Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 328–332

doi: 10.1111/jcpt.12258

Pharmacokinetics

Pharmacokinetic interactions of OBE001 and betamethasone in healthy female volunteers O. Pohl* DVM MSc MPH PhD, M.-C. Homery† MD, F. Lemaux† PharmD, A. Patat† MD and A. Chollet* PhD *ObsEva SA, Plan-les-Ouates, Geneva, Switzerland and †Biotrial International Ltd., Rennes, France

Received 9 January 2015, Accepted 5 February 2015

Keywords: corticosteroid, drug interaction, OBE001, pharmacokinetic, preterm labour

SUMMARY

WHAT IS KNOWN AND OBJECTIVE

What is known and objective: To treat preterm labour, antenatal corticosteroids and tocolytics are often co-administered. OBE001 is an orally active oxytocin receptor antagonist under development for preterm labour treatment. Methods: Co-administration of OBE001 and betamethasone to determine pharmacokinetic interactions was studied during an open-label, randomized, three-period crossover study. Twelve healthy post-menopausal volunteers received either two consecutive OBE001 administrations of 600 mg/day, two intramuscular injections of 12 mg/day betamethasone or the two drugs administered in combination. The area under the plasma concentration–time curve (AUC), the maximum plasma concentration (Cmax) and the time to Cmax (tmax) for OBE001 and betamethasone were measured. Results and discussion: There was no effect on geometric mean Cmax after the second administration and AUCs of OBE001 [geometric mean ratio point estimate (90% CI): Cmax Day2 1
05 (0
98–1
12) and AUC0–24 h 1
11 (0
99–1
23)/AUC24 h–∞ 0
99 (0
93– 1
06), respectively]; Cmax after the first administration together with betamethasone was increased by 12% [geometric mean ratio point estimates (90% CI): Cmax Day1 1
12 (0
96–1
32)]. Tmax after concomitant administration with betamethasone occurred with a median delay of 1 h. Geometric mean Cmax and AUCs of betamethasone were not affected by concomitant OBE001 administration [geometric mean ratio point estimate (90% CI): Cmax Day1 1
02 (0
98–1
07)/ Cmax Day2 1
03 (0
98–1
08) and AUC0–24 h 1
07 (1
04–1
11)/AUC24 h–∞ 1
04 (1
01–1
08), respectively], with no effect on median tmax. No subject was discontinued from the study due to adverse events. What is new and conclusion: AUC and Cmax of the betamethasone and OBE001 combination did not differ significantly between treatments. Co-administration of OBE001 and betamethasone was well tolerated and resulted in a tmax median delay of 1 h for OBE001 but not for betamethasone. Co-administration of OBE001 and betamethasone in clinics is feasible and does not require any specific precaution or administration adaptation.

Preterm birth is the major cause of neonatal morbidity and mortality.1 There are many causes of spontaneous preterm labour, but the common final expression of this pathology is an increase in uterine contractions. The use of competitive antagonists of the oxytocin receptor was shown to reduce spontaneous preterm uterine activity in animal models and women.2 OBE001 is an orally active, small molecule that acts as a competitive antagonist of the human oxytocin receptor. It thereby inhibits the oxytocin-mediated rise of the intracellular calcium concentration that induces muscle contraction and thus spontaneous preterm uterine activity. In vitro studies in human liver microsomes have shown that OBE001 at concentrations of 10 lM had no inhibitory effects on the cytochrome P450 enzymes (CYP), suggesting that OBE001 will most probably not cause clinically significant CYP inhibition (ObsEva, data on file). Current treatment guidelines strongly recommend the administration of antenatal corticosteroids such as betamethasone or dexamethasone to women in preterm labour before 34 weeks of gestational age to promote foetal lung maturation.3–6 In a clinical setting, OBE001 and betamethasone (12 mg/day intramuscularly during 2 days) may therefore often be used concomitantly. As the administration of OBE001 could delay preterm delivery, this could leave enough time for betamethasone to be effective. The betamethasone is either excreted unchanged in urine (approximately 50%) or as glucuronides and sulphates formed by oxidation and conjugation in the liver.7 An open-label interaction study in healthy post-menopausal female subjects mimicking the clinical exposure scenario was conducted to investigate the safety, tolerability and pharmacokinetic implications of the co-administration of OBE001 with betamethasone. METHODS This open-label, randomized, three-period crossover pharmacokinetic study was carried out at the Clinical Pharmacology Unit of Biotrial, Rennes, France between 29 April 2014 and 4 June 2014 (Fig. 1). The study protocol was approved by the local Ethics Committee and French Health Authorities and conducted according to current ICH Good Clinical Practice guidelines.8 Participants were informed of the purpose of the studies and had to give written informed consent before being enrolled. Healthy post-menopausal women were recruited from the local population. All participants were screened within 18 days of the

Correspondence: O. Pohl, DVM, MSc, MPH, PhD, Senior Director NCD & Phase I, ObsEva SA, Chemin des Aulx 12, CH-1228 Plan-lesOuates, Geneva, Switzerland. Tel.: +41 (0)22 552 1555; fax: +41 (0)22 743 2921; e-mail: [email protected]

© 2015 John Wiley & Sons Ltd

328

O. Pohl et al.

Interactions of OBE001 and betamethasone

Screening

Period I

Period II

Period III

End of Study

(≤3 weeks)

(Day -1 − 6)

(Day 7 − 13)

(Day 14 − 21)

(Day 22)

OBE001 & OBE001 betamethasone β-methasone

OBE001 OBE001 β-methasone

Betamethasone OBE001

OBE001 & betamethasone

Betamethasone

OBE001

OBE001 OBE001

OBE001 OBE001& betamethasone

OBE001 Betamethasone

OBE001

Betamethasone

OBE001 & betamethasone

β-methasone

β-methasone

OBE001 & betamethasone

β-methasone

Betamethasone Betamethasone

OBE001

N = 12

Screening & Randomisaon

β-methasone

EOS

OBE001 OBE001 & betamethasone

Fig. 1. Study design scheme. The sequence of treatments was randomized. OBE001 600 mg/day was given orally as a dispersion of three tablets (200 mg) in 150 mL of water on the first and second day of each treatment period. Betamethasone was administered as a single 12 mg/day intramuscular injection on the first and second day of each treatment period. planned first drug administration. Subjects considered to be healthy according to medical history, complete physical examination and vital signs, electrocardiogram (ECG), tests for alcohol and drugs and routine laboratory measurements of blood (hepatitis B/C, HIV, pregnancy) and urine were included in the study. The exclusion criteria included a history of clinically relevant allergies, drug hypersensitivity, hepatic or renal disorders, endocrine disorders, hypotension, heart disease, gastrointestinal illness and tuberculosis. For the duration of the study, the participants were requested to abstain from smoking or the consummation of caffeine, methylxanthine or grapefruitcontaining products. A total of 12 healthy female post-menopausal volunteers were administered, on three separate treatment periods, either two consecutive OBE001 administrations of 600 mg/day or two intramuscular injections of 12 mg/day betamethasone or the two drugs in combination. The second doses of each of the three treatments were given 24 h after the first. OBE001 (ObsEva, Switzerland) was administered orally as a dispersible tablet formulation using three tablets (200 mg OBE001/tablet) in 150 mL of water. To treat preterm labour, OBE001 may be administered as a loading dose (29 the maintenance dose) on day 1 followed by a daily maintenance treatment. Based on the available pharmacology data (ObsEva, data on file), a maintenance treatment at 300 mg/day should provide efficacy. Thus, a dose of 600 mg was considered to be appropriate in the context of this study. Betamethasone (Celesteneâ, Schering-Plough, France) was administered by intramuscular injection of 12 mg/3 mL into the gluteus muscle, which is the recommended dose for antenatal betamethasone in preterm labour for the prevention of respiratory distress syndrome in neonates.3–6 A 2-day dosage regimen was selected to mimic the clinical situation. For each period, participants were admitted to the Clinical Pharmacology Unit on the evening before the first drug administration, treated on days 1 and 2 and discharged 24 h after the second administration. For safety reasons, physical examinations, vital signs, ECG and standard laboratory parameters were measured predose and after each drug administration. The washout period between treatment courses was 5 days. On study day 22, that is 6 days after the last drug administration, post-study safety examinations were performed.

Adverse events were monitored continuously throughout the study. During each treatment period, blood samples for the analysis of OBE001 and betamethasone were collected and analysed using validated LC-MS/MS methods. Pharmacokinetic parameters were estimated by non-compartmental methods using the Phoenixâ WinNonLinâ version 6.3 (Certara, LP, USA). The following pharmacokinetic parameters were calculated for OBE001 or betamethasone during each treatment period: measured maximum concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve (AUC) and terminal plasma half-life (t1/2). Values for Cmax and tmax were directly obtained from the concentration–time curves for two periods: Cmax1 and tmax1 refer to the values calculated for the first dose of OBE001 or betamethasone, and Cmax2 and tmax2 refer to the values calculated for the dose of OBE001 or betamethasone given 24 h later. AUC was determined using the linear trapezoidal method. AUC from time zero to infinity was calculated as the sum of AUC to the last quantifiable concentration (Ct) and Ct/ke, where ke was the terminal rate constant, estimated by log-linear regression. Terminal half-life was calculated as t1/2 = ln2/ke. A lack of an interaction for the pharmacokinetic parameters was tested by applying bioequivalence criteria for Cmax and AUC by analysis of variance (ANOVA), utilizing general linear models (GLM) on ln-transformed data (SASâ software (Version 9.2)).9,10 Ratios of the means of the combined versus the single treatment were derived together with the corresponding 90% confidence intervals (CIs). Bioequivalence was concluded if the 90% CI of the ratio lcombined/lsingle was fully contained within the acceptance range for AUC and Cmax (80%, 125%). Observed tmax values were evaluated based on the nonparametric Wilcoxon test together with the derivation of nonparametric CIs using the Hodges-Lehmann estimator. Safety data were assessed using descriptive statistics. A formal sample size calculation was not performed. Based on the experience with OBE001 in previous pharmacokinetic studies (ObsEva, data on file) and published pharmacokinetic data for betamethasone,7 a sample size of 12 subjects was deemed to be sufficient for a reliable assessment of the impact of OBE001 and betamethasone on their relative bioavailability.

© 2015 John Wiley & Sons Ltd

Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 328–332 329

O. Pohl et al.

Interactions of OBE001 and betamethasone

treatment conditions, mean plasma concentration–time curves followed a very similar pattern. The mean terminal half-life (SD) of betamethasone alone and concomitant administration with OBE001 was 6
6  1
1 h and 6
7  1
0 h, respectively. In this study, 11 of 12 patients experienced 28 treatment emergent adverse events (TEAEs), of which two were possibly related to OBE001 alone, 13 were considered to be related to betamethasone alone, and 13 were associated with the combination of both treatments (Table 3). All adverse events resolved spontaneously. Of the drug-related TEAE, headache and insomnia of mild intensity were reported most often (19 of 28 TEAEs). The eight remaining adverse events were of mild intensity. During the predose assessments of the second treatment period, one participant experienced persistently increased systolic blood pressure between 170 and 180 mmHg. In the context of an upcoming administration of betamethasone, the investigator decided to withdraw this participant from the study for medical reasons. All other assessments of this participant were within the reference range of findings. Neither trends nor relevant changes from baseline were observed in vital signs, ECG values, physical examination or laboratory parameters. Overall, all treatments conditions were well tolerated. There was no serious adverse event and no withdrawal due to drug-related adverse event.

RESULTS AND DISCUSSION Twelve healthy Caucasian women aged 54–62 years (mean 58
3 years) with a weight of 51–67 kg (mean 60
6 kg  5
1) and a body mass index ranging between 19
4 and 25
5 kg/m2 (mean 23
12 kg/m2  2
05) were enrolled. One subject was withdrawn from the study after the first treatment period (OBE001), due to high predose blood pressure in the second treatment period which precluded safe administration of betamethasone. The subject was not replaced, as the loss of statistical power was considered to be acceptable. OBE001 pharmacokinetic parameters were calculated for 12 subjects; pharmacokinetic parameters for betamethasone and the treatment combination and bioequivalence statistics were assessed for 11 participants. Treatment with OBE001 alone or in combination with betamethasone resulted in similar mean concentration–time curves (Fig. 2). OBE001 alone or in combination with betamethasone was rapidly absorbed. The first measurable OBE001 plasma concentrations were observed at 0
25 h and mean OBE001 concentrations at 0
5 h attained 53–68% of mean Cmax values after the first administration. On both treatment days, median tmax occurred 2 and 3 h after administration for OBE001 and OBE001&betamethasone, respectively. Following the co-administration of OBE001 and betamethasone, a median delay in tmax of 1 h was observed for OBE001 compared to OBE001 alone, whereas no significant effect on tmax was observed for betamethasone. During the elimination phase, plasma levels declined according to a multi-exponential and similar pattern for both treatments. The mean terminal half-life (SD) of OBE001 alone was 12
02  1
96 h and concomitant administration with betamethasone resulted in a t1/2 of 11
28  1
89 h, respectively. The co-administration of betamethasone had no effect on the bioavailability of OBE001. For the AUC extrapolated to infinity, the 90% CIs for the ratio between treatments were well within bioequivalence limits (Table 1). Similarly, the 90% CIs of the Cmax1 and Cmax2 ratios were borderline outside or within bioequivalence limits, respectively. For betamethasone, the co-administration of OBE001 did not affect bioavailability, in terms of Cmax, tmax and AUC (Table 2 and Fig. 3). All 90% CIs for ratios between treatments were well within bioequivalence limits (80–125%). After intramuscular injection on days 1 and 2, plasma concentrations of betamethasone rose rapidly with a median peak at 1
5 h for betamethasone alone or concomitantly with OBE001. For both

WHAT IS NEW AND CONCLUSION This study investigated the safety, tolerability and pharmacokinetic interactions of the orally available oxytocin receptor antagonist OBE001 which is being developed to treat preterm labour and threatened preterm delivery. In accordance with current drug interaction guidelines,9,10 we assessed a dose of OBE001 which significantly exceeded the highest anticipated clinical dose and combined it with the entire recommended dosing regimen for antenatal corticosteroid therapy (24 mg within 2 days). In vitro studies with OBE001 and a review of relevant literature of betamethasone indicated that it was unlikely that a pharmacokinetic drug–drug interaction would occur in vivo.11 Furthermore, a previous drug interaction study using the peptidic oxytocin receptor antagonist, atosiban, suggested that safety and tolerability concerns due to pharmacodynamic drug interactions would be unlikely.7 The results of this interaction study are very conclusive. Based on the CI inclusion rule for AUC and Cmax and an assessment of

Fig. 2. Mean (SD) plasma concentration–time curves of an oral dose of 600 mg/day OBE001 when administered alone ( ) or in combination with an intramuscular injection of 12 mg/day betamethasone ( ).

© 2015 John Wiley & Sons Ltd

Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 328–332 330

O. Pohl et al.

Interactions of OBE001 and betamethasone

Table 1. Pharmacokinetic parameters of OBE001 administered alone or in combination with betamethasone to healthy post-menopausal volunteers (n = 11)

AUC0–24 (h ng/mL) AUC24–∞ (h ng/mL) Cmax1 (ng/mL) Cmax2 (ng/mL) tmax1 (h) tmax2 (h)

OBE001a (A)

OBE001&betamethasone (C)

Ratio C/A

90% CI

33862
0 64038
8 3003
1 3873
2 2

37005
1 62367
0 3343
5 4096
0 3

(25
3%) (23
7%) (29
6%) (17
5%) (1–6)

1
105 0
993 1
122 1
050 1
000

27 (26–28)

1
000

0
990; 1
232 0
933; 1
057 0
955; 1
317 0
983; 1
121 0
3; 2
1 P = 0
0469 0
5; 1
5 P = 0
0020

(17
9%) (23
2%) (23
0%) (17
2%) (0
75–4)

26 (24
75–28)

The AUC and Cmax are presented as geometric means and CV%, whereas tmax is presented as the median and range. AUC0–24 is the AUC up to 24 h after the first dose of OBE001, and AUC24–∞ represents the AUC after the second dose of OBE001 extrapolated to infinity. Cmax1 and tmax1 refer to the first dose of OBE001 for a given treatment period, whereas Cmax2 and tmax2 refer to the second dose of OBE001 given 24 h later. For tmax, the Hodges-Lehmann shift estimate (90% confidence interval) for the (C) – (A) and the P-value of Wilcoxon signed-rank test are presented. a n = 12, one subject was withdrawn from the study for medical reasons and is thus not treated with OBE001&betamethasone.

Table 2. Pharmacokinetic parameters of betamethasone administered alone or in combination with OBE001 to healthy post-menopausal volunteers (n = 11)

AUC0–24 (h ng/mL) AUC24–∞ (h ng/mL) Cmax1 (ng/mL) Cmax2 (ng/mL) tmax1 (h) tmax2 (h)

Betamethasone (B)

OBE001&betamethasone (C)

1636
0 2126
8 167
13 173
81 1
5

1748
6 2223
1 171
02 178
86 1
5

(13
4%) (17
2%) (14
0%) (11
9%) (0
75–4)

25
5 (24
75–27)

(14
6%) (16
0%) (11
3%) (15
0%) (1–3)

25
5 (24
5–27)

Ratio C/B

1
073 1
044 1
021 1
029 0
071 0
125

90% CI

1
035; 1
112 1
009; 1
081 0
976; 1
068 0
980; 1
080 0
5; 0
6 P = 0
5078 0
9; 0
6 P = 0
7109

The AUC and Cmax are presented as geometric means and CV%, whereas tmax is presented as the median and range. AUC0–24 is the AUC up to 24 h after the first dose of betamethasone, and AUC24–∞ represents the AUC after the second dose of betamethasone extrapolated to infinity. Cmax1 and tmax1 refer to the first dose of betamethasone for a given treatment period, whereas Cmax2 and tmax2 refer to the second dose of betamethasone given 24 h later. For tmax, the HodgesLehmann shift estimate (90% confidence interval) for the (C) – (B) and the P-value of Wilcoxon signed-rank test are presented.

Fig. 3. Mean (SD) plasma concentration– time curves of an intramuscular injection of 12 mg/day betamethasone when administered alone ( ) or in combination with an oral dose of 600 mg/day OBE001 ( ).

plasma concentrations exceeding 50% of Cmax within the first 30 min after administration. This fast absorption may allow a rapid onset of action which is highly desirable in case of threatened preterm labour. Following the co-administration of OBE001 and betamethasone, a median delay in tmax of 1 h was observed for

tmax, it can be concluded that the co-administration of OBE001 had no clinically relevant influence on the bioavailability of betamethasone. Similarly, the co-administration of betamethasone had no clinically relevant influence on the bioavailability of OBE001. Furthermore, oral OBE001 was swiftly absorbed and attained

© 2015 John Wiley & Sons Ltd

Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 328–332 331

O. Pohl et al.

Interactions of OBE001 and betamethasone

Table 3. Treatment emergent adverse events (TEAEs) of OBE001 and betamethasone administered alone or concomitantly healthy postmenopausal volunteers (n = 11) OBE001a

CNS and psychiatric disorders (20/28 TEAEs)

Vascular disorders (3/28 TEAEs) Gastrointestinal disorders (2/28 TEAEs) Musculoskeletal disorders (2/28 TEAEs) General disorders (1/28 TEAEs) Total number of TEAEs

Headache Insomnia Psychic excitement Hot flushes Nausea Vomiting Pain in calves Fatigue

2

2

Betamethasone

OBE001&betamethasone

3 5 1 2

4 5 1 1 1 1

1 1 13

13

Total of TEAEs

9 10 1 3 1 1 2 1 28

n = 12.

a

that co-administration of OBE001 and betamethasone in clinics is feasible and does not require any specific precaution or dosage administration. In addition, it was shown that OBE001 was rapidly absorbed following oral administration. The pharmacokinetic characteristics of OBE001 are suitable for treating women with threatened preterm labour.

OBE001 compared to OBE001 alone, whereas no significant effect on tmax was observed for betamethasone between the two treatments. The frequency of TEAEs was equal during betamethasone monotherapy and combined OBE001&betamethasone treatment. All TEAEs after combined OBE001&betamethasone administration were of mild intensity. Headache and insomnia were reported most often which is in agreement with observations from a comparable drug interaction study7 and the described adverse effects of betamethasone.12 During OBE001 monotherapy, adverse events were limited to two mild episodes of headache. Overall, the co-administration of OBE001 and betamethasone resulted in similar tolerability as the administration of each substance alone. In conclusion, the use of OBE001 with betamethasone has revealed a lack of pharmacokinetic interactions or changes in tolerability, with no serious adverse events being noted indicating

SOURCE OF FUNDING This work was funded by ObsEva SA (Plan-les-Ouates, Geneva, Switzerland). CONFLICT OF INTERESTS OP and AC are salaried employees of ObsEva SA. The conduct and reporting of the clinical trial was contracted to BioTrial. MCH, FL and AP are salaried employees of Biotrial International Ltd.

REFERENCES 1. Howson CP, Kinney MV, McDougall L, Lawn JE. Born too soon: preterm birth matters. Reprod Health, 2013;10(Suppl 1):S1. 2. Vrachnis N, Malamas FM, Sifakis S, DeligeoroglouE,IliodromitiZ.Theoxytocin-oxytocin receptor system and its antagonists as tocolytic agents. Int J Endocrinol, 2011;2011:350546. 3. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev, 2006;3:CD004454. 4. SOGC Committee Opinion No.122: Antenatal Corticosteroid Therapy for Fetal Maturation. Available at: http://sogc.org/wp-content/ uploads/2013/01/122E-CO-Janvier2003.pdf. (accessed 17 September 2014). 5. RCOG Green-top Guideline No.7: Antenatal Corticosteroids to Reduce Neonatal Morbidity and Mortality. Available at: https:// www.rcog.org.uk/globalassets/documents/

6.

7.

8.

9.

guidelines/gtg-7.pdf. (accessed 17 September 2014). ACOG Committee Opinion No. 475: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol, 2011;117:422–424. Rasmussen BB, Larsen LS, Senderovitz T. Pharmacokinetic interaction studies of atosiban with labetalol or betamethasone in healthy female volunteers. BJOG, 2005;112: 1492–1499. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R1). Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Gui delines/Efficacy/E6/E6_R1_Guideline.pdf. (accessed 17 September 2014). EMA: Guideline on the Investigation of Drug Interactions. Available at: http:// www.ema.europa.eu/docs/en_GB/docum ent_library/Scientific_guideline/2012/07/

© 2015 John Wiley & Sons Ltd

WC500129606.pdf. (accessed 17 September 2014). 10. FDA Guidance for Industry: Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations - DRAFT GUIDANCE. Available at: http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryIn formation/Guidances/ucm292362.pdf. (acc essed 17 September 2014). 11. HSDB: BETAMETHASONE CASRN: 37844-9. Available at: http://toxnet.nlm.nih. gov/cgi-bin/sis/search2/f?./temp/~bLxM Fy:3. (accessed 17 September 2014). 12. drugs.com: Betamethasone Sodium Phosphate and Betamethasone Acetate. Available at: http://www.drugs.com/pro/beta methasone-sodium-phosphate-and-betamet hasone-acetate.html. (accessed 17 September 2014).

Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 328–332 332