Twice weekly dosing with Sebelipase alfa (Kanuma®) rescues severely ill infants with Wolman disease.

BACKGROUND: Sebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3-5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials. METHODS: We recruited 3 patients receiving Sebelipase alfa 5 mg/kg twice weekly. We measured LAL activity in leukocytes and plasma oxysterol concentration in two patients and LAL activity in fibroblasts in one patient. Clinical follow up was also assessed. RESULTS: Analyses of LAL activity and oxysterols demonstrate that there is short-lived enzyme activity post-dosing which is associated with the release of stored lipids. Clinical data demonstrate that 5 mg/kg twice weekly dosing is well tolerated and effective. CONCLUSION: 5 mg/kg twice weekly dosing with Sebelipase alfa rescues severely ill infants with WD by increasing substrate clearance. There is biologically relevant lipid accumulation in the 'trough' periods before the next dosing, even with this intensive regimen.

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies.

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.

Changes in practice and management of placenta accreta spectrum disorder: A 20-year retrospective cohort study.

BACKGROUND: Placenta accreta spectrum disorder is an increasingly prevalent cause of maternal morbidity in developed countries. AIMS: This study aimed to review the management and outcomes of cases of placenta accreta spectrum, and compare blood loss and blood transfusion rates, over time after an institutional change in planned primary surgeon from gynaecological oncologists to experienced obstetricians. METHODS: This retrospective cohort study included all cases of suspected or confirmed placenta accreta spectrum disorder (PASD) between 1999 and 2021 at Monash Health. Data were collected by reviewing medical records to obtain baseline characteristics, details of surgical planning and management and major maternal morbidity outcomes over a 20-year period. The primary surgical lead was recorded as either gynaecological oncologist or experienced obstetricians. The primary outcomes were estimated maternal blood loss and number of units of blood transfused. RESULTS: A total of 88 patients were identified: 43 between 1999 and 2015 where gynaecological oncologists were the primary surgeon in 79% of cases and 45 between 2016 and 2021 where experienced obstetricians were the primary surgeon in 73.3% of cases. There was no statistically significant difference in the estimated blood loss between the two time periods (median: 2000 vs 2500 mL, P = 0.669). Hysterectomy rates were significantly reduced in the second time period, from 100 to 73.3%, P < 0.001. CONCLUSION: Management of cases of PASDs has improved over time with changes in antenatal diagnosis and perioperative management, and management by experienced obstetricians has similar maternal outcomes compared to those whose management includes the presence of gynaecological oncologists.

Development and validation of bioanalytical methods to support investigations of AZD9496 in the clinic.

Aim: AZD9496 is an oral nonsteroidal, potent and selective antagonist and degrader of ER-α. Two major active metabolites (M3 and M5 as diastereomers) were identified in humans. Methodology/results: Multianalyte, sensitive LC-MS/MS method in human plasma was developed and validated that overcame the challenges encountered. The method demonstrated acceptable precision, accuracy and selectivity for AZD9496 and two major metabolites. Incurred sample reanalysis was acceptable from evaluation in clinical studies, indicating adequate reproducibility. In addition, a urine method for AZD9496 was also developed and validated. Conclusion: Robust and sensitive LC-MS/MS assays for the quantitation of AZD9496 and two diastereomeric metabolites in human plasma and AZD9496 in human urine have been validated and successfully applied to clinical studies.

Bioequivalence of Dapagliflozin/Metformin Extended-release Fixed-combination Drug Product and Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Russian Subjects.

PURPOSE: Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation. METHODS: Healthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center. Pharmacokinetic parameters (AUC0-t, Cmax, and Cmax/AUC0-t) were used to assess bioequivalence of dapagliflozin/metformin XR (10/1000 mg) FCDP to the individual component tablets (dapagliflozin [10 mg] plus metformin XR [2 × 500 mg]) under standard fed conditions. Safety and tolerability were also assessed. FINDINGS: Forty healthy subjects were included (47.5% male; mean age, 30 years; and mean body mass index, 24.2 kg/m2). Dapagliflozin and metformin XR in the FCDP were bioequivalent to the individual component tablets marketed in the Russian Federation, with the 90% CIs of the geometric least-squares mean ratios for all key pharmacokinetic parameters being contained within the 80% to 125% bioequivalence limits. Both FCDP and the individual component formulations were well tolerated, with no serious adverse events. IMPLICATIONS: Bioequivalence of dapagliflozin/metformin XR FCDP and the individual components was established without any new safety concerns, presenting a safe alternative for patients currently receiving regimens including each component individually. ClinicalTrials.gov identifier: NCT02722239.

AstraZeneca and Covance Laboratories Clinical Bioanalysis Alliance: an evolutionary outsourcing model.

The AstraZeneca and Covance Laboratories Clinical Bioanalysis Alliance (CBioA) was launched in 2011 after a period of global economic recession. In this challenging environment, AstraZeneca elected to move to a full and centralized outsourcing model that could optimize the number of people supporting bioanalytical work and reduce the analytical cost. This paper describes the key aspects of CBioA, the innovative operational model implemented, and our ways of ensuring this was much more than simply a cost reduction exercise. As we have recently passed the first 5-year cycle, this paper also summarizes some of the concluding benefits, wins and lessons learned, and how we now plan to extend and develop the relationship even further moving into a new clinical laboratory partnership.

Assessing the quality of bereavement care after perinatal death: development and piloting of a questionnaire to assess parents' experiences.

Understanding parents' experience of care is essential to develop high-quality perinatal bereavement services. This study aimed at developing a questionnaire to identify parents' needs and record their experience of care. The patient experience questionnaire was developed by professionals and parents, and piloted in a tertiary maternity unit. Responses were received from 58 parents. Sensitivity and kindness of staff and time spent with their baby were ranked as 'very important' by 95% of parents. Care in these areas largely met their needs (90%), although 5% of respondents stated that partners could have been more involved. Between 8% and 15% of respondents did not feel that language used at the diagnosis of fetal death was sensitive, clear and unambiguous. Parents did not always receive written information about their care (5%) or post-mortem (13%). Analysis of bereaved parents' responses identified areas for improvement including greater involvement of partners and a need for timely information. Impact statement What is already known on this subject?: Good quality bereavement care after perinatal death reduces the negative emotional, psychological and social effects for parents. Description of parents' experiences is a potential means to improve the quality of perinatal bereavement care. What do the results of this study add?: Parents' needs and experiences of care after perinatal death were recorded using a patient-experience questionnaire designed by a multi-professional team and parents. Staff behaviour, particularly sensitivity and kindness was highly valued by parents. Giving both verbal and written information could be improved. Training is needed for professionals, particularly those who come into contact with bereaved parents less frequently. What are the implications of these findings for clinical practice and/or further research?: Description of parents' priorities and views can be used to identify areas for improvement in perinatal bereavement care. Parents' views should be regularly sought and used to develop local services in an iterative process.

Educating about female genital mutilation.

Female genital mutilation (FGM) is illegal in the UK but nevertheless practised in some immigrant communities. Effective educational approaches are required to inform policy and to direct resources, often in the voluntary sector. The opinions in this article arise from discussions with professionals and members of FGM-practising communities. We highlight the importance of sharing experiences and expertise across health and social care professionals as well as working in partnership with culturally sensitive Non-Governmental Organisations. Enlisting the support of men and religious leaders is crucial to breaking down barriers in male-dominated communities and dispelling myths about FGM being a 'requirement' of faith.

Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End-Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects.

Two phase I open-label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of selumetinib in subjects with end-stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of selumetinib 50 mg; those with ESRD received selumetinib before and after dialysis (with a between-treatment washout period of ≥7 days). In the hepatic impairment study, subjects received varying single doses of selumetinib (20-50 mg) depending on liver dysfunction (mild, moderate, or severe as per Child-Pugh classification). PK, safety, and tolerability data were collected from both studies. Overall, 24 subjects were included in the renal impairment study (ESRD, N = 12; healthy subjects, N = 12). Selumetinib exposure (AUC and Cmax ) was not increased in the ESRD group vs healthy subjects. Selumetinib exposure was lower when selumetinib was dosed before vs after dialysis, although individual exposure was variable. Overall, 32 subjects were included in the hepatic impairment study (mild, moderate, and severe impairment, N = 8 per group; healthy subjects, N = 8). Generally, dose-normalized total selumetinib exposure was increased by 25% to 59% in subjects with moderate and severe hepatic impairment compared with healthy subjects. Increasing Child-Pugh score, decreasing serum albumin, and increasing prothrombin time correlated with increasing unbound selumetinib exposure. In both studies, selumetinib was well tolerated with no new safety concerns. These studies will inform dose adjustment considerations in patients.

Evaluation of the Effect of Selumetinib on Cardiac Repolarization: A Randomized, Placebo- and Positive-controlled Crossover QT/QTc Study in Healthy Subjects.

PURPOSE: Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective allosteric mitogen-activated protein kinase 1/2 inhibitor with a short t1/2. The purpose of this study was to characterize the effect of selumetinib on cardiac repolarization and a potential exposure-QT effect relationship. METHODS: A double-blind (selumetinib), randomized, 3-period crossover study was conducted to assess the effects of a single oral dose of selumetinib (75 mg) on the QTc interval compared with placebo, using moxifloxacin as an open-label positive control, in healthy male subjects aged 18 to 45 years. QT intervals were evaluated by using the Fridericia formula (QTcF) and the Bazett formula. Further analysis was conducted by using nonlinear mixed effects modeling to characterize any relationship between selumetinib exposure and QTc and was used to predict the effect if selumetinib 150 mg was administered. All adverse events were characterized and recorded. FINDINGS: A total of 54 healthy male subjects were enrolled, and 48 completed all treatments. Mean age was 27 years; four subjects were of Hispanic or Latino ethnicity, and 53.7% were White and 46.3% were Black. The BMI of subjects ranged from 19.4 to 29.6 kg/m2. After a single oral dose of selumetinib 75 mg, the highest upper bound of the 2-sided 90% CI for placebo-corrected, baseline-adjusted QTcF (ΔΔQTcF) over the 24-hour postdose measurement interval was 2.5 milliseconds, which was well below the 10-millisecond upper bound for concluding no effect. The relationship between ΔΔQTcF and selumetinib concentrations was adequately described by using a nonlinear mixed effect model. The mean estimated ∆∆QTcF interval prolongation based on the geometric mean Cmax of 75 mg selumetinib was 2.38 milliseconds (90% CI, 1.25 to 3.52), which was in good agreement with the statistical analysis results. The model also predicted mean ∆∆QTcF interval prolongations of 4.70 milliseconds (90% CI, 2.46 to 6.95) after a single supratherapeutic dose of selumetinib 150 mg, indicating the upper bound of 2-sided 90% CIs for ΔΔQTcF are predicted to be <10 milliseconds. Selumetinib, administered as a single 75 mg oral dose, was generally safe and well tolerated. IMPLICATIONS: Selumetinib 75 mg did not cause any QT/QTc interval prolongation in these healthy subjects, and selumetinib is not expected to have a clinically relevant effect on cardiac repolarization in patients at the anticipated therapeutic dose of 75 mg. The model also demonstrated the low potential for any QTc effects of selumetinib at doses higher than the standard therapeutic dose.

Determination of selumetinib, N-desmethyl selumetinib and selumetinib amide in human biological samples by LC-MS/MS.

AIM: Selumetinib is an inhibitor of MEK1/2 in Phase III development that has activity in multiple tumor types. Validated bioanalytical methods were required to quantitate selumetinib and its N-desmethyl and amide metabolites in a variety of human biological matrices. Methodology & results: LC-MS/MS assays were developed and validated that demonstrated acceptable precision, accuracy and selectivity for selumetinib and the two metabolites in human plasma, urine, blood dialysate and plasma ultrafiltrate. Incurred sample re-analysis was acceptable and issues observed in plasma with the amide metabolite, due to potential instability, were addressed. CONCLUSION: Robust and sensitive LC-MS/MS assays for the quantification of selumetinib and two of its metabolites were validated in human biological matrices and are being used to support the clinical development program.

Quantitative determination of alkylated quaternary amines and their n-hydroxylated metabolites in an enzyme incubation matrix by liquid chromatography electrospray ionization mass spectrometry.

A simple, rapid and sensitive reversed-phase liquid chromatography method coupled to electrospray ionization mass spectrometry has been developed for studying the in vitro metabolism of the long-chain quaternary ammonium compounds dodecyltrimethylamine, tetradecyltrimethylamine and hexadecyltrimethylamine. Samples were prepared from the biological matrix by a simple protein precipitation stage. The separation was performed using a BDS Hypersil C8 3 microm particle size (100 x 3 mm i.d.) column with a fast gradient separation (60% B to 100% B) using a mobile phase of 10 mm aqueous ammonium acetate (pH 4.0, with 0.06% triethylamine; (A)-acetonitrile (B) at 0.7 mL min(-1). To minimize contamination of the MS source a switching value was used to divert the solvent front to waste. Decylammonium bromide was used as the internal standard and analytes were identified and quantified by positive ion electrospray selected ion monitoring of their intact molecular cations. The assay had a limit of quantitation of 0.25 microm (6.25 pmol on column) and was linear over the range 0.25--100 microm assay concentration for this series of long-chain quaternary amines. The precision of intra- and inter-day assays was better than 19% and the accuracy was between 93 and 109%. The method was used to assess the in vitro metabolism of the quaternary amines by wild-type cytochrome P450 enzyme CYP 4 A 1 and mutants in an artifical membrane system.

A gas chromatography-mass spectrometry method for the measurement of fatty acid omega and omega(-1) hydroxylation kinetics by CYP4A1 using an artificial membrane system.

A gas chromatography-mass spectrometry assay method for the analysis of lauric, myristic, and palmitic acids and their omega and omega(-1) hydroxylated metabolites from in vitro incubations of cytochrome P450 CYP4A1, involving solid-phase extraction and trimethysilyl derivatization, was developed. The assay was linear, precise, and accurate over the range 0.5 to 50microM for all the analytes. It has the advantages of a more rapid analysis time, an improved sensitivity, and a wider range of analytes compared with other methods. An artificial membrane system was optimized for application to purified CYP4A1 enzyme by investigating the molar ratios of cytochrome b(5) and cytochrome P450 reductase present in the incubation mixture. Using this method, the kinetics of omega and omega(-1) oxidation of lauric, myristic, and palmitic acids by CYP4A enzymes were measured and compared in rat liver microsomes and an artificial membrane system.