Clinical and pharmacological approaches to the choice of a drug for a tension-type headache relief

The article goes to describe clinical and pharmacological approaches to choosing a drug with an optimal efficacy/safety profile, providing the necessary analgesic effect in tension-type headache. TRPV1 brain receptors are considered the main action point of the mediator. Aim. The purpose of this study is a comparative analysis of the pharmacodynamic and pharmacokinetic parameters of ibuprofen and paracetamol as a part of fixed dose combination and as monotherapy in tension type headaches. Materials and methods. Comparative dissolution kinetics test; Comparative analysis of pharmacokinetic parameters using the PubMed/MEDLINE database. Results. The median Tmax of ibuprofen as a part of a fixed-dose combination and as a monotherapy is 75 minutes. The median Tmax of paracetamol is 30 min when taken in a fixed dose combination and 40 min as a monotherapy. In patients who received the fixed dose combination, the concentration of ibuprofen in the blood plasma after 10 minutes 6.64 g/ml-1; after 20 minutes 16.81 g/ml-1, while when taken in the same dose in as a monotherapy, respectively, 0.58 and 9.00 g/ml-1. The mean plasma concentrations of paracetamol after 10 and 20 minutes in patients receiving the fixed combination were 5.43 and 14.54 g/ml-1, respectively, compared with 0.33 and 9.19 g/ml-1 for paracetamol as monotherapy. dissolution kinetics test of the Paracytolgin: after 5 minutes, 20% of paracetamol passed into the solution in a system with a pH of 1.2; in a system with a pH of 4.5 36.4%; in a system with a pH of 6.8 33.5%; after 10 minutes, respectively 68.5, 98.0 and 89.6%. After 15 minutes, almost complete dissolution was noted in all systems: 98.5, 98.8 and 100.5%, respectively. Discussion. The combination of ibuprofen and paracetamol makes it possible to enhance the analgesic effect as a result of additive action by the help of central mechanisms. The fixed dose combination of ibuprofen and paracetamol significantly increases the rate of absorption of paracetamol, which has potential therapeutic benefits in terms of a faster analgesias onset. Conclusion. The fixed dose combination of ibuprofen and paracetamol provides faster and long-term anaesthesia with a comparatively lower dosage of each analgesic.

Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study.

3097 Background: Allosteric oncogenic mutations occur outside the canonical ATP-binding site of EGFR and HER2, and there are no approved therapies that target such mutations. BDTX-189 is a potent, selective, irreversible inhibitor of 48 allosteric EGFR and HER2 mutant variants under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465). BDTX-189 was designed to rapidly and irreversibly occupy the active site of targeted ErbB mutants, leading to sustained pharmacodynamic (PD) effects, and with selectivity over EGFR-WT in order to minimize EGFR-WT mediated toxicities. The pharmacokinetic (PK) profile was designed for rapid absorption and fast elimination to maintain target occupancy while minimizing prolonged drug exposure that could contribute to off-target associated toxicities. Methods: In MasterKey-01, BDTX-189 was administered orally once daily in continuous 21-day cycles, taken fasted. Dose escalation included cohorts of 1-2 patients receiving doses between 25 and 200 mg QD followed by 5-7 patients receiving 400 mg, 800 mg, or 1,200 mg QD fasted. The possible effects of a high fat meal on the PK of BDTX-189 were assessed in a subset of patients receiving single doses of 400 mg BDTX-189 fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 3 days between doses. In addition, a dose escalation cohort investigating administration of BDTX-189 non-fasted was enrolled at 800 mg QD. Serial blood samples for analysis of plasma BDTX-189 concentrations were collected after each dose on C1D1 and C1D15. BDTX-189 levels were determined using LC-MS, and data analyzed using non-compartmental methods. Results: After single and multiple doses, BDTX-189 was rapidly absorbed (median tmax 1-2 h), with an elimination t1/2 of 2-6 h. Dose-dependent increases in exposure from 200 to 800 mg QD fasted were observed, with no apparent accumulation or decline in exposures observed at steady-state. Administration of BDTX-189 with a high-fat meal increased AUC approximately 1.7-fold with minimal effect on Cmax, relative to administration in the fasted state. At 800 mg QD, mean AUC was similar in the non-fasting state relative to fasting and was within the target efficacious range defined by mouse models harboring allo-ErbB mutated tumors. Median tmax and t1/2 values were similar after administration in the non-fasted and fasted states. Conclusions: BDTX-189 demonstrated rapid absorption and a short PK half-life consistent with the desired PK/PD profile, with exposures in the efficacious target range based on preclinical data. The pilot high fat food-effect data and non-fasting QD dosing regimen show similar or improved systemic exposure relative to dosing in the fasted state. The MasterKey-01 trial is ongoing, including refinement of the dosing regimen and identification of the recommended phase 2 dose. Clinical trial information: NCT04209465.

Effect of Food on MDM2 Inhibitor KRT-232 Pharmacokinetics and Macrophage Inhibitory Cytokine-1 (MIC-1) Response in Healthy Volunteers

Background: KRT-232 is a potent, selective, orally available, small-molecule drug that binds to mouse double minute 2 homolog (MDM2) and inhibits its interactions with tumor suppressor protein p53. KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia, and Merkel cell carcinoma. Increased serum MIC-1 (pg/mL) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with KRT-232 (Allard,HemaSphere, 2020;4:S1, Abstract EP519). The aim of this study was to assess the safety and effect of a high-fat meal on KRT-232 pharmacokinetics (PK) and MIC-1 PD of a new tablet formulation in healthy volunteers. This is the first characterization of a MDM2-inhibitor-induced MIC-1 response in healthy volunteers. Methods: KRT-232-105 was a single-center, open-label, 60-mg single-dose, 3-treatment, 4-period, and 3-sequence study with a partial replicate crossover design. Volunteers (N=30) were randomized to three treatment groups: A: new tablet, fasted (reference, dosed twice in Periods 2-4); B: new tablet, 30 min after a high-fat, high-calorie meal (test 1, dosed once in periods 2-4); C: current tablet, fasted (test 2, period 1 only). Plasma KRT-232, its acyl glucuronide metabolite (M1) and serum MIC-1 concentrations were measured over 0-96 h. Urine from group C was collected over 0-48 h. Doses were one week apart. All volunteers had aH pyloribreath test and were genotyped for UGT1A1*28 polymorphisms. Results: Volunteers were 43% female, 7% African American and 77% Hispanic/Latino. Mean age was 38.1 y (range, 18-54), and mean body mass index was 26.9 kg/m2 (range, 21.4-30.9). No deaths, serious adverse events (SAEs), or discontinuations were reported. Twenty-one treatment-emergent AEs (TEAEs) were observed in 13 (43%) volunteers; constipation was the most frequent AE, followed by headache. All TEAEs were grade 1 (n=17) or grade 2 (n=4: 1 headache event [possibly study drug-related] and 3 events of headache, influenza-like illness, and pharyngitis). Mean (SD) concentration-time plots of KRT-232 and M1 were similar across the 3 groups (Figure 1a and b). A second peak was observed, consistent with enterohepatic recirculation. With a meal (test 1), KRT-232 geometric least-squares mean (GLSM) maximum concentration (Cmax) was similar (431 and 442 ng/mL (GLSM ratio [90% CI], 103% [87.4-121]) and KRT-232 GLSM area under the curve (AUC0-t) decreased from 2858 to 2325 ng∙h/mL (GLSM ratio [90% CI], 81.4 [76.2-86.9]). Median time of Cmax (Tmax) was 2 h fasted and 3 h fed. Geometric mean half life (t1/2) was unchanged (17.0 vs 17.1 h). Under fasting conditions, the current tablet (C, test 2) vs new tablet (A, reference), KRT-232 GLSM Cmax decreased from 431 to 337 ng/mL (GLSM ratio [90% CI], 78.4% [72.0-85.3]) and KRT-232 GLSM AUC0-t had a possible small decrease (2858 and 2455 ng∙h/mL, GLSM ratio [90% CI], 85.9 [80.5-91.7]). Median Tmax (~2 h) and geometric mean t1/2 (17 h) were unchanged. The fraction of the KRT-232 dose in urine as KRT-232 and M1 was negligible at 0.0201% and 0.0220% of dose, respectively. KRT-232 is a carboxylic acid with pH-dependent solubility that increases with increasing pH.H pyloriinfection, which can increase stomach pH, did not have any discernable impact on KRT-232 PK. KRT-232 and M1 exposure in heterozygous UGT1A1*28 poor metabolizers (6/7 TA repeats, N=16) was generally comparable to exposure in wild-type (WT) UGT1A1*28 (6/6 TA repeats, N=12) subjects. MIC-1 concentrations in serum were variable and followed the PK time course with a median Tmax lag of ~8-12 h. Group A: Mean Cmax 2115 pg/mL, C0 (Baseline) 170 pg/mL, AUC0-T 89267 pg*h/mL and mean t1/2 27 h. MIC-1 Cmax and AUC were generally comparable over 96 h across groups (Figure 1c).Figure 1dshows the statistically significant correlation between KRT-232 AUC0-t and MIC-1 AUC0-t. Conclusions: Based on generally comparable PK, KRT-232 can be administered with or without food, and no dose adjustment is warranted with a new tablet formulation. KRT-232 PK was not affected byH pylori, inferring that higher gastric pH did not alter absorption of KRT-232. KRT-232 exposure in UGT1A1*28 heterozygous poor metabolizers was generally comparable to WT UGT1A1*28 wild type healthy volunteers. The 60-mg KRT-232 dose elicited a reproducible and robust MIC-1 response that correlated with KRT-232 exposure, indicating MDM2-p53 target engagement. Disclosures Wong: Kartos Therapeutics:Current Employment;AbbVie Biotherapeutics:Ended employment in the past 24 months.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Lee:Kartos Therapeutics:Current Employment.Harris:Gilead Sciences:Current equity holder in publicly-traded company;Kartos Therapeutics:Current Employment, Current equity holder in private company;BeiGene:Ended employment in the past 24 months;Clovis:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Simard:Certara:Current Employment;AltaScience:Ended employment in the past 24 months.Wang:Certara:Current Employment.Rubets:Certara:Current Employment.Allard:Certara:Consultancy, Ended employment in the past 24 months;CytomX Therapeutics:Ended employment in the past 24 months;Telios Pharma:Current Employment, Current equity holder in private company.Podoll:IV/PO, LLC:Consultancy.O'Reilly:Celerion:Current Employment.Slatter:Amgen:Divested equity in a private or publicly-traded company in the past 24 months;Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor.

Computed Tomography Perfusion After Thrombectomy

Background and Purpose— Despite recanalization, almost 50% of patients undergoing endovascular treatment (EVT) experience poor outcome. We aim to evaluate the value of computed tomography perfusion as immediate outcome predictor postendovascular treatment. Methods— Consecutive patients receiving endovascular treatment who achieved recanalization (modified Thrombolysis in Cerebral Ischemia [mTICI] 2a-3) underwent computed tomography perfusion within 30 minutes from recanalization (CTPpost). Hypoperfusion was defined as the Tmax>6 second volume; hyperperfusion as visually increased cerebral blood flow/cerebral blood volume with reduced Tmax compared with unaffected hemisphere. Dramatic clinical recovery (DCR) was defined as 24-hour National Institutes of Health Stroke Scale score ≤2 or ≥8 points drop. Delayed recovery was defined as no-DCR with favorable outcome (modified Rankin Scale score 0–2) at 3 months. Results— We included 151 patients: median National Institutes of Health Stroke Scale score 16 (interquartile range, 10–21), median admission ASPECTS 9 (interquartile range, 8–10). Final recanalization was the following: mTICI2a 11 (7.3%), mTICI2b 46 (30.5%), and mTICI3 94 (62.3%). On CTPpost, 80 (52.9%) patients showed hypoperfusion (median Tmax>6 seconds: 4 cc [0–25]) and 32 (21.2%) hyperperfusion. There was an association between final TICI and CTPpost hypoperfusion(median Tmax>6: 91 [56–117], 15 [0–37.5], and 0 [0–7] cc, for mTICI 2a, 2b, and 3, respectively, P <0.01). Smaller hypoperfusion volumes on CTPpost were observed in patients with DCR (0 cc [0–13] versus non-DCR 8 cc [0–56]; P <0.01) or favorable outcome (modified Rankin Scale score 0–2: 0 cc [0–13] versus 7 [0–56] cc; P <0.01). No associations were detected with hyperperfusion pattern. An hypoperfusion volume <3.5 cc emerged as independent predictor of DCR (OR, 4.1 [95% CI, 2.0–8.3]; P <0.01) and 3 months favorable outcome (OR, 3.5 [95% CI, 1.6–7.8]; P <0.01). Conclusions— Hypoperfusion on CTPpost constitutes an immediate accurate surrogate marker of success after endovascular treatment and identifies those patients with delayed recovery and favorable outcome.

A Randomized Phase 1 Safety Study of Repeated Doses of Intranasal OP0201 Metered Dose Inhaler Compared to Placebo in Healthy Adults: A Potential Treatment for Otitis Media

Background OP0201 Nasal Aerosol is a novel drug-device surfactant product being developed for treatment and prevention of otitis media. The active ingredients in OP0201, dipalmitoylphosphatidylcholine (DPPC) and cholesteryl palmitate (CP), are endogenous to the human nasal and respiratory systems. This phase 1 study evaluated the safety and tolerability of OP0201 in healthy adults. Methods This was a randomized, double-blind, placebo-controlled, parallel-group study with a dose-escalation cohort design to evaluate 30 mg/day (Cohort A) and 60 mg/day (Cohort B) of OP0201. Subjects were randomized 4:1 to receive either OP0201 or placebo 3 times per day for 14 consecutive days. Treatment was administered via a metered dose inhaler and sprayed directly backwards into each nostril. Primary endpoints were adverse events, otoscopy, tympanometry, nasal and epipharynx endoscopy, University of Pennsylvania Smell Identification Test (UPSIT), audiology pure-tone hearing test, 12-lead electrocardiography, physical examination, vital signs, and clinical laboratory tests. Exploratory endpoints included baseline-adjusted maximum serum concentration (Cmax) and time to maximum concentration (tmax) of DPPC and CP on Day 14 in Cohort B. Results 101 participants were screened, and 30 were randomized (15 per cohort; n=12 OP0201, n=3 placebo). No deaths, serious adverse events, or treatment-emergent adverse events leading to study discontinuation were reported. No clinically significant deviations from baseline were found in any of the primary endpoints. Serum DPPC and CP concentrations on Day 14 were comparable to baseline in the OP0201 group and numerically higher in the placebo group. Mean baseline-corrected serum DPPC Cmax on Day 14 was 0.82 µg/mL with OP0201 and 4.51 µg/mL with placebo, with a median tmax observed at 0.05 hours for both groups. Mean baseline-corrected serum CP Cmax on Day 14 was 14.89 µM with OP0201 and 89.50 µM with placebo, with a median tmax observed at 0.05 and 0.22 hours for OP0201 and placebo, respectively. Conclusions OP0201 was safe and well tolerated in healthy adults. There were no supraphysiologic systemic concentrations of DPPC or CP after local intranasal administration of a 60 mg/day dose of OP0201. These outcomes support continued development of OP0201 with future studies in a patient population.