Pharmacokinetics and safety of inhaled oxytocin compared with intramuscular oxytocin in women in the third stage of labour: A randomized open-label study.

AIMS: To compare pharmacokinetics (PK) and safety of heat-stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety. METHODS: A phase 1, randomized, cross-over study was undertaken in 2 UK and 1 Australian centres. Subjects were recruited into 2 groups: Group 1, women in TSL; Group 2, nonpregnant women of childbearing potential (Cohort A, combined oral contraception; Cohort B, nonhormonal contraception). Participants were randomized 1:1 to: Group 1, oxytocin 10 IU (17 µg) IM or oxytocin 240 IU (400 µg) IH immediately after delivery; Group 2, oxytocin 5 IU (8.5 µg) intravenously and oxytocin 240 IU (400 µg) IH at 2 separate dosing sessions. RESULTS: Participants were recruited between 23 November 2016 to 4 March 2019. In Group 1, 17 participants were randomized; received either IH (n = 9) or IM (n = 8) oxytocin. After IH and IM administration, most plasma oxytocin concentrations were below quantification limits (2 pg/mL). In Group 2 (n = 14), oxytocin IH concentrations remained quantifiable ≤3 h postdose. Adverse events were reported in both groups, with no deaths reported: Group 1, IH n = 3 (33%) and IM n = 2 (25%); Group 2, n = 14 (100%). CONCLUSION: Safety profiles of oxytocin IH and IM were similar. However, PK profiles could not be established for oxytocin IH or IM in women in TSL, despite using a highly sensitive and specific assay.

Quantitative decision making for investment in global health intervention trials: Case study of the NEWBORN study on emollient therapy in preterm infants in Kenya.

Background: Partners from an NGO, academia, industry and government applied a tool originating in the private sector - Quantitative Decision Making (QDM) - to rigorously assess whether to invest in testing a global health intervention. The proposed NEWBORN study was designed to assess whether topical emollient therapy with sunflower seed oil in infants with very low birthweight <1500 g in Kenya would result in a significant reduction in neonatal mortality compared to standard of care. Methods: The QDM process consisted of prior elicitation, modelling of prior distributions, and simulations to assess Probability of Success (PoS) via assurance calculations. Expert opinion was elicited on the probability that emollient therapy with sunflower seed oil will have any measurable benefit on neonatal mortality based on available evidence. The distribution of effect sizes was modelled and trial data simulated using Statistical Analysis System to obtain the overall assurance which represents the PoS for the planned study. A decision-making framework was then applied to characterise the ability of the study to meet pre-selected decision-making endpoints. Results: There was a 47% chance of a positive outcome (defined as a significant relative reduction in mortality of ≥15%), a 45% chance of a negative outcome (defined as a significant relative reduction in mortality <10%), and an 8% chance of ending in the consider zone (ie, a mortality reduction of 10 to <15%) for infants <1500 g. Conclusions: QDM is a novel tool from industry which has utility for prioritisation of investments in global health, complementing existing tools [eg, Child Health and Nutrition Research Initiative]. Results from application of QDM to the NEWBORN study suggests that it has a high probability of producing clear results. Findings encourage future formation of public-private partnerships for health.

Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders.

Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4-16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12-0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20-1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26-0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06-0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.

The relative bioavailability of 2 prototype fixed-dose combination formulations for amlodipine and rosuvastatin in healthy white and Chinese subjects.

A fixed-dose combination (FDC) may improve patient compliance and clinical outcomes in the management of cardiovascular risk in hypertensive and dyslipidemic patients. The study (NCT02075619) evaluated the bioavailability of 2 prototype FDC tablet formulations (FDC1 and FDC2) of amlodipine/rosuvastatin (10 mg/20 mg) compared with coadministered reference tablets. It was a randomized, single-dose, 3-way crossover pilot study in healthy white (n = 12) and Chinese (n = 12) adults. Three treatments (FDC1, FDC2, and reference) were administered after fasting with a washout period of 12-17 days. The pharmacokinetics of amlodipine and rosuvastatin were studied for all subjects (pooled) and by ethnicity. Safety and tolerability were also evaluated. Both FDCs met the bioequivalence criteria (90% confidence intervals falling within the range of 0.80-1.25) for AUC0-t and Cmax for amlodipine and rosuvastatin. Intrasubject variability (AUC0-t and Cmax ) was in the region of 23%-25% for rosuvastatin and 7%-10% for amlodipine. The FDC formulations demonstrated similar bioavailability to coadministered commercially available amlodipine and rosuvastatin. All treatments were generally well tolerated.