A first-in-human study of PDC31 (prostaglandin F2 receptor inhibitor) in primary dysmenorrhea
Bibliographic record
Abstract
STUDY QUESTION: What is the safe and pharmacodynamically active dose range for PDC31 (prostaglandin F2α receptor inhibitor) in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER: The 1 mg/kg/h dose of PDC31 appears to be safe and potentially effective in reducing intrauterine pressure (IUP) and pain associated with excessive uterine contractility when given as a 3-h infusion in patients with PD. WHAT IS KNOWN ALREADY: PDC31 has previously been shown to reduce the duration and strength of PGF2α-induced contractions in human uterine myometrial strip models and to delay delivery in animal models of preterm labor. STUDY DESIGN, SIZE, DURATION: This was a prospective, multi-center, dose-escalating first-in-human Phase I study conducted from March 2011 to June 2012. A total of 24 women with PD were enrolled and treated with one of five doses (0.01, 0.05, 0.15, 0.3, 0.5 and 1 mg/kg/h) of PDC31 given as a 3-h infusion. Patients were observed for a further 24 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted at four hospitals in Europe in non-pregnant, menstruating women with PD. Women with PD (n = 24) received PDC31 infused over 3 h within 8-10 h of the onset of menstruation. IUP and pain monitoring through the visual analog scale (VAS) was assessed prior to, during and following the infusion. Patients were observed for dose-limiting toxicities and other adverse events. Pharmacokinetic samples were also taken to profile the drug. MAIN RESULTS AND THE ROLE OF CHANCE: A 3-h infusion of PDC31 was safe up to and including doses of 1 mg/kg/h. Most adverse events were mild (n = 15; 83.3%) and not considered associated with PDC31 (n = 14; 77.8%). PDC31 infusion decreased uterine activity based on IUP and pain (VAS) scores. IUP was decreased by 23% over all dose levels, reaching a minimum at 135-150 min. There appeared to be a dose-dependent effect on IUP, with the high dose group (1 mg/kg/h) showing the largest decrease in IUP. There was a statistically significant linear dose-effect and concentration-effect relationship for several IUP parameters over the evaluation period of 60-180 min. A dose differentiating effect on pain was seen with the two highest doses. PDC31 demonstrated uncomplicated, linear pharmacokinetics with a terminal half-life of ∼2 h. LIMITATIONS, REASONS FOR CAUTION: This was a first-in-human study and exposure to PDC31 was limited for safety reasons. As such, pharmacodynamic parameters were assessed at a two-sided Type I error of 20%, an appropriate level for the exploratory nature of this study without a placebo control arm. This limited the chance of false positive findings to one in five. WIDER IMPLICATIONS OF THE FINDINGS: Like PD, preterm labor is associated with prostaglandin-mediated uterine contractions; therefore, the findings of this study support further development of PDC31 as a treatment for both PD and preterm labor. STUDY FUNDING/COMPETING INTERESTS: This work was funded by PDC Biotech GmbH, Vienna, Austria. B.B., R.M.L., L.W., R.J.S., K.J.B. and C.F.S. received reimbursement for the conduct of this study from PDC Biotech GmbH. W.H., M.S. and R.P.S. are paid consultants for PDC Biotech GmbH. P.G. is a paid consultant and shareholder of PDC Biotech GmbH. TRIAL REGISTRATION NUMBER: NCT01250587 at www.clinicaltrials.gov.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".