pharmacokinetics of busulfan were estimated with a population analysis using the nonlinear mixed-effects modelling software NONMEM VI. Covariates were selected on the basis of their known or theoretical relationships with busulfan pharmacokinetics and were plotted independently against the individual pharmacokinetic parameters and the weighted residuals of the model without covariates to visualize relations. Potential covariates were formally tested in the model. RESULTS: In a two-compartment model, body weight was the most predictive covariate for clearance, volume of distribution and inter-compartmental clearance and explained 65%, 75% and 40% of the observed variability, respectively. The relationship between body weight and clearance was characterized best using an allometric equation with a scaling exponent that changed with body weight from 1.2 in neonates to 0.55 in young adults. This implies that an increase in body weight in neonates results in a larger increase in busulfan clearance than an increase in body weight in older children or adults. Clearance on the first day was 12% higher than that of subsequent days (p < 0.001). Inter-occasion variability on clearance was 15% between the 4 days. Based on the final pharmacokinetic-model, an individualized dosing nomogram was developed. CONCLUSIONS: The model-based individual dosing nomogram is expected to result in predictive busulfan exposures in patients ranging between 3 and 65 kg and thereby to a safer and more effective conditioning regimen for HSCT in children.

Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation.

Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg x h/L (95% confidence interval=74 to 82 mg x h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC >74 mg x h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.

Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients.

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.