DoE-assisted HPLC method development and validation of enzalutamide and repaglinide in rat plasma.

Aim: A simple and rapid HPLC technique was developed and validated to simultaneously estimate enzalutamide (ENZ) and repaglinide (REP) in rat plasma.Methods: In silico predictions using DDinter and DDI-Pred indicated possible drug-drug interactions between ENZ and REP. A central composite design was used to identify factors influencing the separation of the drugs. Interactions between chromatographic parameters were studied through 51 experiments, followed by illustration with three-dimensional response surface plots. The four factors optimized for the separation of the two drugs are column temperature (A), % organic strength (B), pH (C) and column type (D).Results: Plate count(R1), tailing factor (R2) and resolution (R3) responses in the experimental design were analyzed with the favorable chromatographic conditions predicted to be 0.1% formic acid and acetonitrile as mobile phases on a Phenomenex C18 LC column (250 × 4.6 mm, 5 µm). The method was applied to estimate the drugs in rat plasma using a simple protein-precipitation step and found to be linear, accurate and precise within the ranges of 0.5-16 and 5-50 µg/ml for ENZ and REP, respectively.Conclusion: The optimized method can be used in future bioanalytical workflow for drug quantification and drug-drug compatible studies.

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4-Iodobenzonitrile as a fluorogenic derivatization reagent for chromatographic analysis of L-p-boronophenylalanine in whole blood samples using Suzuki coupling reaction.

BACKGROUND: L-p-Boronophehylalanine (BPA) is used in boron neutron capture therapy (BNCT), which is a novel selective cancer radiotherapy technique. It is important to measure BPA levels in human blood for effective radiotherapy; a prompt gamma-ray spectrometer, ICP-AES, and ICP-MS have been used for this purpose. However, these methods require sophisticated and expensive apparatuses as well as experienced analysts. Herein, we propose an HPLC-FL method for the determination of BPA after precolumn derivatization. A new fluorogenic reagent for aryl boronic acid derivatives, namely, 4-iodobenzonitrile, was employed for the fluorogenic derivatization of BPA based on the Suzuki coupling reaction. RESULTS: After the fluorogenic derivatization, a fluorescent cyanobiphenyl derivative is formed with maximum fluorescence at 335 nm after excitation at 290 nm. The developed method showed good linearity (r2=0.997) over the concentration range of 0.5-1000 nmol/L, and the detection limit (S/N = 3) was 0.26 nmol/L. The proposed method is more sensitive than previously reported methods for the determination of BPA, including the ICP-MS. Finally, the proposed method was successively applied to the measurement of BPA in human whole blood samples with a good recovery rate (≥95.7 %) using only 10 µL of blood sample. The proposed method offers a simple and efficient solution for monitoring BPA levels in BNCT-treated patients. SIGNIFICANCE: 4-Iodobenzonitrile was investigated as a new fluorogenic reagent for BPA based on Suzuki coupling. A new HPLC-FL method for BPA in whole blood samples with ultrasensitivity was developed. The developed method is superior in sensitivity to all previously reported methods for BPA. The method requires only a very small sample volume, making it suitable for micro-blood analysis of BPA via fingerstick sampling.

Analytical challenges related to the measurement of chlorothalonil in serum in the perspective of human biomonitoring studies.

Chlorothalonil (CTN) is a popular fungicide widely used in the world. However, its determination in serum samples is highly challenging, preventing a reliable investigation of human CTN internal exposure. We first investigated CTN's behaviour all along this analytical process on spiked serum samples. We used a radiolabelled 14C-CTN standard to monitor CTN in spiked serum samples and observed (1) a complete degradation of CTN in deproteinised serum samples after 4 h of contact; (2) a strong interaction between serum proteins and CTN by-products, with only 20 % of the radioactivity found to be extractable after 24 h of contact and (3) a slightly improved stability of CTN in serum following a first step of acidification or EDTA addition to samples. Using liquid chromatography coupled to high resolution mass spectrometry, 4-hydroxy-2,5,6-trichloroisophthalonitrile (HCTN) was identified as the major serum by-product of CTN. A protocol was developed to monitor both extractable CTN and HCTN from serum. This method was implemented on 36 human adult serum samples from the French "Esteban" Cohort. No free CTN was identified in these serum samples. Conversely, HCTN was detected in all samples at concentrations around 15 ± 2 ng mL-1, corresponding to the extractable fraction of CTN. Thus, HCTN may constitute a relevant biomarker of human internal exposure. Of note, the potential CTN contamination during blood collection could also be a source of HCTN detection in serum samples. Finally, blood sampling in EDTA tubes would seem more appropriate than in dry tubes for any future internal exposure studies on CTN.

Quantification of the aromatase inhibitor letrozole and its carbinol metabolite in mouse plasma by UHPLC-MS/MS.

A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase inhibitor, and its main carbinol metabolite (CM) in support of murine pharmacokinetic studies. Using polarity switching, simultaneous ESI-MS measurement of letrozole and CM was achieved in positive and negative mode, respectively. The assay procedure involved a one-step protein precipitation and extraction of all analytes from mouse plasma requiring only 5 µL of sample. Separation was optimized on an Accucore aQ column with gradient elution at a flow rate of 0.4 mL/min in 5 min. Two calibration curves per day over four consecutive measurement days showed satisfactory linear responses (r2 > 0.99) over concentration ranges of 5-1000 ng/mL and 20-2000 ng/mL for letrozole and CM, respectively. No matrix effect was found, and the mean extraction recoveries were 103-108 % for letrozole and 99.8-107 % for CM. Precision and accuracy within a single run and over four consecutive measurement days were verified to be within acceptable limits. Application of the developed method to preclinical pharmacokinetic studies in mice receiving oral letrozole at a dose 1 or 10 mg/kg revealed that the systemic exposure to letrozole was dose-, formulation-, and strain-dependent. These findings may inform the future design of preclinical studies aimed at refining the pharmacological profile of this clinically important drug.

Therapeutic response to leflunomide in combo therapy and monotherapy is associated to serum teriflunomide (A77 1726) levels.

There is a significant rate of therapeutic failure in rheumatoid arthritis (RA) patients treated with leflunomide (LEF). This study investigates the utility values of teriflunomide levels (A77 1726) in identifying RA patients who remained with moderate or severe disease activity after the treatment with LEF. In this cross-sectional study, we compared: (a) RA patients who achieved a DAS28-ESR ≤ 3.2, and (b) RA patients who maintained a DAS28-ESR > 3.2 after treatment. ROC curves determined the cut-off of A77 1726 with the better performance to identify patients achieving a DAS28-ESR ≤ 3.2. Of the 115 patients treated with LEF, 69 (60%) remained with moderate/severe disease activity and 46 (40%) achieved low disease activity/remission. Higher A77 1726 levels showed a negative correlation with DAS28-ESR (r = - 0.42, p < 0.001) and other parameters of disease activity. We obtained the following utility values with the cut-off of A77 1726 > 10 µg/mL to identify RA patients who achieved a DAS28-ESR ≤ 3.2: sensitivity of 91.31%; specificity of 73.91%; positive predictive value of 70.00%; and negative predictive value of 92.73%. Serum A77 1726 discriminated between RA patients who remained with moderate/severe disease activity despite the treatment with LEF both as monotherapy and LEF as combo therapy.

Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial.

PURPOSE: Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. METHODS: 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. RESULTS: Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). CONCLUSION: Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.

Isavuconazole for treatment of refractory coccidioidal meningitis with concomitant cerebrospinal fluid and plasma therapeutic drug monitoring.

Coccidioidal meningitis (CM) is a life-threatening infection with limited treatment options. Small series have reported success with isavuconazole; however, limited data exist on cerebrospinal fluid (CSF) penetration. Paired plasma and CSF isavuconazole concentrations were measured. Eleven CSF levels were tested, (7 ventricular, 4 lumbar) in three CM patients. Ventricular CSF levels were undetectable despite detectable plasma levels. All lumbar CSF levels were detectable (mean 1.00 µg/ml). Three pairs of lumbar CSF/plasma concentrations taken within 1 h of each other yielded a mean CSF/plasma ratio of 0.31. Isavuconazole was detectable in lumbar but not ventricular CSF in three patients treated for refractory CM. LAY SUMMARY: Isavuconazole is a triazole antifungal that has been used as salvage therapy in the treatment of coccidioidal meningitis (CM). Few data exist characterizing its concentration in the cerebrospinal fluid (CSF). We report tandem plasma and CSF concentrations of isavuconazole in three patients with CM.

Utilization of rGO-PEI-supported AgNPs for sensitive recognition of deltamethrin in human plasma samples: A new platform for the biomedical analysis of pesticides in human biofluids.

In this study, the rGO-PEI-AgNPs sensor was designed as a new effective platform to sensitive monitoring of deltamethrin in human plasma samples. For this purpose, reduced graphene oxide (rGO)-supported polyethylenimine (PEI) was used as a suitable substrate for dispersion of silver nanoparticles (AgNPs) as amplification and catalytic element. Therefore, a novel interface (rGO-PEI-AgNPs) was prepared by the fully electrochemical method on the surface of glassy carbon electrodes. The engineered nano-sensor showed a wide dynamic range of 10 nM to 1 mM and low limit of quantification (LLOQ) as 10 nM in human plasma sample, which revealed excellent analytical performance for the recognition of deltamethrin with high sensitivity and reproducibility through differential pulse voltammetry and square wave voltammetry techniques. The results confirm that rGO-PEI-AgNPs as a novel biocompatible interface can provide appropriate, reliable, affordable, rapid, and user-friendly diagnostic tools in the detection of deltamethrin in human real samples.

Efficacy and safety of bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia in the Asian subpopulation of the phase 3 BFORE trial.

Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (n = 33 vs 34) and non-Asian (n = 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.

Physiologically-based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment.

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

High-throughput liquid chromatography/electrospray ionization-tandem mass spectrometry method using in-source collision-induced dissociation for simultaneous quantification of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in human plasma.

Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high-performance LC/electrospray ionization-tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR-ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000-fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in-source collision-induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment. The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high-throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice.

Effects of SLC22A2 808G>T polymorphism and bosutinib concentrations on serum creatinine in patients with chronic myeloid leukemia receiving bosutinib therapy.

The purpose of this study was to investigate the effects of SLC22A2 808G>T polymorphism and trough concentrations (C0) of bosutinib on serum creatinine in 28 patients taking bosutinib. At 1, 3, 6, 12, 24, and 36 months after administration, analysis of bosutinib C0 and creatinine was performed at the same time of day. Significant correlations were observed between bosutinib C0 and the change rate of serum creatinine or the estimated glomerular filtration rate (eGFR; r = 0.328, P < 0.001 and r = - 0.315, P < 0.001, respectively). These correlations were particularly high in patients having the SLC22A2 808G/G genotype (r = 0.345 and r = - 0.329, respectively); however, in patients having the 808T allele, there were no significant differences. In multivariate analyses, the SLC22A2 808G/G genotype, patient age, bosutinib C0 and second-line or later bosutinib were independent factors influencing the change rate of creatinine. Bosutinib elevated serum creatinine through organic cation transporter 2 (OCT2). We observed a 20% increase in serum creatinine with a median bosutinib C0 of 63.4-73.2 ng/mL. Periodic measurement of serum creatinine after bosutinib therapy is necessary to avoid progression to severe renal dysfunction from simple elevation of creatinine mediated by OCT2 following bosutinib treatment.

Clinical experience of abrupt discontinuation of perampanel: a case series.

With an elimination half-life of 105 hours, perampanel (PER) allows a once-daily dosing regimen. In pivotal trials, when PER was tapered, it was therefore usually discontinued abruptly. Thus, in our hospital we have always practiced abrupt cessation. In this case series, we investigated how long PER serum concentrations still remain measurable after abrupt discontinuation of PER and whether withdrawal symptoms, such as an increase in seizures or status epilepticus, occur. PER serum levels and the clinical course of 15 adult in-patients were monitored for three weeks based on a retrospective study design following abrupt discontinuation of PER. After one week, PER was still detected in 13 of 15 patients, after two weeks in 10, and after three weeks in three. Neither a severe increase in seizure frequency nor status epilepticus occurred. However, modifications of the concomitant antiseizure drugs were necessary. The abrupt discontinuation of PER leads to a slow decrease in plasma concentration, thus resembling self-evident gradual discontinuation of PER. In some cases, PER may still be measurable and thus clinically active even weeks after its discontinuation. Efficacy and safety of other antiseizure drugs can be estimated appropriately only thereafter.

Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients With Rheumatoid Arthritis.

OBJECTIVE: Leflunomide is a commonly used disease-modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease-modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. METHODS: Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed-effects modeling. RESULTS: A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (ß = 0.70, P < 0.001) and was higher in those who carried the DHODH haplotype 2 (ß = 0.56. P = 0.01) and did not carry the shared epitope (ß = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower (P < 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower. CONCLUSION: Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response.

Characterization of Isavuconazole serum concentrations after enteral feeding tube administration in a hospitalized cohort: A case series.

WHAT IS KNOWN AND OBJECTIVE: Invasive fungal infections often occur in patients with comorbidities that complicate oral administration. Serum concentrations of isavuconazole were characterized after enteral tube administration. CASE DESCRIPTION: Thirteen of 14 isavuconazole concentrations were >1 mg/dl (median 1.6 mg/dl) among those receiving enteral tube administration, which was comparable to intravenous (median 1.9 mg/dl). Higher concentrations were observed during oral administration (median 3 mg/dl). WHAT IS NEW AND CONCLUSION: Administration of isavuconazole via tube resulted in concentrations comparable to FDA-approved routes of administration. This route may be feasible and appropriate for select patients.

Development and validation of HPLC-UV method for quantitation of a new antithrombotic drug in rat plasma and its application to pharmacokinetic studies.

A selective and sensitive procedure for quantitation of a new antithrombotic drug (GRS) in rat plasma was developed and validated using an HPLC-UV. The method was validated according to recommendations of the FDA, EMA in terms of selectivity, linearity, accuracy, precision, recovery, matrix effect, stability, and carry-over. The preparation of the biological sample included liquid-liquid extraction with acetonitrile, separation of water-organic mixture with inorganic salts, organic phase clean-up with a sorbent (QuEChERS method), its evaporation to dryness and reconstitution of the residue with A:B eluents mixture (1:1). The chromatographic separations were performed on a micro-column 75 × 2 mm, 5 µm particle size sorbent ProntoSIL 120-5-C18 AQ. The flowrate was of 0.15 ml/min, detector wavelength was set at 360 nm for GRS and at 230 nm for papaverine (IS). It was found that GRS recovery from rat plasma is 94%, the response linearity is in the range of 10 to 1000 ng ml-1. The accuracy values for intra-day determination were of 93.2 to 101.8%, for inter-day determination were of 91.2 to 102.2%, coefficient of variation for intra- and inter-day precision did not exceed 4.1 to 9.3%. The application of the method was shown in pharmacokinetic studies of GRS in rats at a dose of 20 mg kg-1.

Differential lymphatic versus portal vein uptake of the synthetic pyrethroids deltamethrin and cis-permethrin in rats.

The objective of this study was to obtain data on pathways of absorption of the synthetic pyrethroids deltamethrin (DLM) and cis-permethrin (CPM) following oral administration to rats. Adult male Sprague-Dawley rats with cannulated mesenteric lymph ducts and hepatic portal veins were given single doses of either 5 mg/kg DLM or 60 mg/kg CPM via the duodenum and lymph and portal blood samples collected for up to 300 min. The pyrethroid dosing vehicles (5 mL/kg body weight) were either corn oil or glycerol formal. Levels of DLM and CPM in lymph and portal blood samples were determined by high-performance liquid chromatography-mass spectrometry-mass spectrometry. Over the time period studied, levels of both DLM and CPM following administration in either corn oil or glycerol formal were greater in lymph than in portal blood. Lymphatic uptake of both DLM and CPM was enhanced following dosing in glycerol formal than in corn oil. The results of this study suggest that after oral administration to rats, these two pyrethroids are predominantly absorbed via the lymphatic system rather than via portal blood. The data obtained in this study thus support a recently developed physiologically-based pharmacokinetic (PBPK) model to evaluate age-related differences in pyrethroid pharmacokinetics in the rat, where it was assumed that absorption of pyrethroids was predominantly via lymphatic uptake.

Pharmacokinetics, Activity, and Residue Elimination of R- and S-Diclazuril in Broiler Chickens.

Diclazuril (DIC) is widely used as a racemic mixture to prevent and treat coccidiosis in farm animals, while the pharmacokinetics, bioactivity, and toxicity of DIC enantiomers are not known at all. This study first established a simple, sensitive, and reliable liquid chromatography tandem mass spectrometry method for separation of R-DIC and S-DIC and their analyses. Then, it was applied to investigate the stereoselective pharmacokinetics and residual elimination of individual enantiomers, and their anticoccidial activity was also evaluated in broiler chickens. The results indicated that the area under the concentration-time curve (AUC) and elimination half-life (t1/2ß) were significantly different (p < 0.05) for two enantiomers in chicken plasma. The AUC and t1/2ß of S-DIC were approximately 2 and 1.4 times those of R-DIC, respectively. The residual elimination of DIC enantiomers in chicken tissues was also stereoselective. The concentrations of S-DIC in chicken muscle and liver were greater than those of R-DIC, and it is the opposite in the kidney. There was no significant difference (p > 0.05) in the anticoccidial activity of racemate and enantiomers when a single enantiomer in feed was added above 0.5 mg kg-1. However, the anticoccidial activity of R-DIC (0.25 mg kg-1) was significantly higher (p < 0.05) than that of S-DIC (0.25 mg kg-1) in the diet. It should be mentioned that in chicken small intestine and cecum, the enantiomerization rate of each enantiomer in the infection group was faster than that in the uninfected group.

The Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia.

We recently treated a chronic myeloid leukemia (CML) patient with liver and renal dysfunction, who was undergoing hemodialysis (HD). He was treated with 50 mg dasatinib (DAS) once daily just before HD. The maximum plasma concentration of DAS was 227 ng/mL on a non-HD day and 46.9 ng/mL on a HD day. He was subsequently treated with 200 mg bosutinib (BOS) once daily. The plasma concentration of BOS changed from 74.5 ng/mL before HD to 58.8 ng/mL after HD. Our results indicate that close monitoring of the plasma tyrosine kinase inhibitor concentrations should be considered in CML patients with organ impairment.

Lessons from isavuconazole therapeutic drug monitoring at a United Kingdom Reference Center.

We determined isavuconazole serum concentrations for 150 UK patients receiving standard isavuconazole dosing regimens, including serial therapeutic drug monitoring for several patients on prolonged therapy. Mean trough isavuconazole concentrations in these patients were virtually identical to those reported previously from clinical trials, although greater variability was seen in patients below 18 years of age. Serial monitoring in patients receiving prolonged therapy suggested gradual, near-linear accumulation of the drug over many weeks.