Biosimilar Pegfilgrastim: Improving Access and Optimising Practice to Supportive Care that Enables Cure

Febrile neutropenia (FN) is a serious complication of chemotherapy, which can cause significant morbidity and mortality, result in dose delays and reductions and, ultimately, reduce cancer survival. Over the past decade, the availability of biosimilar filgrastim (short-acting granulocyte colony-stimulating factor [G-CSF]) has transformed patient access, with clear evidence of clinical benefit at preventing FN at reduced costs. In 2019, seven biosimilar pegfilgrastims (long-acting G-CSFs) were licensed, creating optimal market conditions and choice for prescribers. FN affects up to 117 per 1000 cancer patients, with mortality rates in the range of 2–21%. By reducing FN incidence and improving chemotherapy relative dose intensity (RDI), G-CSF has been associated with a 3.2% absolute survival benefit. Guidelines recommend primary prophylaxis and that filgrastim be administered for 10–14 days, while pegfilgrastim is administered once per cycle. When taken according to the guidelines, pegfilgrastim and filgrastim are equally effective. However, in routine clinical practice, filgrastim is often under-dosed (< 7 days) and has been shown to be inferior to pegfilgrastim at reducing FN incidence, hospitalisations and maintaining RDI. Once-per-cycle administration with pegfilgrastim might also aid patient adherence. The introduction of biosimilar pegfilgrastim should instigate a rethink of neutropenia management. Biosimilar pegfilgrastim

Susceptibility to Adrenal Crisis Is Associated With Differences in Cortisol Excretion in Patients With Secondary Adrenal Insufficiency

Objective: To compare cortisol pharmacokinetics and pharmacodynamics mapped through several glucocorticoid sensitive pathways in patients on hydrocortisone substitution with or without an adrenal crisis. Design: A post-hoc analysis of a previously conducted randomized controlled trial in patients with secondary adrenal insufficiency examining the effects of 2 weight-adjusted hydrocortisone doses. Methods: Comparisons were primarily made on a hydrocortisone dose of 0.2-0.3 mg/kg/day for plasma cortisol and cortisone, 24-hour urinary steroid profile, the glucocorticoid sensitive tryptophan-kynurenine pathway, the renin-angiotensin-aldosterone system and aspects of quality of life. Variables of interest were also analyzed on the hydrocortisone dose of 0.4-0.6 mg/kg/day. Results: Out of 52 patients, 9 (17%) experienced at least one adrenal crisis (AC+ group) and 43 did not develop an adrenal crisis (AC- group) during an observation period of 10 years. 24-hour urinary excretion of cortisol and cortisone were lower in the AC+ group (0.05 [IQR 0.03; 0.05] vs. 0.09 [0.05; 0.12] µmol/24h, P=0.01and 0.13 [0.10; 0.23] vs. 0.24 [0.19; 0.38] µmol/24h, P=0.04, respectively). No differences in pharmacokinetics of cortisol were observed. Kynurenine concentrations were higher in the AC+ group (2.64 [2.43; 3.28] vs. 2.23 [1.82; 2.38] µmol/L, P=0.03) as was general fatigue (Z-scores 1.02 [-0.11; 1.42] vs. -0.16 [- 0.80; 0.28], P=0.04). On the higher hydrocortisone dose urinary excretion of cortisol and cortisone was still significantly lower between the AC- and AC + group. The differences in glucocorticoid sensitive variables disappeared. Conclusion: Patients susceptible to an adrenal crisis demonstrated differences in cortisol and cortisone excretion as well as in pharmacodynamics when compared to patients who did not experience an adrenal crisis, suggesting a biological predisposition in certain patients for the development of an adrenal crisis

Residual endogenous corticosteroid production in patients with adrenal insufficiency

Objective This study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency. Design Twenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies. Patients and measurements Patients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC-MS/MS Results Compared to controls, progressively lower concentrations of the glucocorticoid precursors 11-deoxycortisol, 11-deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11-deoxycortisol, 11-deoxycorticosterone and corticosterone conce ntrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11-deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24-hour free cortisol excretion in urine. Conclusions Adrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined

An end-user perspective on Organ-on-a-Chip: Assays and usability aspects

Analytical BioScience

Direct on-chip differentiation of intestinal tubules from induced pluripotent stem cells

Intestinal organoids have emerged as the new paradigm for modelling the healthy and diseased intestine with patient-relevant properties. In this study, we show directed differentiation of induced pluripotent stem cells towards intestinal-like phenotype within a microfluidic device. iPSCs are cultured against a gel in microfluidic chips of the OrganoPlate, in which they undergo stepwise differentiation. Cells form a tubular structure, lose their stem cell markers and start expressing mature intestinal markers, including markers for Paneth cells, enterocytes and neuroendocrine cells. Tubes develop barrier properties as confirmed by transepithelial electrical resistance (TEER). Lastly, we show that tubules respond to pro-inflammatory cytokine triggers. The whole procedure for differentiation lasts 14 days, making it an efficient process to make patient-specific organoid tubules. We anticipate the usage of the platform for disease modelling and drug candidate screening

Lab-on-a-Chip hyphenation with mass spectrometry: strategies for bioanalytical applications

The Lab-on-a-Chip concept aims at miniaturizing laboratory processes to enable automation and/or parallelization via microfluidic chips that are capable of handling minute sample volumes. Mass spectrometry is nowadays the detection method of choice, because of its selectivity, sensitivity and wide application range. We review the most interesting examples over the last two-and-a-half years where the two techniques were used for bioanalytical applications. Furthermore, we discuss the merits and limitations of such hyphenated systems. We inventorize the reported applications and approaches. We see an ongoing trend towards chip-based liquid chromatography-mass spectrometry usage and small volume analysis applications, particularly in the field of proteomics where bottom-up approaches profit from chip-based technologies and hyphenation with complex cell cultures.Seventh Framework Programme (FP7)Analytical BioScience

Rationale and design of the CORE (COrticosteroids REvised) study:protocol

Introduction Corticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used. Current clinical bioequivalence data are however based on animal studies or studies with subjective endpoints. Furthermore, advancement in steroid physiology with regard to metabolism, intracellular handling and receptor activation have not yet been incorporated. Therefore, this study aims to re-examine the clinical bioequivalence and dose effects of the most widely used synthetic corticosteroids, prednisolone and dexamethasone. Methods and analysis In this double-blind, randomised cross-over clinical trial, 24 healthy male and female volunteers aged 18-75 years, will be included. All volunteers will randomly receive either first a daily dose of 7.5 mg prednisolone for 1 week, immediately followed by a daily dose of 30 mg prednisolone for 1 week, or first a presumed clinical bioequivalent dose of 1.125 mg dexamethasone per day, immediately followed by 4.5 mg of dexamethasone per day for 1 week. After a wash-out period of 4-8 weeks, the other treatment will be applied. The primary study endpoint is the difference in free cortisol excretion in 24 hours urine. Secondary endpoints will include differences in immunological parameters, blood pressure and metabolic measurements. Ethics and dissemination This study has been approved by the Medical Ethics Committee of the University Medical Center Groningen (METC 2020.398). The results of this study will be submitted for publication in peer-reviewed journals