Intramuscular IM oxytocin international units IU was identif

Intramuscular (IM) Aminoallyl-dCTP - Cy3 (10 international units [IU]) was identified as one of 13 life-saving commodities for women and children in a 2012 United Nations (UN) Commission Report (United Nations, 2012), and was included in the World Health Organization (WHO) model list of essential medicines (World Health Organization, 2015b). Oxytocin is supplied as an aqueous solution in an ampoule and requires cold-chain storage, sterile needles with sharps disposal, and trained healthcare professionals for administration. This significantly limits access in resource-poor settings, where many women cannot attend medical facilities, their birth attendants are not allowed to administer injections, or the oxytocin cannot be refrigerated, leading to use of material of degraded quality. A review of studies assessing the quality of oxytocin ampoules for injection in low- and middle-income countries found that 58% and 22% of ampoules collected in Africa and Asia, respectively, contained less than the specified content of oxytocin, according to pharmacopoeial limits (Torloni et al., 2016). Inhaled (IH) delivery of heat-stable oxytocin could offer a practical means to deliver this medicine without the need for cold-chain storage and provide access in those resource-poor settings of greatest unmet need. The Innovation Countdown 2030 Initiative has estimated that the introduction of non-injectable, heat-stable formulations of oxytocin could prevent 146,000 maternal deaths over a period of 8years (Innovation Countdown 2030, 2015). We have developed a heat-stable dry powder formulation of oxytocin for inhalation and sought to evaluate the safety, tolerability and pharmacokinetics (PK) in this study. Subjects also received IM oxytocin 10IU for PK comparison.
Materials and Methods
Results The study was conducted between September 14, 2015 (first subject first visit) and December 16, 2015 (last subject last visit). Subjects were recruited between September 14, 2015 and October 12, 2015. A total of 26 subjects were enrolled, of whom 16 received study treatment and 15 completed the study (trial profile Fig. 2). In the pilot group, two subjects were randomized to receive IH oxytocin and one subject to IH placebo. Among the other subjects, ten subjects were randomized to receive IH oxytocin and two subjects to IH placebo. One subject was withdrawn prior to dosing, at the investigator\'s discretion, due to inability to cannulate. This subject was replaced and assigned the same randomization sequence. All 16 subjects received IM oxytocin 10IU and were included in the safety and PK populations. Baseline demographics and characteristics are shown in Table 1. The mean (range) age of the study population was 28.5 (23–35) years, and all subjects were of White/Caucasian/European heritage. A total of 13 (81%) subjects experienced at least one AE during the study. AEs occurred in four (25%) subjects who received oxytocin IM 10IU; five (33%) subjects who received IH oxytocin 50μg; three (25%) subjects who received IH oxytocin 200μg; five (42%) subjects who received IH oxytocin 400μg; six (50%) subjects who received IH oxytocin 600μg; and five (33%) subjects who received IH placebo. Overall, 45 AEs were reported, of which seven were moderate in intensity, and none were severe. The most common AE was headache, reported in six (38%) subjects. Nine AEs reported in five subjects were determined by the investigator to be drug-related. Of these drug-related AEs, headache and cough were the most common drug-related AEs (three subjects each, 19%). Drug-related AEs occurred in one (6%) subject who received oxytocin IM 10IU (headache); three (25%) subjects who received IH oxytocin 400μg (cough and headache in two subjects [17%] each); three (25%) subjects who received IH oxytocin 600μg (cough, headache and flushing in one [6%] subject each); and one (6%) subject who received IH placebo (cough). No trends or clinically important differences in AEs were noted between groups or with escalating doses. There were no discontinuations or withdrawals from the study due to AEs, and no deaths or SAEs were reported (Table 2). No trends or clinically significant abnormal spirometry, laboratory, vital signs, ECG, or telemetry findings were reported or noted during review of the data.