p38 MAPK

Dilmapimod (SB-681323) potently inhibits p38 MAPK signaling, measured by inhibition of sorbitol-induced pHSP27 expression[1].

Biomarker Measurements [2]
Upon review of final data, the observed times since trauma were similar enough such that analyses using both time of trauma and time of first dose gave consistent results. Spline-based analyses using time of trauma for key prespecified biomarkers (CXCL8 [IL-8], CRP, IL-6, and MPO) are presented in Figures S1–S4 (Supplemental Digital Content 1, https://links.lww.com/CCM/B328). Changes in IL-6 over time following initial dose are shown in Figure 4A. In the combined placebo arms, mean IL-6 levels rose from 509.4 (95% CI, 404.3, 641.9) at 6 hours from time of first dose to a peak mean of 556.1 (95% CI, 396.8, 779.2) at 24 hours, before falling to a mean level of 250.2 (95% CI, 162.4, 385.4) at 72 hours. As noted in Figure 4A, at all dose levels, Dilmapimod treatment was associated with a trend toward lower levels of IL-6 over time compared with patients who received placebo, with effects present at 24 hours following dosing initiation. The ratio of IL-6 in a given treatment arm relative to placebo is presented in Figure 4A, indicating that the continuous 10-mg infusion yielded values consistently below a ratio of 1, with treatment-related effects present early after the initiation of the infusion.
Changes over time in IL-8 and MPO were not as consistent as IL-6 and CRP (Fig. S5, a and b, Supplemental Digital Content 1, https://links.lww.com/CCM/B328) and did not display consistent treatment effects across all arms, although the highest continuous dose arm had significantly lower IL-8 levels beginning early after study initiation. The sTNFR1 levels were significantly lower than placebo in the highest dose arm (10 mg 24 hr infusion) (Fig. S5c, Supplemental Digital Content 1, https://links.lww.com/CCM/B328), but these effects, while appearing quite different, seemed confined to the highest Dilmapimod doses. Other exploratory biomarkers, listed in Table S2 (Supplemental Digital Content 1, https://links.lww.com/CCM/B328), did not reveal consistent trends or treatment effects (data not shown).

Study Design [2]
Between October 2009 and February 2013, we conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel-group study at six sites in the United States to evaluate the safety, tolerability, systemic PK, and PD profiles of Dilmapimod, compared with placebo in patients with major trauma exclusive of severe head injury and at risk for developing ARDS (ClinicalTrial.gov NCT00996840). Patient eligibility was defined by known or potential contraindications with Dilmapimod and by injury severity, as calculated by Injury Severity Score (ISS) (28). Eligible patients were randomized into the trial within the first 26 hours after known trauma had occurred.
Over the three treatment days, safety tests were performed (detailed in the Primary and Secondary Endpoints section) and blood samples were collected for PK and PD analysis. Patients remained in the hospital for the entire study period. A follow-up visit was conducted on day 7, that is, 4 days after IV dosing had finished or at discharge from the hospital if earlier than day 7 (but no earlier than 12 hr after dosing had completed). The study was 7 days in length for all patients. Study progression to the next cohort only occurred after completion and review of safety, tolerability, and PK data from the previous cohort in conjunction with an Independent Data Monitoring Committee.

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Dose Rationale [2]
To ensure patient safety and to investigate the relationship between drug exposure and biomarkers of p38 inhibition, four separate patient cohorts were recruited to evaluate different dose levels and infusion regimens. Patients in each cohort received either Dilmapimod or placebo as an IV infusion for three consecutive days as follows: cohort 1 received dilmapimod 3 mg infused over 4 hours or placebo; cohort 2 received Dilmapimod7.5 mg infused over 24 hours or placebo; cohort 3 received Dilmapimod 7.5 mg infused over 4 hours or placebo; cohort 4 received dilmapimod 10 mg infused over 24 hours or placebo (Fig. 1). Progression from cohort 1 to 2 was expected to increase area under the concentration-time curve (AUC) and progression from cohort 2 to 3 was expected to increase Cmax, while maintaining safety cover based on preclinical testing and previous studies with dilmapimod. The maximum dose of 10 mg/d was selected based on safety cover margins and to maximize the chance of altering proinflammatory biomarkers in this patient population. As such, cohorts 3 and 4 were expected to provide the best opportunity for detecting a PD signal. Although there is a lack of available data and information to support quantitative prediction of the pharmacology of dilmapimod in trauma patients, doses that result in 50% inhibition of ex vivo TNF-α have been shown to reduce markers of inflammation in other diseases, such as COPD and atherosclerosis (29, 30). Subjects were randomized to receive either dilmapimod or placebo in accordance with the central randomization schedule generated by Discovery Biometrics, prior to the start of the study, using validated internal software.

Pharmacokinetic analysis[2]
The dataset included 471 Dilmapimod concentration records from 56 patients. Population pharmacokinetic analysis showed that the plasma concentration-time curve after intravenous infusion best fit the three-compartment model, where input was zero-order kinetics and elimination was first-order kinetics. The plasma concentration of Dilmapimod was approximately proportional to the dose. BMI was an important factor affecting clearance and intercompartment clearance; clearance decreased by 21% when BMI was 1 standard deviation below the mean (23 kg/m2); clearance increased by 23% when BMI was 1 standard deviation above the mean (32 kg/m2). Figure 3 shows the model-predicted PK curves and observed concentration data for different treatment allocation groups. Table 4 shows the daily exposure AUC (0–24) of dilmapimod. Based on these data, the continuous dosing group appeared to maintain the most favorable PK characteristics, and the 10 mg dosing regimen was superior to 7.5 mg.

Safety [2]
A total of 77 patients were randomized; 7 patients withdrew during the study (Figure 2). Table 1 lists the characteristics of the study population assigned according to treatment, and Table S5 (Supplemental Data 1, https://links.lww.com/CCM/B328) details the randomization distribution by center. This was a group of young, predominantly male, critically injured patients who were enrolled within 26 hours of admission.
The overall incidence of adverse events (AEs) was comparable across all treatment groups, and no dose-related factors were found (Table 2). Adverse events were relatively common in this critically ill patient population. The most common adverse events were fever (reported in 20 patients out of 20), nausea (reported in 18 patients out of 18), and hypertension (reported in 18 patients out of 19), which occurred more frequently in the placebo group than in the treatment group. A detailed list of all adverse events is provided in Table S6 (Supplemental Data 1, https://links.lww.com/CCM/B328). A retrospective review of data from patients with elevated liver enzymes revealed no drug-related hepatotoxicity. Three patients experienced elevated liver enzymes. Two of these patients received the active drug, and one received placebo; both adverse events were considered drug-related (one in the active drug group and one in the placebo group). A total of 19 hypertension cases were reported in 18 patients; all but one were moderate hypertension. The incidence of hypertension was highest in the placebo group and was similar across different Dilmapimod dose groups. Of the hypertension cases reported in the Dilmapimod treatment group, the investigators considered only one drug-related. The number of clinically significant ECG abnormalities was higher in the placebo group. No significant changes were observed in the mean ECG variables compared to baseline. One patient reported two adverse events: QT interval prolongation and ST segment inhibition on ECG, believed to be drug-related, but this patient was receiving placebo.

[1]. A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J Clin Pharmacol. 2010 Jan;50(1):94-100.

[2]. A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome. Crit Care Med . 2015 Sep;43(9):1859-69.

Dilmapimod has been used in multiple studies to explore its applications in the treatment and diagnosis of neuropathic trauma, inflammation, pain, neuropathic pain, arthritis, rheumatoid arthritis, and coronary heart disease. Dilmapimod (SB-681323) is a p38 MAP kinase inhibitor with potential use in the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Previous p38 MAP kinase inhibitors have been hampered by hepatotoxicity. Methotrexate (a commonly used treatment for RA patients) also has potential hepatotoxicity.

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Drug Indications
Dilmapimod has been used in clinical trials investigating the treatment and diagnosis of diseases such as neuropathic trauma, inflammation, pain, neuropathic pain, arthritis, rheumatoid arthritis, and coronary heart disease.

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Mechanism of Action
Dilmapimod reduces the levels of pro-inflammatory cytokines and chemokines and decreases cell infiltration at sites of inflammation, thereby alleviating local damage. In diseases such as RA and IBD, TNFα can be blocked by anti-TNFα antibodies or by using soluble TNFα receptors. Inhibition of p38α significantly suppresses TNFα and cytokines such as IL-1β and IL-6, thereby enhancing therapeutic efficacy. The p38 mitogen-activated protein kinase (MAPK) signaling pathway upregulates inflammatory responses and is known to have enhanced activity in chronic obstructive pulmonary disease (COPD). The authors evaluated the pharmacological properties of the novel p38 MAPK inhibitor Dilmapimod/SB-681323 in COPD patients using blood biomarkers. Seventeen COPD patients (with a forced expiratory volume in one second (FEV1) of 50%–80% of predicted value) participated in a double-blind, double-dummy, randomized, crossover study, all of whom were using short-acting bronchodilators. Patients received single oral doses of SB-681323 7.5 mg and 25 mg, prednisolone 10 mg and 30 mg, or placebo, respectively. Blood samples were collected before administration and at 1, 2, 6, and 24 hours after administration. The levels of sorbitol-induced phosphorylated heat shock protein (pHSP)27 (a marker of p38 pathway activation) and lipopolysaccharide-induced tumor necrosis factor (TNF)-α in whole blood were assessed. Compared with placebo, both doses of SB-681323 (but not prednisolone) significantly reduced the weighted mean pHSP27 level (0–6 h) by 58% (P < 0.0001). Compared with placebo, SB-681323 25 mg (40%, P = .005) and 7.5 mg (33.4%, P = .02) significantly reduced white matter TNF-α production (0–24 h), while prednisolone 30 mg and 10 mg inhibited it by 81.5% and 58.2%, respectively (both P < .0001). SB-681323 showed stronger inhibitory activity against the p38 MAPK pathway than prednisolone. SB-681323 inhibits the production of TNF-α. SB-681323 is a potent p38 MAPK inhibitor that may suppress inflammation in COPD. [1]

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Target: There are currently no drug therapies for the prevention or treatment of acute respiratory distress syndrome. Early inflammatory dysregulation may play a role in the development and prognosis of acute respiratory distress syndrome. p38 mitogen-activated protein kinase plays a central role in the regulation of a variety of inflammatory mediators associated with acute organ dysfunction and is a target for novel cytokine-inhibiting anti-inflammatory drugs. In preclinical models, p38 inhibitors have been shown to reduce pancreatitis and lung injury following burns.
Design: We conducted a phase IIa randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and tolerability of the novel p38 mitogen-activated protein kinase inhibitor Dilmapimod in patients at risk of developing acute respiratory distress syndrome and with an injury severity score (ISS) greater than 16 on admission (excluding head trauma). Enrolled patients were divided into four independent cohorts and received different doses of dilmapimod or placebo intravenously over 4 hours or 24 hours daily for 3 days.
Study Background: A multicenter randomized clinical trial at a large academic trauma center.
Measurements and Primary Outcomes: A total of 77 patients were enrolled. Although adverse events are more common in critically ill patients, Dilmapimod was well tolerated, and no clinically significant safety issues were found. Pharmacokinetic models showed that the higher dose of 10 mg administered over 24 hours had the best plasma concentration profile. Similarly, the most significant differences were observed between the dosing and placebo groups in soluble inflammatory markers, including interleukin-6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1. Although this study was not specifically designed with acute respiratory distress syndrome (ARDS) as the endpoint, the number of patients who developed ARDS was small (2/77). Conclusion: The novel p38 mitogen-activated protein kinase inhibitor Dilmapimod was well tolerated and warrants further evaluation in larger clinical trials to prevent acute respiratory distress syndrome and other organ damage. Furthermore, the results of this early trial may help design future studies aimed at preventing acute respiratory distress syndrome and other organ damage. [2]

C23H19F3N4O3

456.42

456.141

C, 60.52; H, 4.20; F, 12.49; N, 12.28; O, 10.52

444606-18-2

937169-00-1;444606-18-2;

10297982

White to light yellow solid powder

2.36

3

9

6

33

702

0

O=C1C=CC2=C(C3=CC=C(F)C=C3C)N=C(NC(CO)CO)N=C2N1C4=C(F)C=CC=C4F

ORVNHOYNEHYKJG-UHFFFAOYSA-N

InChI=1S/C23H19F3N4O3/c1-12-9-13(24)5-6-15(12)20-16-7-8-19(33)30(21-17(25)3-2-4-18(21)26)22(16)29-23(28-20)27-14(10-31)11-32/h2-9,14,31-32H,10-11H2,1H3,(H,27,28,29)

8-(2,6-difluorophenyl)-2-(1,3-dihydroxypropan-2-ylamino)-4-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-7-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.56 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)