Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2α receptor antagonist tocolytic: A first‐in‐human trial in healthy postmenopausal women

Pohl, Oliver; Marchand, Line; Gotteland, Jean‐Pierre; Coates, Simon; Täubel, Jörg; Lorch, Ulrike

doi:10.1111/bcp.13622

Cited by 12 publications

(15 citation statements)

References 38 publications

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“…The results from this study, as well as favourable tolerability and safety results from the FIH study using OBE022, enabled the initiation of a Phase 2a study with OBE022 in pregnant women with spontaneous preterm labour with a gestational age of 24 0/7 –33 6/7 weeks (PROLONG, NCT03369262).…”

Section: Resultsmentioning

confidence: 99%

“…Protocol 1) with acceptable safety and tolerability, i.e. dosing regimens at which no study specific criteria stopping dose progression and/or escalations were met . Based on the safety, tolerability and PK data from Protocol 1, the safety review committee selected single doses of 1100 mg of OBE022 .…”

Section: Methodsmentioning

confidence: 99%

“…Doses of OBE022 for Part B were also selected from Protocol 1, the highest multiple dose (1000 mg) was selected to be administered from Days 4–12.…”

Section: Methodsmentioning

confidence: 99%

“…The early phase drug development programme consisted of 2 interdependent, adaptive trial protocols. The first protocol (Protocol 1) consisted of first‐in‐human (FIH) single ascending dose and multiple ascending dose parts in healthy nonpregnant female volunteers to assess OBE022's safety, tolerability and pharmacokinetics (PK) . Cardiac safety assessments and an assessment of the effect of food on the PK were integrated into the multiple ascending dose part …”

Section: Introductionmentioning

confidence: 99%

“…It was important to first conduct trials in healthy nonpregnant female volunteers rather than preterm labour patients as it was important to determine the safety and tolerability of OBE022 when coadministered with various standard of care medications. Data from the FIH trial demonstrated that OBE022 would not expose them to an increased risk …”

Section: Introductionmentioning

confidence: 99%

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Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone

Pohl

Marchand

Gotteland

et al. 2019

Brit J Clinical Pharma

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Aims:To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development. Methods: PartA: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO 4 . Part B: open-label, singlesequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13).Results: OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination.There were no clinically significant pharmacokinetic interactions when coadministered with MgSO 4 . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [C max ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (C max + 18%, AUC +27%) and OBE002 exposure (C max + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (C max + 29%, AUC +24%) and markedly increased nifedipine exposure (C max by 2-fold and AUC by 2-fold), which may be clinically significant.Conclusions: The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Doses of OBE022 for Part B were also selected from Protocol 1, the highest multiple dose (1000 mg) was selected to be administered from Days 4–12.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone

Pohl

Marchand

Gotteland

et al. 2019

Brit J Clinical Pharma

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Pharmacology‐Guided Rule‐Based Adaptive Dose Escalation in First‐in‐Human Studies

Hoogdalem¹,

Iersel²,

Winter

et al. 2020

Clin Pharma and Therapeutics

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First‐in‐human (FIH) studies typically progress through cohorts of fixed, standard size throughout the escalation scheme. This work presents and tests a pharmacology‐guided rule‐based adaptive dose escalation design that aims at making "best use" of participants in early clinical drug evaluation; it is paper based, not requiring real‐time access to computational methods. The design minimizes the number of participants exposed to dose levels with low likelihood of being therapeutically relevant. Using criteria based on dose‐limiting adverse event rate and on target exposure or target pharmacodynamics, the design increases the sample size when approaching the dose range of potential clinical relevance. The adaptive escalation design was retrospectively tested on actual data from a sample of 40 recently executed FIH studies with novel small and large molecules, and it was evaluated by simulating trials with three compounds with different therapeutic windows, i.e., representing a promising, unacceptable, and dubious profile. In retrospective evaluation of the adaptive escalation design, none of the cases overshot the actually reported top dose; one case resulted in a top dose that was within 20% under the estimated maximum tolerated dose in the original study. The median reduction of total number of participants per study was 38%. Trial simulations confirmed the retrospective evaluation, showing a similar performance of the adaptive escalation design compared with the conventional 6 + 2 design, at a reduced study size for compounds with a presumed acceptable therapeutic window. The adaptive escalation design was shown to make "best use" of participants in FIH studies without compromising safety.

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Preterm Birth Therapies to Target Inflammation

Pavlidis

Stock

2022

The Journal of Clinical Pharma

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Preterm birth (PTB; defined as delivery before 37 weeks of pregnancy) is the leading cause of morbidity and mortality in infants and children aged <5 years, conferring potentially devastating short‐ and long‐term complications. Despite extensive research in the field, there is currently a paucity of medications available for PTB prevention and treatment. Over the past few decades, inflammation in gestational tissues has emerged at the forefront of PTB pathophysiology. Even in the absence of infection, inflammation alone can prematurely activate the main components of parturition resulting in uterine contractions, cervical ripening and dilatation, membrane rupture, and subsequent PTB. Mechanistic studies have identified critical elements of the complex inflammatory molecular pathways involved in PTB. Here, we discuss therapeutic options that target such key mediators with an aim to prevent, postpone, or treat PTB. We provide an overview of more traditional therapies that are currently used or being tested in humans, and we highlight recent advances in preclinical studies introducing novel approaches with therapeutic potential. We conclude that urgent collaborative action is required to address the unmet need of developing effective strategies to tackle the challenge of PTB and its complications.

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Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2α receptor antagonist tocolytic: A first‐in‐human trial in healthy postmenopausal women

Abstract: Administration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients.

Cited by 12 publications

References 38 publications

Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone

Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone

Pharmacology‐Guided Rule‐Based Adaptive Dose Escalation in First‐in‐Human Studies

Preterm Birth Therapies to Target Inflammation

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