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•LC–MS/MS determination of nitrosamines using APCI.•Analysis of a large number of different batches.•Analysis of different sartans.•Analysis of different manufacturers for several ...sartans.
In July 2018 one of the bestselling antihypertensive agents valsartan manufactured in China was found to be contaminated by the “probably carcinogenic” nitrosamine N-nitrosodimethylamine (NDMA), followed by the detection of N-nitrosodiethylamine (NDEA) by us and others soon after. Our work also revealed that two additional non-nitrosamine contaminations valeramide (VLA) and N,N-dimethylvaleramide (VLA-DEM) were present in sartan tablets. Early measurements by others and us were performed by GC–MS or GC–MS/MS, which does not reach the sensitivity needed to find and quantitate trace levels of NDMA and NDEA. A highly sensitive LC–MS/MS method with APCI ionization was developed to detect and quantitate NDMA, NDEA, VLA and VLA-DIM in 152 sartan tablets from 8 structurally different sartan molecules. Good linearity for each compound could be demonstrated over calibration ranges in the lower nanograms. The assay for all substances was accurate and precise. With this method, a LLOQ of 0.00026 ppm for NDMA and 0.00013 ppm for NDEA could be achieved. NDMA, NDEA, VLA and VLA-DIM were found in 21 (13.8%), 9 (5.9%), 13 (8.6%) and 7 (4.6) % of the tablets, respectively. In addition, one candesartan product was found contaminated with NDEA. The implications of our findings for the testing of pharmaceutical products are discussed.
This study aimed to assess the content of caffeine and its metabolites-paraxanthine, theophylline, and theobromine-in breast milk according to selected factors. Samples of human milk were collected ...from 100 women living in the east-northeast region of Poland. Information on the consumption of beverages and foods containing caffeine was collected using a 3 day food record. The determination of caffeine and its metabolite content was performed using liquid chromatography-mass spectrometry (LC-MS/MS). This study research showed that more caffeine was found in the milk of women living in cities, with secondary education, aged 34-43, and also in milk from the 3rd and 4th lactation periods (
≤ 0.05). Factors such as place of residence, level of education, age, and stage of lactation influenced the nutritional choices of breastfeeding women, which had an impact on the level of caffeine and its metabolites in breast milk. A positive correlation was found between the consumption of caffeine with food and drinks and its level in human milk.
Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that ...both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects.
To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples.
Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations.
The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.
A sensitive, precise and accurate quantitative liquid chromatography/tandem mass spectrometry (LC–MS/MS) method for the measurement of sunitinib (SU11248) and
N-desethyl sunitinib (SU12662) in human ...plasma was developed and validated. All sample handling was done under strict light protection. The sample preparation method employed acetonitrile protein precipitation using
d
5-SU11248 as an internal standard. The processed samples were chromatographed on a polymeric reversed-phase analytical column and analyzed by triple-quadrupole MS/MS in multiple reaction monitoring (MRM) mode using positive TurboIonSpray
® (TISP). The LC–MS/MS method described in this paper presents high absolute recovery (86.2% SU11248, 84.8% SU12662), high sensitivity (lower limit of quantitation of 0.06
ng/mL for both analytes), high inter-day precision (1.6–6.1% SU11248, 1.1–5.3% SU12662) and high analytical recovery (99.8–109.1% SU11248, 99.9–106.2% SU12662), as well as excellent linearity over the concentration range 0.060–100
ng/mL (
r
2
>
0.999) with a short runtime of only 4.0
min. Results on the stability of SU11248 and SU12662 in human plasma are presented. During validation plasma from intensive care patients receiving many drugs were tested for interference and incurred samples were analyzed. The method met all criteria of the EMA and FDA guidelines during validation and was successfully applied to a pharmacokinetic study in healthy human volunteers.
•Impurity profiling of Bisoprolol fumarate with targeted and untargeted approaches.•Maximized number of detectable analytes by combining different LC and MS conditions.•In silico fragmentation of ...potential impurities derived from a reaction matrix.•Development of structures for unknowns considering synthesis and tandem MS data.•Quantification of impurities with respect to internal standards.
Several examples of the emergence of unexpected impurities in medicinal products in the past, e.g. the 2018 valsartan scandal, disclosed the need for sophisticated approaches in impurity profiling. Advanced techniques in mass spectrometry offer the possibility to detect impurities in untargeted approaches complementing the targeted search for potential impurities. In this study, a combination of targeted and untargeted approaches using LC-MS/HRMS was applied in creating an impurity profile of bisoprolol fumarate. In the targeted approach, a reaction matrix was used to predict potential impurities, which were searched for in addition to the related substances stated in the European Pharmacopoeia. For the untargeted analytics, general unknown comparative screening was performed to detect unexpected impurities. To cover a maximum range of detectable analytes, two complementary mobile phases, i.e. buffered to acidic and basic pH, were combined with four mass spectrometric ionization conditions, i.e. electrospray ionization and atmospheric pressure chemical ionization in both positive and negative mode. Information-dependent acquisition was used to generate MS and MS/MS data in a single run. The targeted and the untargeted approach revealed the presence of 18 and 17 impurities, respectively. The plausibility of proposed/elucidated structural formulae was checked by in silico fragmentation and assignment of characteristic fragments/neutral losses. Quantification of the impurities was performed with respect to the internal standard metoprolol. The analyzed batches showed contents of up to 0.05% of single impurities. A thorough procedure for the development of a complete impurity profile for drug substances was demonstrated. To ensure a maximum of patient safety, the described approach is prototypical and should be implemented during drug development and after relevant changes in manufacturing processes.
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Background
Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF‐MEK‐ERK and PI3K‐AKT‐mTOR.
Methods
...Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5‐10.0 mg/d in a 14‐day run‐in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS‐mutated non–small‐cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG‐PET. Efficacy was assessed by CT scans every 6 weeks of combination.
Results
Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose‐limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG‐PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively.
Conclusions
Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG‐PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS‐mutant solid tumors.
The study investigated the combination of sorafenib and everolimus in patients with solid tumors (dose escalation part) and KRAS mutated NSCLC (expansion part). Although the trial showed manageable safety profile of sorafenib and everolimus, it failed in providing long terms responses for patients with solid tumors and KRAS mutated NSCLC. The novelty of the study was the early pharmacodynamics assessment using FDG‐PET implemented in a phase‐I.
Fungal peritonitis is a life-threatening condition which is not only difficult to diagnose, but also to treat. Following recent guidelines, echinocandins and azoles are the recommended antimycotics ...for the management of intra-abdominal Candida spp. infections, with a favor for echinocandins in critically ill patients. However, the new extended spectrum triazole isavuconazole also has a broad spectrum against Candida spp. Data on its target-site penetration are sparse. Therefore, we assessed isavuconazole concentrations and penetration ratios in ascites fluid of critically ill patients. Obtaining of Isavuconazole plasma and ascites fluid levels as well penetration ratios using paracentesis in critically ill patients. Isavuconazole concentrations were quantified in human plasma and ascites by a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. Isavuconazole concentrations in plasma and ascites fluid were measured in sixteen critically ill patients. Isavuconazol levels in ascites fluid (1.06 µg/mL) were lower than plasma levels (3.08 µg/mL). Penetration ratio was 36%. In two out of sixteen patients, Candida spp., in detail C. glabrata and C. tropicalis, could be isolated. Cmax/MIC Ratio in plasma of 560 for C. glabrata and 2166 for C. tropicalis could be observed. Following our results, isavuconazole penetrates into ascites. Successful treatment in Candida spp. peritonitis depends on pathogen susceptibility.
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