INTRANASAL ADMINISTRATION OF MEROTOCIN FOR IMPROVING LACTATION

Abstract

The present disclosure relates to the use of a novel dosage form of merotocin in improving lactation in a female in need thereof. The disclosure particularly provides the use of a composition suitable for intranasal administration that provides a dose of merotocin greater than 100 μg or substantially about 400 μg to the female. The disclosure encompasses methods of treatment as well as compositions for use in such methods.

Claims

1-26. (canceled)

27. A method of treating or preventing compromised lactation conditions or improving lactation in a female in need thereof, comprising intranasally administering to the female a dose of merotocin of at least 100 μg.

28. The method of claim 27, comprising intranasally administering a dose of merotocin selected from at least 200 μg, at least 300 μg, and at least 400 μg.

29. The method of claim 27, wherein the female is a preterm female.

30. The method of claim 27, comprising administering the dose of merotocin by way of two or more sub-doses.

31. The method of claim 27, comprising administering the dose of merotocin by way of multiple sprays, wherein the total dose administered is divided between each spray to provide multiple sub-doses of merotocin.

32. The method of claim 31, wherein the total dose is 400 μg of merotocin and is delivered by way of two or more sub-doses.

33. The method of claim 27, comprising administering the merotocin at a time selected from up to 5 minutes, up to 10 minutes, up to 15 minutes, up to 20 minutes, and up to 30 minutes, each before a milk expression session or before a breast feed.

34. The method of claim 27, comprising administering the merotocin according to a regimen selected from once per day, 2 to 10 times per day, 5 to 10 times per day, and 6 and 8 times per day.

35. The method of claim 27, comprising administering the merotocin to the female according to a regimen selected from about 1 to 20 minutes, 10 to 20 minutes, 12 to 15 minutes, 2 to 15 minutes, and 5 to 10 minutes, each before milk expression is desired or intended, and for a number of times per day selected from 5 to 10 times and 6 to 8.

36. The method of claim 27, comprising administering the merotocin to the female each time milk expression is desired or intended.

37. The method of claim 27, comprising administering the merotocin to the female at intervals selected from 1 to 6 hour intervals and 2 to 5 hour intervals.

38. The method of claim 27, comprising administering the merotocin to the female at a time selected from within 12 hours of delivery, within 24 hours of delivery, within 48 hours of delivery, and within 72 hours of delivery.

39. The method of claim 27, comprising administering the merotocin to the female following an attempt at initial milk expression within 12 hours of delivery.

40. The method of claim 27, comprising administering the merotocin to the female after milk expression has been attempted multiple times following delivery.

41. The method of claim 27, wherein the amount of merotocin present in milk expressed from the female following administration of the merotocin is at a level selected from minimal, negligible, and below the lower limit of quantification (LLOQ).

42. The method of claim 41, wherein the concentration of merotocin in milk expressed from the female is selected from less than 50 μg/mL and less than 25 μg/mL.

43. The method of claim 27, wherein the method is effective for achieving one or more of the following outcomes: (i) increasing milk production; (ii) facilitating, stimulating and/or promoting the onset of lactation; (iii) facilitating and/or promoting the maintenance of lactation; and (iv) increasing the likelihood of lactation.

44. The method of claim 27, wherein the female produces a greater volume of milk during a period following administration of the merotocin selected from 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 17 days, and 20 days.

45. The method of claim 27, wherein the female produces a greater volume of milk during a period following initiation of a treatment regimen comprising the merotocin selected from 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 17 days, and 20 days.

46. The method of claim 27, wherein the female produces for the first time a daily volume of milk selected from greater than or equal to 500 mL and greater than or equal to 750 mL, on any or all of days 1, 2, 3, 4, 5, 10, and 14 following administration of the merotocin.

47. The method of claim 27, wherein the merotocin is administered in an aqueous preparation of merotocin.

48. The method of claim 47, wherein the aqueous preparation of merotocin has one or more of the following features: (i) a citrate/phosphate buffer; (ii) a concentration of merotocin between 0.05 mg/mL to 2 mg/mL; (iii) sodium chloride (NaCl); and (iv) a pH of from 5.2 to 6.

Description

DETAILED DESCRIPTION

[0088] The present disclosure will now be further described with reference to the following data:

[0089] FIG. 1 shows merotocin plasma concentration (mean) after single intranasal administration of 5 μg, 15 μg, 50 rig, 100 μg, 200 μg, 300 μg and 400 μg merotocin and a placebo.

[0090] FIG. 2 shows merotocin plasma concentration (mean) after multiple intranasal administrations of 50 μg, 200 μg and 400 μg merotocin and a placebo (16 doses over 49 hours).

[0091] FIG. 3 shows the effect of merotocin on daily milk yield in ewes with induced pre-term delivery. Merotocin (FE 202767) and oxytocin were administered as intramuscular bolus doses. Data are presented as mean±S.E.M.

CLINICAL PHARMACOLOGY TRIALS

[0092] A total of 104 healthy female volunteers, of whom 84 were exposed to merotocin, have been included in two Phase 1 trials: one was a single ascending-dose and multiple ascending dose trial; the other was a milk-transfer trial.

[0093] An overview of the trial designs, dose regimens, study populations and key results is presented in Table 1.

TABLE-US-00001 TABLE 1 Overview of the clinical studies Investigational Study drug code and Study Dosage Study Key objective design regimen/route population results Trial Double-blind 5-400 μg Healthy No safety 000015 (partially), merotocin women concerns First in placebo single dose i.n. N = 86, tmax ≈ 15 min, human controlled, 50, 200, 400 μg 66 active t½ ≈ 30 min sequential merotocin treatment, after i.n. dose every 3 hours 20 placebo administration escalation, for 45 hours i.n. within 20 μg i.v., dose 400 μg i.n. randomised merotocin cross-over Trial Open label 5 and 20 μg i.v. Healthy No milk 000028 women transfer Milk 5 μg: detectable transfer N = 6 No safety 20 μg concerns N = 12

[0094] Trial 000015 (Safety and Pharmacokinetics after Single and Multiple Intranasal and Single Intravenous Doses in Healthy Women)

[0095] The first clinical trial in human, Trial 000015, was a double-blind, placebo-controlled, single dose, within dose panel randomised, sequential dose escalating study. The trial was divided into three parts:

[0096] Part 1. Ascending single i.n. doses. There were 7 dose panels with 8 healthy women in each dose panel (6 active, 2 placebo). The doses investigated were 5 μg, 15 μg, 50 μg, 100 μg, 200 μg, 300 μg, and 400 μg.

[0097] The subjects in Part 1 of the trial received a single intranasal administration of either FE 202767 or placebo. Seven dose levels were investigated: 5, 15, 50, 100, 200, 300, and 400 μg. Each of the doses were administered as a nasal spray based on one or multiple puffs per nostril.

[0098] Part 2. Ascending multiple i.n. doses. There were 3 dose panels with 8 healthy women in each dose panel (6 active, 2 placebo). The dosing schedule was every 3 hours for 45 hours, i.e. 16 doses in all. The doses investigated were 50 μg, 200 μg, and 400 μg.

[0099] The subjects in Part 2 of the trial received up to 16 intranasal administrations 3 hours apart of either FE 202767 or placebo. Three dose levels were investigated: the first dose was 50 μg, the second dose was 200 μg (intermediate between the first dose and the maximal tolerated dose in Part 1), and the highest dose was 400 μg (the maximal dose in Part 1).

[0100] Part 3. Open-label cross-over single i.n. and single i.v. dose in 6 healthy women. The doses investigated were 20 μg as an i.v. infusion over 25 minutes, and 400 μg as a single i.n. dose.

[0101] The subjects in Part 3 of the trial received a single intranasal administration and a single intravenous infusion of FE 202767 with a wash-out period in between. The intranasal dose was 400 μg (4×140 μl, the same as the highest dose in Part 1), the i.v. dose was 20 μg infused in 2 mL over 25 minutes.

[0102] The intravenous dose and infusion rate were determined from the intranasal pharmacokinetic data in Part 1. The infusion was performed so that the plasma concentration of FE 202767 resembled the absorption pattern of the corresponding intranasal administration and adjusted in order not to exceed the maximum plasma concentration of, or exposure to, FE 202767 in Part 1. The duration of the infusion was chosen to 25 minutes, which was not less than the t.sub.max observed in Part 1 of the trial, and the dose, 20 μg, based on an assumed bioavailability of 5%.

[0103] The main objectives were to assess the safety, tolerability, and pharmacokinetics of merotocin, and to estimate the highest tolerable dose.

[0104] Trial 000028 (Milk Transfer)

[0105] Healthy women received 5 or 20 μg merotocin i.v. shortly after delivery (Part A) or 20 μg merotocin i.v. when lactation was established (Part B). Milk was expressed by pumping at 15 minutes, 3 hours, 6 hours, 9 hours, 12 hours, 18 hours and 18-24 hours after start of infusion and analysed for merotocin and metabolites.

[0106] Identity of Investigational Medicinal Product

[0107] FE 202767 was provided as an isotonic citrate/phosphate buffered solution of pH 5.5 in water in vials containing an extractable volume of 0.9 mL (Table 2). The concentration of FE 202767 was 0.7 mg/mL, to be used appropriately diluted with buffer or, for Part 3, NaCl for injection. The buffer used for FE 202767 was used as placebo in this study.

TABLE-US-00002 TABLE 2 Composition Component Amount per mL FE 202767  0.7 mg/mL Sodium phosphate dibasic dihydrate 3.24 mg/mL Citric acid monohydrate 1.43 mg/mL Sodium chloride 7.50 mg/mL NaOH/HCl To pH 5.5

[0108] Pharmacokinetics

[0109] Single Intranasal Dose

[0110] The mean plasma concentration curves are illustrated in FIG. 1 and the pharmacokinetic parameters in healthy women administered a single intranasal (i.n.) dose are presented in Table 3. For the doses 5-50 μg the plasma concentrations above the LLOQ were too few for meaningful calculations of AUC and t.sub.1/2, as was the case for AUC and t1/2 with 100 μg. The t.sub.max and terminal half-lives were similar in all dose groups, with a t.sub.max of 12-15 minutes and a t1/2 of 25-35 minutes. Increasing dose increased the exposure by means of AUC and C.sub.max in a close to dose proportional manner, albeit with substantial inter-individual variation.

TABLE-US-00003 TABLE 3 Pharmacokinetic parameters of merotocin after single intranasal administration (Trial 000015) 100 μg 200 μg 300 μg 400 μg N = 6 N = 6 N = 6 N = 6 AUC.sub.t Geom. mean (% CV) ND 35.7 (59%) 77.8 (72%) 88.6 (89%) [h*pg/mL] Median 52.5  94.3  119    C.sub.max Geom. mean (% CV)  37.9 (106) 84.1 (43) 143 (41) 153 (68) [pg/mL] Median 32.2  99.9  148    199    t.sub.max Mean (SD) 0.25 (0.09) 0.25 (0.09) 0.20 (0.07) 0.22 (0.08) [h] Median 0.25 0.25 0.17 0.17 t.sub.1/2 Harmonic mean ND 0.43 0.43 0.56 [h] Median 0.39 0.48 0.55 N = number of subjects; ND = not determined

[0111] Multiple Intranasal Doses

[0112] The mean plasma concentration curves are illustrated in FIG. 2, and the pharmacokinetic parameters in healthy women administered multiple i.n. doses are presented in Table 4. For the 50 μg dose, the plasma concentrations above the LLOQ were too few for meaningful calculations of AUC and t1/2. The t.sub.max and t.sub.1/2 were similar in all dose groups, with a t.sub.max of 12-15 minutes and a t.sub.1/2 of 25-35 minutes, consistent with the observations after single dose administration.

[0113] There were no indications of relevant accumulation during the 16 administrations over 48 hours, as demonstrated by the pre-dose concentrations falling constantly below the LLOQ. The AUC and C.sub.max after the last 200 μg dose were unexpectedly high, the pre-dose sample did not indicate that this was due to accumulation.

TABLE-US-00004 TABLE 4 Pharmacokinetic parameters of merotocin after multiple intranasal administrations (Trial 000015) Dose 50 μg 200 μg 400 μg No. N = 6 N = 6 N = 6 AUC.sub.t Geom. mean (% CV) 1 ND 80.4 (33%) 77.1 (104%) [h*pg/mL] Median 87.6  70.2  Geom. mean (% CV) 2 ND 75.2 (28%) 88.8 (75%) Median 70.6  142    Geom. mean (% CV) 16 ND 160 (61%) 112 (71%) Median 147    112    C.sub.max Geom. mean (% CV) 1 27.5 (52%) 124 (27%) 156 (114%) [pg/mL] Median 30.7 125    136    Geom. mean (% CV) 2 26.0 (89%) 115 (25%) 169 (107%) Median 30.2 118    195    Geom. mean (% CV) 16 23.6 (93%) 218 (54%) 180 (56%) Median 26.6 225    192    t.sub.max Mean (SD) 1 0.23 (0.09) 0.18 (0.08) 0.11 (.05) [h] Median  0.17 0.17 0.08 Mean (SD) 2 0.34 (0.24) 0.28 (0.08) 0.16 (0.09) Median  0.25 0.33 0.15 Mean (SD) 16 0.34 (0.24) 0.31 (0.12) 0.30 (0.21) Median  0.25 0.33 0.33 t.sub.1/2 Harmonic mean 1 ND 0 43 0.35 [h] Median 0.43 0.43 Harmonic mean 2 ND 0.44 0.39 Median 0.48 0.48 Harmonic mean 16 NF 0.51 0.56 Median 0.47 0.65 N = number of subjects; ND = not determined

[0114] Simile Intranasal and Intravenous Cross-Over Doses

[0115] The pharmacokinetic parameters in healthy women administered a single intravenous (i.v.) dose of 20 μg infused over 25 minutes and a single 400 μg i.n. dose are presented in Table 5. The pharmacokinetic parameters after the i.n. administration were similar to the single dose pharmacokinetic parameters found in the preceding part of the trial, both with respect to exposure and C.sub.max, and to t.sub.max and t.sub.1/2. However, the t.sub.1/2 after i.v. administration was considerably shorter compared to i.n. administration, indicating that the absorption was the rate limiting step for the kinetics of merotocin after i.n. administration. The bioavailability was calculated to 3.7% (range 2.2-6.2%), similar to what is found with other peptides of comparable size.

TABLE-US-00005 TABLE 5 Pharmacokinetic parameters of merotocin after a single intranasal administration and a single intravenous infusion (Trial 000015) 400 μg i.n. 20 μg i.v. N = 6 N = 6 AUC.sub.t Geom. mean (% CV) 83.0 (38%) 146 (25%) [h*pg/mL] Median 72.8  150    C.sub.max Geom. mean (% CV) 151 (43%) 463 (11) [pg/mL] Median 156    463    t.sub.max Mean (SD) 0.11 (0.05) 0.36 (0.05) [h] Median 0.08 0.33 t.sub.1/2 Harmonic mean 0.43 0.17 [h] Median 0.61 0.18 CL Mean (SD) — 134 (37) [L/h] Median 128    V.sub.z Mean (SD) — 37.5 (22.6) [L] Median 31.2  F Mean (SD) 3.7 (1.5) — [%] Median 3.4  N = number of subjects

[0116] Metabolism

[0117] Plasma and urine samples from Trial 000015 were investigated for the presence of metabolites of merotocin. No metabolites of merotocin could be detected in the plasma or urine samples analysed.

[0118] Milk Transfer

[0119] None of the milk samples contained merotocin concentration above the LLOQ, 25 μg/mL. The mean total amount of milk collected was about 500-700 mL over 24 hours in the various groups studied.

[0120] Clinical Safety—Adverse Events

[0121] Single Dose Administration

[0122] In Trial 000015, 48 treatment-emergent AEs (TEAEs) were reported by 30 (44%) of the 68 subjects (62 unique subjects) administered a single dose of merotocin or placebo (subjects receiving both i.v. and i.n. administration are regarded as separate treatments and are counted in both groups) (Table 6). All TEAEs except those in the 50 μg or 100 μg groups were assessed by investigators to be related to IMP (i.e. adverse drug reactions (ADRs)). The most frequently reported TEAEs were headache (reported by 19 subjects and in all treatment groups), flushing or hot flush (reported by 6 subjects, 4 of whom in the 20 μg i.v. group), and dizziness (reported by 4 subjects, 2 of whom were in the placebo group). Dry mouth was reported in 3 subjects receiving merotocin. Tachycardia or sinus tachycardia were reported in 3 subjects in the 20 μg i.v. group. Other TEAEs were reported by only 1 or 2 subjects.

[0123] All adverse events after single dose administration were regarded as mild.

TABLE-US-00006 TABLE 6 Treatment-emergent adverse events after single administration in Trial 000015. 5 μg i.n. 15 μg i.n. 50 μg i.n. 100 μg i.n. 200 μg in. 300 μg i.n. 400 μg i.n. 20 μg i.v. Placebo System Organ Class N = 6 N = 6 N = 6 N = 6 N = 6 N = 6 N = 12 N = 6 N = 14 Preferred Term n (%) E n (%) E n (%) E n (%) E n (%) E n (%) E n (%) E n (%) E n (%) E Any AE 3 (50) 5 2 (33) 2 2 (33) 3 1 (17) 1 4 (67) 7 1 (17) 2 6 (50) 7  6 (100) 11  5 (36) 10 Cardiac disorders Sinus 1 (17) 1 tachycardia Tachycardia 2 (33) 2 Nervous system disorders Headache 2 (33) 2 1 (17) 1 2 (33) 3 1 (17) 1 3 (50) 3 1 (17) 1 4 (33) 4 2 (33) 2  3 (21) 3 Dizziness 1 (8) 1  1 (17) 1  2 (14) 2 Dysgeusia 2 (33) 2 Gastrointestinal disorders Dry mouth 2 (33) 2 1 (17) 1 Nausea 1 (17) 1 1 (7) 1 Reproductive system and breast disorders Breast 1 (17) 1 1 (7) 1 tenderness Breast 1 (7) 1 discharge Skin and subcutaneous tissue disorders Hyperhidrosis 1 (17) 1 1 (7) 2 Ear and labyrinth disorders Vertigo 1 (17) 1 Respiratory, thoracic, and mediastinal disorders Intranasal 1 (17) 1 hypoasthesia Vascular disorders Flushing 1 (17) 1 1 (8) 1  3 (50) 3 Hot flush 1 (17) 1 AE = adverse event, N = Number of subjects in the Safety Analysis Set, n = Number of subjects with AE, % = Proportion of subjects in the analysis having an AE, E = Number of AEs.

[0124] Treatment-emergent AEs in early postpartum women participating in the milk transfer study (Trial 000028) and receiving a single dose of merotocin by i.v. administration are summarized in Table 7. No severe or serious AE occurred, and no AE lead to death or discontinuation from the study. The most frequently reported TEAEs were uterine spasm (in both the 5 μg and 20 μg dose groups), breast engorgement (in the 20 μg dose group), and headache (in the 5 μg dose group). All TEAEs in the trial were of mild intensity, with the exception of 1 event of uterine spasm of moderate intensity reported in the 5 μg dose group in Part A. All TEAEs in the trial, except 1 event of muscle spasm reported in the 5 μg dose group in Part A, were regarded as ADRs by investigators.

TABLE-US-00007 TABLE 7 Treatment-emergent adverse events by system organ class and preferred term after a single intravenous infusion in early postpartum women in Trial 000028. Part A Part A Part B 5 μg 20 μg 20 μg Total System Organ Class (N = 6) (N = 6) (N = 6) (N = 18) Preferred Term n (%) E n (%) E n (%) E n (%) E Any AE 3 (50) 9 5 (83) 7 0 8 (44) 16 Reproductive system and breast disorders Uterine spasm 3 (50) 4 3 (50) 3 — 6 (33) 7 Breast engorgement 3 (50) 3 — 3 (17) 3 Musculoskeletal and connective tissue disorders Back pain 1 (17) 1 — — 1 (6) 1 Muscle spasms 1 (17) 1 — — 1 (6) 1 Nervous system disorders Headache 2 (33) 3 — — 2 (11) 3 Pregnancy, puerperium and perinatal conditions Lactation puerperal increased — 1 (17) 1 — 1 (6) 1 AE = adverse event, N = Number of subjects in the Safety Analysis Set, n = Number of subjects with AE, % = Proportion of subjects in the analysis having an AE, E = Number of AEs.

[0125] Single i.v. administration of 5 and 20 μg merotocin to early postpartum women and 20 μg to women with established lactation were safe and well tolerated as assessed by AEs, vital signs, ECG, and clinical laboratory measurements. All AEs, except one event of moderate intensity, were of mild intensity. No serious adverse event or death occurred.

[0126] Multiple Dose Administration

[0127] A total of 14 TEAEs were reported by 10 (42%) of the 24 subjects administered multiple doses of merotocin in Trial 000015 (Table 8). All of these TEAEs were regarded as ADRs by investigators.

[0128] The most frequently reported AEs were headache (reported by 4 subjects in all treatment groups) and dry mouth (reported by 5 subjects in the 200 and 400 μg groups). Other TEAEs were single observations among all treatment groups. All TEAEs after multiple dose administrations were regarded as mild.

[0129] One subject was withdrawn from the 400 μg group due to nausea. The event was regarded as mild, and the subject recovered.

TABLE-US-00008 TABLE 8 Treatment-emergent adverse events reported after multiple intranasal administrations in Trial 000015. 50 μg i.n. 200 μg i.n. 400 μg i.n. System Organ Class N = 6 N = 6 N = 6 Placebo Preferred Term n (%) E n (%) E n (%) E N = 12 Any AE 3 (50%) 3 4 (67%) 5 3 (50%) 6 0 Gastrointestinal disorders Dry mouth 3 (50%) 3 2 (33%) 2 Nausea 1 (17%) 1 Nervous system disorders Headache 2 (33%) 2 1 (17%) 1 1 (17%) 2 Vascular disorders Flushing 1 (17%) 1 1 (17%) 1 Reproductive system and breast disorders Breast tenderness 1 (17%) 1 AE = adverse event, N = Number of subjects in the Safety Analysis Set, n = Number of subjects with AE, % = Proportion of subjects in the analysis having an AE, E = Number of AEs.

Overview and Conclusions

[0130] A single-ascending dose, multiple-ascending dose Phase 1 trial has been conducted in healthy women. The mean C.sub.max after single dose i.n. administration in the highest dose group was 151 μg/mL, and 463 μg/mL after a single i.v. infusion of 20 μg over 25 minutes. The t.sub.max and t.sub.1/2 was approximately 12-15 minutes and 25-35 minutes, respectively, similar at all i.n. dose levels and irrespective of single or multiple administration.

[0131] With i.n. administration, the absorption is the rate limiting process controlling the kinetics of merotocin. The most frequently reported AEs were headache, dry mouth and flushing or hot flush. The occurrence of headache in the placebo group was not different from the active treatment groups, while dry mouth and flushing or hot flush were recorded after active treatment only. All AEs were regarded as mild.

[0132] The possible transfer of merotocin from plasma to the breast milk was investigated in early postpartum women and in women with established lactation. Following i.v. administration of 20 μg merotocin, corresponding to an i.n. dose of 400 μg, merotocin concentration was below LLOQ, 25 μg/mL, in all milk samples collected up to 24 hours. In early postpartum women, the most frequently reported AEs were uterine spasm, breast engorgement, and headache.

[0133] Only occasional events of blood pressure shifts were recorded. High concentrations of merotocin appeared to increase the pulse rate. The ECG and safety laboratory parameters were not affected to any measurable extent by merotocin, and there were no signs of urinary retention at any dose level.

[0134] Effect of Merotocin on Milk Production in Pre-Term Sheep

[0135] The effect of merotocin on milk production was also investigated in ewes that were induced to deliver pre-term. The ewes were administered vehicle or merotocin intramuscularly twice daily for 14 consecutive days, 10 minutes before morning and evening milking. Merotocin was administered at 10 and 30 μg/animal. The milk volume was measured and the lactose, protein, and fat content analysed.

[0136] The 30 μg merotocin treatment group showed an increased daily milk yield relative to vehicle during the first week of treatment, which gradually decreased during the second week of treatment (see FIG. 3). The daily milk yield in the 10 μg merotocin treatment group was only marginally greater compared to the vehicle group during the whole two weeks of treatment.

[0137] The total milk yield over the treatment period increased by 27% and 62% in the 10 and 30 μg merotocin groups, respectively. No relevant changes were seen in the lactose, protein, or fat content of the milk.

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

[0138] AUC area under the plasma concentration-time curve

[0139] ADR adverse drug reaction

[0140] Cmax maximum plasma concentration

[0141] CHO Chinese hamster ovary

[0142] CL clearance

[0143] CYP cytochrome P450

[0144] EC50 drug concentration producing 50% of the maximal effect

[0145] ED50 drug dose producing 50% of the maximal effect

[0146] Emax maximal response

[0147] HEK human embryonic kidney

[0148] hERG human ether-á-go-go gene

[0149] hOTR human oxytocin receptor

[0150] hV1a(R) human vasopressin 1a (receptor)

[0151] hV1b(R) human vasopressin 1b (receptor)

[0152] hV2(R) human vasopressin 2 (receptor)

[0153] IC50 concentration producing 50% of the maximal inhibition

[0154] i.n. intranasal(ly)

[0155] i.v. intravenous(ly)

[0156] IMP Investigational Medicinal Product

[0157] INN international nonproprietary name

[0158] Ki binding affinity

[0159] LLOQ lower limit of quantitation

[0160] MFD maximum feasible dose

[0161] MTD maximum tolerated dose

[0162] NK2 neurokinin A

[0163] NOAEL no observed adverse effect level

[0164] PK pharmacokinetics

[0165] PND post-natal day

[0166] s.c. subcutaneous(ly)

[0167] TEAE treatment-emergent adverse event

[0168] tmax time to maximum plasma concentration

[0169] t1/2 terminal half-life