The pharmacokinetics and pharmacodynamics of dexamethasone following epidural SP-102 or intravenous dexamethasone sodium phosphate injection in subjects with lumbosacral radicular pain.

OBJECTIVES: To evaluate the pharmacokinetics, pharmacodynamics (PD), safety, and tolerability of epidural SP-102 (10 mg dexamethasone sodium phosphate injectable gel) compared to an intravenous injection of 10 mg dexamethasone sodium phosphate, USP (IV USP). MATERIALS AND METHODS: Subjects with lumbosacral radiculopathy received a single dose of epidural SP-102, followed by a single dose of IV USP 4 weeks later. Dexamethasone plasma levels, cortisol levels, white blood cells (WBC), and blood glucose levels were assessed. RESULTS: Twelve subjects entered and completed the study. The mean total dexamethasone exposure (AUClast and AUCinf) following SP-102 by epidural injection was equivalent to the total exposure following IV USP. A lower mean plasma Cmax (~ 50% lower) was observed following epidural administration compared to IV injection. PD parameters were similar between treatments. Adverse events (AEs) were mild, with no serious AEs or study discontinuations due to AEs. CONCLUSION: In this small study, epidural SP-102 injection was well tolerated, was not associated with greater systemic dexamethasone exposure than IV USP, and both treatments had similar PD effects on cortisol suppression, blood glucose, and WBC levels.

Repeat Epidural Injections of SP-102 (Dexamethasone Sodium Phosphate Injectable Gel) in Subjects with Lumbosacral Radiculopathy.

PURPOSE: SP-102 is a novel epidural steroid injection (ESI) formulation of 10 mg dexamethasone sodium phosphate in a viscous gel solution. Repeat dosing of ESIs is possible if required for pain relief, but with consideration of hypothalamic-pituitary-adrenal (HPA) axis suppression from prolonged systemic exposure. This phase I/II study investigated the effect of initial and repeat SP-102 injections on HPA suppression and analgesia. METHODS: Subjects with lumbosacral radiculopathy received an initial epidural SP-102 injection (T1) on day 1, followed by a repeat injection (T2) on ≥28 days later. To determine HPA suppression, area under the effect curve over 28 days and maximum change from baseline were calculated for cortisol, glucose levels, and white blood cell (WBC) count. Equivalent effect on HPA suppression of T1 relative to T2 was determined if the 90% CIs for ratios of these measures were within 80%-125%. The effect of repeat injections on leg and back pain was also assessed. RESULTS: Based on the responder analysis, all subjects had achieved a cortisol response by day 3 after initial injection and by day 2 after repeat injection. The repeat injection had similar effects on glucose levels and WBC count to the initial injection. Pain scores decreased after each injection and remained low for the 28-day follow-up, with some evidence of improved analgesic effect of the second dose compared with the first. There were no serious adverse events or discontinuations due to adverse events. CONCLUSION: The lack of cumulative effect and rapid resolution of HPA suppression following repeated SP-102 dosing suggests that consideration of HPA pharmacodynamics is not clinically relevant when making decisions regarding repeat dosing. SP-102 ESIs provided prolonged pain relief, with preliminary evidence of greater efficacy after repeat injection. A phase III trial is ongoing. CLINICAL TRIAL IDENTIFIER: ClinicalTrials.gov: NCT03613662.

Differences in the molecular profile of endometrial cancers from British White and British South Asian women.

OBJECTIVES: To identify differences in the mutational profile of endometrial tumours between British White (BW) and South Asian (BSA) women. METHODS: We analysed primary tumours from matched cohorts of British White (BW) and British South Asian (BSA) women resident in Leicestershire diagnosed with EC. Next Generation Sequencing was performed to investigate mutational differences in a panel of 10 genes previously identified as being commonly mutated in EC. The presence of somatic Mismatch Repair (MMR) gene deficiencies was determined by immunohistochemistry. RESULTS: In total, 57 tumours (27 BSA and 30 BW) were sequenced. There was no significant difference in the overall mutation frequency of the 10 genes analysed; however, numerous differences were observed between the groups. There was a positive association between PIK3CA and PTEN mutations in the BSA group, with 78% of PIK3CA-mutant tumours harbouring a PTEN mutation, whereas only 11% of PIK3CA wild-type (wt) tumours were PTEN mutant positive (p = 0.0012). In BW women, 90% of ARID1A mutant tumours had co-existent PI3K pathway mutations versus 50% of wild-type (wt) ARID1A patients (p = 0.0485). This trend was not significant in the BSA group (p = 0.66). The age at diagnosis was significantly higher in the BW group with a somatic MMR gene deficiency compared to those with no deficiency (72.8 years versus 59.6 years, p = 0.007), whereas this difference was not seen in the BSA group (64 years versus 60 years, p = 0.37). CONCLUSION: We have identified differences in the mutational profile of primary EC tumours from BW and BSA women. Further research is needed to confirm these findings and to explore their potential implications for early detection, treatment response and prognosis.

rTMS with a two-coil array: Safety and efficacy for treatment resistant major depressive disorder.

BACKGROUND: Therapeutic repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a standard of care for individuals with major depressive disorder (MDD) who do not benefit from, or are unable to tolerate, antidepressant pharmacotherapy. Depth of stimulation is limited with currently approved figure-eight coils and larger coils capable of deeper penetration may be associated with loss of stimulation focality and undesired recruitment of motor cortex. A second generation 2-coil array rTMS system was designed to target converging brain pathways for potentially deeper prefrontal cortex stimulation. METHODS: A randomized, double-blind, sham-controlled trial examined the safety and efficacy of an investigational 2-coil rTMS device. Antidepressant treatment-resistant or treatment-intolerant MDD patients (n = 92) received 20 daily rTMS treatments with coil centers positioned over left dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC). 10 Hz stimulation (maximum summated power for both coils ≤ 120% motor threshold) was delivered. Primary efficacy endpoint was change in HAMD-24 score from baseline to the conclusion of treatments. RESULTS: Data from n = 75 (per-protocol sample) showed significantly greater improvement (mean HAMD-24 change) over time for the active (n = 38) versus sham (n = 37) group after 20 sessions (F = 7.174; p = 0.008) and also at the one-month follow-up (F = 6.748; p = 0.010). Response rates were 55.3% (active) versus 32.4% (sham) (p = 0.063); remission rates were 26.3% versus 18.9% (p > 0.05). Other secondary outcomes were generally supportive. CONCLUSIONS: The results confirmed safety and acute efficacy of the 2-coil rTMS device. Despite modest sample size, primary outcome was clinically and statistically significant, and the effect size was comparable with those reported for regulatory trials with FDA-cleared devices.