A Single Center, Open-Labeled Trial To Investigate The Pharmacokinetics of Insulin Detemir in Healthy Taiwanese Subjects

Backgrounds: Insulin detemir(nn304) is a long-acting insulin analogue reported to provide more predictable blood glucose level throughout the day, leading to a lower within-subject variability compared to NPH insulin. Pharmacokinetic profiles of insulin detemir had not been investigated in Taiwanese. This study was to determine whether there is a differencebetween Taiwanese subjects in pharmacokinetic profile of insulin detemir compared to Caucasian subjects.Methods: Pharmacokinetic profile of insulin detemir was measured in twenty male Taiwaneses(nn304-3023). Eligible subjects were given insulin detemir as a single dose subcutaneous injection at 0.5 U/kg body weight in the mid-thigh using NovoPen® 3 device. 32-hour serum insulin detemir concentrations were measured. Hypoglycemia and adverse events were recorded. The results were compared to data obtained from a previous trial inCaucasian subjects (nn304-1451).Results: There was no significant difference between Taiwanese (nn304-3023) and Caucasian(nn304-1451) in the primary endpoint, AUC(0–∝), and the secondary endpoints, AUC(0–24h), and t1/2. However, the secondary endpoints, Cmax was 40% higher, tmax was shorter(270.0 vs. 420.0 min) and AUC(0–5h) was 2-fold more in Taiwanese. When only male subjects were included in the comparator trial (nn304-1451), the t1/2 was significantly shorter in Taiwanese(348 min vs 404 min). There was no significant difference in the mean blood glucose concentrations between Taiwanese and Caucasian subjects. A single episode of hypoglycemia(53 mg/dL) was reported in a 24-year-old male approximately 2.5 hours after the administration of insulin detemir. He was able to treat himself for the episode.Conclusion: In this pharmacokinetic evaluation of a single dose administration of insulin detemir in Taiwanese male subjects, the AUC(0–∝), and AUC(0–24h) were not different from that of Caucasians in the comparator trial. However, insulin detemir appeared to be more rapidly absorbed in Taiwanese males. Further studies are warranted to elucidate its pharmacodynamic response and mechanisms. Finally, there was no clinically relevant safety concern raised in this study. (Funded by research grant from Novo Nordisk, Taiwan; first registration date 22/12/2011 ClinicalTrials.gov number, NCT01497587.

Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor

Objective The aim of this study is to assess the efficacy and safety of retosiban in spontaneous preterm labor (sPTL). Study Design Two multicenter, randomized, and double-blind trials compared retosiban with placebo and retosiban with atosiban in women with a singleton pregnancy and intact membranes in sPTL at 24 to 336/7 weeks' gestation. Coprimary endpoints in the placebo-controlled trial were time to delivery (TTD) or treatment failure (whichever occurred first) and neonatal composite morbidity and mortality. The primary endpoint of the atosiban comparator trial was TTD. Results The trials were terminated early because of slow recruitment. The placebo-controlled trial enrolled 23 participants (February 2016–July 2017; 2.6% of target);the atosiban-comparator trial enrolled 97 (March 2015–August 2017; 29% of target). Baseline participant characteristics were similar between treatments. In the placebo-controlled trial, mean gestational ages at randomization were 30.8 (retosiban, n = 10) and 30.5 weeks (placebo, n = 13), and mean times to delivery/treatment failure were 18.9 days (retosiban) and 11.1 days (placebo). Two and four neonates in the retosiban and placebo groups, respectively, had ≥1 component of the neonatal composite endpoint. In the atosiban-comparator trial, mean gestational age at randomization was 31.5 weeks (for both retosiban, n = 47, and atosiban, n = 50), and adjusted mean TTDs were 32.51 days (retosiban) and 33.71 days (atosiban; p > 0.05). Adverse events were no more common with retosiban than placebo or atosiban. Conclusion Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL.