Using a cancer registry to capture signals of adverse events following immune and targeted therapy for melanoma.

Background Toxicity of oncology treatments in real-life patients is frequently disregarded and hence underreported. Objective To characterize adverse events (AEs) of immunotherapy and targeted therapy reported in patients with locally advanced or metastatic melanoma. Setting District Hospital for Cancer treatment (Instituto Português de Oncologia de Lisboa Francisco Gentil). Method A retrospective cohort of melanoma patients was established, comprising adult patients diagnosed with malignant melanoma treated with immunotherapy or targeted therapy. Exposure was characterized by nature, time and intensity of exposure. To account for different exposure periods, person-time was used as unit of analysis. Main outcomes measure Occurrence of AEs. Results Data from 111 patients included in the cohort indicates the majority received immunotherapy regimens (CTLA-4, anti-PD-1 and combination therapy; (n = 70; 63.1%), among which anti-PD-1 were the predominant treatment. Pembrolizumab was the most frequently prescribed drug (n = 30; 45.7%). Three hundred and seventy-one AEs were extracted. The incidence of AEs was lower in the anti-PD-1 mAc group (54 AEs per 1000 person.months) and the number of AEs/patient was also lower (3.1 ± 2.0). Grade 3 to 4 AEs occurred in 15.3% (n = 17) of the cohort, being more common in the targeted therapy group. Forty-two (11.6%) of the extracted AEs were not described in the Summary of Product Characteristics of the drugs under study. Conclusion This study suggests various known and unknown AEs of immunotherapy and targeted therapy may be identified using the Cancer Registry database. These events should be considered as signals worth further investigation for assessment of causality as the underreporting of AEs in cancer may have potential implications for the patient's quality of life.

Production and characterization of spray-dried theophylline powders prepared from fresh milk for potential use in paediatrics.

OBJECTIVE: This work evaluates the potential of using fresh milk to deliver theophylline to children. METHODS: Theophylline-fresh milk systems were prepared using different solids ratios (0 : 1-1 : 0) and three fat contents in commercial milks (low, medium and high), which were spray-dried at different inlet air temperatures (Tinlet - 105, 130 and 150 °C). The process was evaluated for yield and the resulting powders for moisture content (MC), particle size and shape, density and wettability. Theophylline-milk potential interactions (differential scanning calorimetry (DSC) and FT-IR) and chemical (theophylline content) and microbiological stability of powders (shelf and in-use) were also evaluated. KEY FINDINGS: The production yield (13.6-76.0%), MC (0.0-10.3%) and contact angles in water (77.29-93.51°) were significantly (P < 0.05) affected by Tinlet , but no differences were found concerning the mean particle size (3.0-4.3 µm) of the different powders. The milk fat content significantly (P < 0.05) impacted on the density (1.244-1.552 g/cm3 ). Theophylline content remained stable after 6 months of storage, before extemporaneous reconstitution. After reconstitution in water, low-fat milk samples (stored at 4 °C) met the microbial pharmacopoeia criteria for up to 7 days. No theophylline-milk components interaction was observed. CONCLUSION: Spray-dried milk-composed powders may be used as vehicles for theophylline delivery in paediatrics following further characterization and in-vivo evaluation.

Quantification of theophylline or paracetamol in milk matrices by high-performance liquid chromatography.

A simple, accurate and sensitive high-performance liquid chromatography (HPLC) method was developed, validated and applied to the determination of either theophylline or paracetamol in milk-based samples. The method allowed drug quantification in fresh and powdered milk with a relatively short run time of analysis and it was also successfully applied to the quantification of the drugs in solid dosage forms intended for pediatric use. Moreover, the main significant advantages over other published works are the simplicity of the sample preparation, reduced assay time and sample loss. The method meets the International Conference on Harmonization guideline for analytical methods validation regarding specificity, linearity, accuracy, precision, specificity and robustness as required by health authorities and applied by industry while designing and marketing new drug products. The technique encompasses the separation of the analytes with a reverse phase C18 column under isocratic conditions and UV detection at 272 nm and 243 nm, respectively, for theophylline and paracetamol. The lower limit of quantification for both drugs was determined as 0.2 µg/mL and the between-batch accuracy was approximately 99.7%. This HPLC method allows quantification of theophylline and paracetamol in milk matrices and it can be applied in the design, development and production of milk-based pediatric dosage forms.