Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin.

BACKGROUND: Busulfan (Bu) conditioning used in hematopoietic stem cell transplantation may induce seizures, and prophylactic antiepileptic treatment is recommended. Following updated guidelines, in August 2019, the adult hematopoietic stem cell transplantation department of the Rambam Health Care Campus (Haifa, Israel) switched the antiepileptic prophylaxis protocol from phenytoin to oral levetiracetam during oral Bu conditioning. The aim of this study was to compare the pharmacokinetic parameters of Bu after oral dosing between patients receiving phenytoin and those receiving levetiracetam prophylaxis. METHODS: This study was a retrospective cohort study in adults undergoing myoablative conditioning with oral Bu between August 2018 and August 2020. Bu pharmacokinetic parameters (AUC0-6, C0, Cmax, and Tmax) were compared in patients treated with phenytoin comedication (during the year before the change in policy) and levetiracetam comedication (during the year after the change). Potential confounders were accounted for including age, azole comedication, and body weight. RESULTS: There were no significant differences in demographic and clinical parameters or weight-corrected Bu dose between the phenytoin group (n = 28) and the levetiracetam group (n = 25). There was no difference in the rate of voriconazole comedication, but fluconazole was more common in the phenytoin group (P = 0.026). The median AUC0-6 was significantly lower in the levetiracetam group (949 µM*min; IQR = 806 to 1101 µM*min) than in the phenytoin group (1208 µM*min; IQR = 1087 to 1389 µM*min; P < 0.001). This is a clinically significant difference of 258 µM*min (21%). Azole use was not associated with Bu exposure. CONCLUSIONS: The findings suggest that, after treatment with oral Bu, oral levetiracetam comedication is associated with reduced systemic exposure compared with phenytoin comedication, possibly because of decreased bioavailability.

Limited Sampling Strategies Supporting Individualized Dose Adjustment of Intravenous Busulfan in Children and Young Adults.

BACKGROUND: Therapeutic drug monitoring (TDM) for busulfan supports dose adjustment during conditioning for stem cell transplantation. The authors aimed to develop and validate limited sampling strategies (LSS) of 4-5 samples for a precise estimation of the area under concentration (AUC)-time curve of busulfan, in plasma as an alternative to an intensive sampling strategy (ISS) requiring 9-10 samples. METHODS: ISS TDM data from 297 patients (≤18 years of age) were used. AUCLSS was calculated using the trapezoidal rule and multiple linear regression (MLR). Unlike more complex modeling methods, MLR does not require sophisticated software or advanced training of personnel. MLR coefficients were estimated in the development subset containing randomly selected 50% of the records and were then used to calculate the AUCLSS of the remaining records (the validation subset). The agreement between dose adjustment recommendations (DAR) based on ISS and LSS, in the validation subset, was evaluated by a Bland-Altman analysis. A DAR deviating from an ISS-based reference by <15% was deemed acceptable. RESULTS: Twelve LSSs were acceptable. Sampling at 0, 120, 180, and 240 minutes after the start of the second infusion (LSS15) yielded the best performance, with DAR deviating from the reference by <10% for 95% of cases; the AUCLSS was determined as follows: AUCLSS = 74.7954 × C(0) + 81.8948 × C(120) + 38.1771 × C(180) + 138.1404 × C(240) + 54.1837. This LSS and LSS13 performed similarly well in an independent external validation. CONCLUSIONS: MLR-based estimates of AUCLSS provide DARs that deviate minimally from the reference. LSSs allow the reduction of patient discomfort, a ∼50% reduction of TDM-related workload for nursing staff and blood loss and a ∼25% reduction in laboratory workload. These benefits may encourage wider use of busulfan TDM, supporting safe and efficacious personalized dosing.

The Effect of a 30-Min Water-Pipe Smoking Session on Cognitive Measures and Cardio-Pulmonary Parameters.

INTRODUCTION: One session of water-pipe tobacco smoking (WPS) can increase carboxyhemoglobin (COHb) to levels comparable to those reported in carbon monoxide poisoning, which may cause memory impairment and confusion. METHODS: A prospective study evaluating healthy volunteers pre- and post-30 min of WPS session. Primary outcome parameters were executive cognitive measures [digit span test and Paced Auditory Serial Addition Test (PASAT)]. The effect of repeated cognitive testing 30 min apart without WPS was evaluated in age- and sex-matched healthy volunteers. Secondary outcome parameters included cardio-pulmonary, COHb, serum nicotine, and cytokine changes. RESULTS: Thirty-five subjects aged 25.6 ± 4.5 years smoked water-pipe for a 30-min session. Control group included 20 subjects aged 25.2 ± 5.1 years. Digit span test median score decreased after WPS (16 and 15, respectively, p = .003), insignificant decrease in controls. Median PASAT score increased after WPS (49 and 52, respectively, p = .009); however, a much larger significant increase was observed in controls (p ≤ .001). One WPS session resulted in significant increases in heart and respiratory rates and significant decrease in FEF25-75%. Post WPS, median COHb levels increased (from 2.2% to 10.7%, p < .0001) as did median serum nicotine levels (from 1.2 to 26.8 ng/mL, p < .0001). Serum cytokines levels: IL-2 and IL-6 increased (p < .0001 for each), and IL-10 and IL-5 decreased (p < .0001 and p = .04, respectively). CONCLUSIONS: One session of WPS resulted in significant negative effects on cognitive executive measures, significant increases in COHb and serum nicotine levels, and significant changes in serum cytokines. Our findings call for increasing awareness towards the possible consequences of cognitive alterations following a 30-min session of WPS. IMPLICATIONS: One 30-min session of water-pipe smoking resulted in negative effects on executive cognitive measures, increased carboxyhemoglobin and serum nicotine, and significant changes in serum cytokine levels. This study adds to the accumulating evidence on the harmful effects of water-pipe smoking, a growing epidemic, and calls for awareness of its possible consequences of acute cognitive alterations.

Comparison of everolimus QMS immunoassay on Architect ci4100 and liquid chromatography/mass spectrometry: lack of agreement in organ-transplanted patients.

BACKGROUND: Liquid chromatography with mass spectrometry (LC-MS/MS) is the method of choice for the determination of everolimus whole blood concentrations but is not always available. Therefore, immunoassays have been developed for clinical monitoring of everolimus. In previous studies, the Quantitative Microsphere System (QMS) immunoassay had a positive bias compared with LC-MS/MS, but was judged acceptable, although clinical agreement (eg, 95% limits of agreement) was not reported. The objective of this study was to assess whether the agreement between the QMS assay and an LC-MS/MS method was clinically acceptable for use interchangeably in therapeutic everolimus monitoring. METHODS: Whole blood samples from organ-transplanted patients on everolimus therapy were analyzed by both QMS (on Architect ci4100 analyzer) and LC-MS/MS. Paired results were compared using paired Student t test, Bland-Altman plots, and Deming regression analysis. The proportions of falsely supratherapeutic and subtherapeutic results on the QMS assay compared with the LC-MS/MS were calculated. RESULTS: Among 250 samples (169 patients), mean everolimus concentrations determined by LC-MS/MS and QMS assays were 4.8 ± 2.1 ng/mL and 6.3 ± 2.1 ng/mL, respectively (P < 0.001), with 95% lines of agreement between -2.1 and 5.2 ng/mL, a range corresponding to 152% of the mean concentration. When stratified by the type of transplant, a similar positive bias was found in each subgroup (all P < 0.014). Sixty-nine percent of the samples yielding supratherapeutic concentrations (>8 ng/mL) on the QMS assay were within the therapeutic range on the LC-MS/MS. CONCLUSIONS: The everolimus QMS immunoassay, using the Architect ci4100 analyzer, had a significant positive bias compared with LC-MS/MS, with a wide range between the limits of agreement. The lack of agreement may result in inadequate everolimus dose adjustments, suggesting that the QMS assay cannot be used interchangeably with the LC-MS/MS method for therapeutic everolimus monitoring in organ-transplanted patients.

Laboratory and clinical acute effects of active and passive indoor group water-pipe (narghile) smoking.

BACKGROUND: Indoor group water-pipe tobacco smoking, commonly referred to as water-pipe smoking (WPS), especially in coffee shops, has gained worldwide popularity. We performed a comprehensive laboratory and clinical evaluation of the acute effects of active and passive indoor group WPS. METHODS: This comparative study evaluated pre- and post-30-min active and passive indoor group WPS. The outcome parameters were carboxyhemoglobin (COHb), nicotine, and cotinine levels; CBC count; and cardiorespiratory parameters. Exhaled breath condensate (EBC) cytokines and endothelial function (using the EndoPat device [Itamar Medical Ltd]) were measured only in active smokers. Statistical methods used were Student t test, Wilcoxon signed rank test, Fisher exact test, analysis of variance, and Newman-Keuls post hoc test where relevant. RESULTS: Sixty-two volunteers aged 24.9±6.2 years were included; 47 were active smokers, and 15 were passive smokers. COHb level increased postactive WPS (active smokers, 2.0%±2.9% vs 17.6%±8.8%; P<.00001); six subjects (12.7%) had a >25% increase, and two subjects (4.2%) had a >40% increase. Plasma nicotine level increased postactive WPS (active smokers, 1.2±4.3 ng/mL vs 18.8±13.9 ng/mL; P<.0001); plasma cotinine and urinary nicotine and cotinine levels also increased significantly. EBC IL-4, IL-5, IL-10, IL-17, and γ-interferon decreased significantly with postactive smoking; endothelial function did not change. WPS was associated with adverse cardiorespiratory changes. In passive smokers, COHb level increased (0.8%±0.25% vs 1.2%±0.8%, respectively, P=.003) as did respiratory rate. CONCLUSIONS: One session of active indoor group WPS resulted in significant increases in COHb and serum nicotine levels (eightfold and 18-fold, respectively) and was associated with adverse cardiorespiratory health effects. The minor effects found in passive smokers suggest that they too may be affected adversely by exposure to WPS. The results call for action to limit the continuing global spread of WPS in coffee shops. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT1237548; URL: www.clinicaltrials.gov.

A simple approximation for busulfan dose adjustment in adult patients undergoing bone marrow transplantation.

Busulfan is an alkylating agent used in preparative regimens before bone marrow transplantation (BMT). Busulfan concentrations in plasma, expressed as the area under the concentration-time curve (AUC), were reported to correlate with treatment outcome. Because busulfan is administered in 16 doses of 1 mg/kg every 6 hours for 4 days, the opportunities to "correct" the dose as a consequence of the measured AUC are limited to the 16-dosage protocol. In the present research busulfan pharmacokinetics were prospectively evaluated in 27 adult patients treated according to the above protocol by measuring the first, second, and fifth dose AUC. The pharmacokinetic analysis was based on a noncompartment model for extravascular absorption, but calculations according to a 1-compartment model gave similar results. A simple mathematical approximation allowed prediction of the AUC of the second dose from that of the first and the busulfan concentration at trough. Fifteen patients had the dose adjusted at the fourth dose to obtain an AUC within the "therapeutic window" of 950-1500 microM-min. This procedure was then validated by the measurement of the fifth dose AUC. It appears that this simple pocket calculator method allows a rapid evaluation of the need and the extent of dose adjustment and proved to be a valuable tool to improve busulfan administration in pre BMT treatment.