Elimination Half-life Research Articles

Population Pharmacokinetic of the Diterpenes ent-Polyalthic Acid and Dihydro-ent-Agathic Acid from Copaifera Duckei Oil Resin in Rats.

Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.

Discovery of a Double-Stapled Short Peptide as a Long-Acting HIV-1 Inactivator with Potential for Oral Bioavailability.

Different from most antiretroviral drugs that act as passive defenders to inhibit HIV-1 replication inside the host cell, virus inactivators can attack and inactivate HIV-1 virions without relying on their replication cycle. Herein, we describe the discovery of a hydrocarbon double-stapled helix peptide, termed D26. D26 is based on the HIV-1 gp41 protein lentiviral lytic peptide-3 motif (LLP3) sequence, which can efficiently inhibit HIV-1 infection and inactivate cell-free HIV-1 virions. It was noted that D26 was highly resistant to proteolytic degradation and exhibited a remarkably extended in vivo elimination half-life. Additionally, relative to its linear, nonstapled version, D26 exhibited much higher exposure in sanctuary sites for HIV-1. Amazingly, this lead compound also demonstrated detectable oral absorption. Thus, it can be concluded that D26 is a promising candidate for further development as a long-acting, orally applicable HIV-1 inactivator for the treatment of HIV-1 infection.

Pharmacokinetics and pharmacodynamics of intravenously and subcutaneously administered pantoprazole in sheep (Ovis aries).

Abomasal ulcers are recognized in sheep of all ages, but research regarding therapeutic interventions is limited. Proton Pump Inhibitors (PPIs) such as pantoprazole, are clinically used with a paucity of evidence regarding efficacy in mature sheep. Intravenous and subcutaneously administered pantoprazole dosed at 1.0 mg/kg in adult sheep will increase the pH of abomasal fluid compared to pre-administration baseline. The objectives were to assess the effect of pantoprazole, after single and multiple administration, on abomasal fluid pH in adult sheep. A third objective was to describe the pharmacokinetic parameters of IV and SC pantoprazole. Four clinically healthy adult Southdown ewes previously fitted with a gastrostomy tube in the abomasum were utilized in this randomized, 2-way cross-over trial. Ewes received pantoprazole (1.0 mg/kg) as a single and 3-dose regimen (every 24 hours). After a 10 day washout period the reverse treatment was applied. Blood for analysis of pantoprazole concentration was collected intermittently for 24 hours, and abomasal fluid pH was measured at intervals for a 96-hour period. The pH of the abomasal fluid was higher in pantoprazole treatments for up to 24 hours after dosing. Following intravenous administration of pantoprazole to study ewes, elimination half-life, volume of distribution, and clearance of pantoprazole was estimated as 3.29 hours, 0.35 L/kg, and 65.26 mL/hr/kg respectively. After subcutaneous dosing, maximum concentration, time to maximum concentration, half-life of elimination, and volume of distribution, were estimated as 2604 ng/mL, 0.55 hours, 2.48 hours, and 0.37 L/kg. Additionally, the bioavailability was estimated as 83.33%. Pantoprazole administered IV or SC may be useful for treatment or prevention of abomasal ulcers in adult sheep.

Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double-blind, placebo-controlled, crossover study.

The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1-antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1-antagonist (ACD440 Gel) in healthy subjects. The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double-blind, placebo-controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB-irradiated skin. Pain induced by thermo-nociceptive CO2 laser impulses generated laser-evoked potentials (LEPs), with readouts of peak-to-peak (PtP) amplitude in vertex-EEG and pain assessments by VAS (0-100). Endpoints include effects at 1 hour post-dose, AUC(Days 1-5) and AUC(0-24, Day 4). In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440. ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB-irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug-induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half-life of ACD400. Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development. This study demonstrates that the topical administration of a TRPV1-antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

The Intoxication Equivalency of 11-Hydroxy-Δ9-Tetrahydrocannabinol Relative to Δ9-Tetrahydrocannabinol.

Δ9-Tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), which may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via intraperitoneal injection, tail vein intravenous injection, or oral gavage, and whole-blood compound levels were measured to determine pharmacokinetic parameters [Cmax, time to Cmax (Tmax), elimination half-life, area under the curve, apparent volume of distribution, systemic clearance, terminal rate constant, and absolute bioavailability] while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved a Tmax at 30 minutes for all routes of administration. The maximum concentration at 30 minutes was not different between intravenous and intraperitoneal routes, but the oral gavage Cmax was significantly lower. THC had a 10-minute time to the maximum concentration, which was the first blood collection time point, for intravenous and intraperitoneal and 60 minutes for oral gavage, with a lower Cmax for intraperitoneal and oral gavage compared with intravenous. When accounting for circulating compound levels and ED50 responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for pharmacokinetic differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies. SIGNIFICANCE STATEMENT: This study establishes that the primary metabolite of THC, 11-OH-THC, displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future in vivo cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.

Enhancing the Bioavailability of the Ellagitannin, Geraniin: Formulation, Characterization, and in vivo Evaluation

Geraniin (GE), an ellagitannin (ET) renowned for its promising health advantages, faces challenges in its practical applications due to its limited bioavailability. This innovative and novel formulation of GE and soy-phosphatidylcholine (GE-PL) complex has the potential to increase oral bioavailability, exhibiting high entrapment efficiency of 100.2 ± 0.8 %, and complexation efficiency of 94.6 ± 1.1 %. The small particle size (1.04 ± 0.11 μm), low polydispersity index (0.26 ± 0.02), and adequate zeta potential (−26.1 ± 0.12 mV), indicate its uniformity and stability. Moreover, the formulation also demonstrates improved lipophilicity, reduced aqueous and buffer solubilities, and better partition coefficient. It has been validated by various analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. Oral bioavailability and pharmacokinetics of free GE and GE-PL complex investigated in rabbits demonstrated enhanced plasma concentration of ellagic acid (EA) compared to free GE. Significantly, GE, whether in its free form or as part of the GE-PL complex, was not found in the circulatory system. However, EA levels were observed at 0.5 h after administration, displaying two distinct peaks at 2 ± 0.03 h (T1max) and 24 ± 0.06 h (T2max). These peaks corresponded to peak plasma concentrations (C1max and C2max) of 588.82 ng/mL and 711.13 ng/mL respectively, signifying substantial 11-fold and 5-fold enhancements when compared to free GE. Additionally, it showed an increased area under the curve (AUC), the elimination half-life (t1/2, el) and the elimination rate constant (Kel). The formulation of the GE-PL complex prolonged the presence of EA in the bloodstream and improved its absorption, ultimately leading to a higher oral bioavailability. In summary, the study highlights the significance of the GE-PL complex in overcoming the bioavailability limitations of GE, paving the way for enhanced therapeutic outcomes and potential applications in drug delivery and healthcare.

FORMULATION AND EVALUATION OF LOSARTAN POTASSIUM MATRIX TABLETS BY USING DIFFERENT POLYMERS

The study aims to create a sustained release matrix tablet for Losartan potassium, an angiotensin II receptor antagonist, to improve patient compliance and maintain therapeutic blood or tissue levels for extended periods. The research investigates the role of novel semi-synthetic polymers and natural polymers in comparison to well-known release retarding agents. Gastroretentive drug delivery systems (GRDDS) are unique technologies designed to improve drug bioavailability and absorption by avoiding the first-pass effect. Losartan potassium, an angiotensin II receptor antagonist, has a bioavailability of 32% and a low elimination half-life, making it suitable for oral controlled release. The study utilized natural and synthetic polymers in matrix tablet preparation, concentration, drug particles size, additives, and excipients to modify drug release. The powder mixtures were tested for pre-compression parameters and post-compression parameters, and in-vitro dissolution studies showed good dissolution profiles for drug release. Formulations with higher concentrations and polymers sustained drug release for 24 hours. FT-IR Spectroscopy confirmed drug compatibility with polymers and other excipients KEYWORDS: matrix tablets, Losartan Potassium, flow properties, pre compression parameters post compression parameters, In-vitro dissolution.

Effect of theophylline on serum and milk pharmacokinetics of tylosin following intramuscular administration in lactating goats

Aim of the workThe study was conducted to evaluate the influence of theophylline pre-treatment on serum pharmacokinetics and milk elimination of tylosin following single intramuscular (IM) administrations in lactating goats.Methods and resultsIn a cross-over study, tylosin was injected via intramuscular (IM) at a single dose of 15 mg/kg b.wt. After a one-month washout period goats received theophylline at a daily IM dose of 2 mg/kg b.wt. for seven consecutive days then tylosin was injected IM dose of 15 mg/kg b.wt. two hours after the last theophylline dosing. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h post-injection. Samples were left to clot and then centrifuged to yield serum. Milk samples were collected before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h post-injection from each goat by hand milking. Tylosin serum concentrations were determined by high-performance liquid chromatography (HPLC). Tylosin concentrations versus time were analyzed by a noncompartmental method. Tylosin Cmax significantly declined from 1.73 ± 0.10 to 1.01 ± 0.11 µg/ml, and attained Tmax values of 2 and 1 h, respectively in theophylline-pretreated goats. Moreover, theophylline pretreatment significantly shortened the elimination half-life (t1/2el) from 6.94 to 1.98 h, t1/2ka from 0.62 to 0.36 h and the mean residence time (MRT) from 8.02 to 4.31 h, also Vz/F and AUCs decreased from 11.91 to 7.70 L/kg and from 12.64 to 4.57 µg*h/ml, respectively, consequently, theophylline enhanced the clearance (Cl/F) of tylosin from the body. Similarly, tylosin milk concentrations were significantly lower in theophylline-pretreated goats than in goats that received tylosin alone and were detected up to 24 and 72 h in both groups, respectively. Moreover, the t1/2el and AUCs were significantly decreased from 14.68 ± 1.97 to 4.72 ± 0.48 h, and from 181 to 67.20 µg*h/ml, respectively.ConclusionsThe withdrawal period for tylosin in goat milk is at least 72 h. Theophylline pretreatment significantly decreases serum and milk tylosin concentrations to subtherapeutic levels, which could have serious clinical consequences such as failure of therapy. This means that after administering tylosin to goats, milk from these animals should not be consumed for at least 96 h to ensure that the milk is free from residues of the antibiotic.

In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1

In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterial β-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species. The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively. The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation, deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat. Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mL were measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients.

The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Therapeutic drug monitoring data from initial vancomycin therapy (first 3days of treatment) in adult obese (BMI ≥ 30kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.

A phase IIA clinical trial to evaluate a reversible Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).

e19042 Background: This clinical study is to evaluate HBW-3220, a novel BTKi with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (approved) and nemtabrutinib (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (enriched in pirtobrutinib resistance), and hematopoietic cell kinase (HCK, a key contributor to BTKi resistance due to kinase-defective BTK). Methods: This phase IIA clinical study is conducted in R/R B-NHL patients who had received two or more prior lines of treatment. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determine whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) are assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment is based on iwCLL 2018 guidelines for chronic lymphocytic leukemia (CLL), IWWM-7 consensus for Waldenstrom macroglobulinemia (WM), and Lugano 2014 guidelines for all other lymphomas, including small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma (FL). Results: 29 patients have been enrolled, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (36%), diarrhea (32%), headache (18%), anemia (39%), infectious pneumonia (18%), decreased neutrophils count (39%), decreased platelet count (29%), increased alanine aminotransferase (21%), etc. Drug-related Grade 3 AEs included decreased neutrophil count (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 23 patients underwent at least 1 response assessment. The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 4 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 83% (5/6), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR, 90% (9/10) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated with no DLT occurred at daily doses up to 150 mg, displaying most promising efficacy in patients with CLL/SLL, MZL, and MCL. Clinical trial information: ChiCTR2200062537.

Safety, efficacy, pharmacokinetics, and pharmacodynamics of the illudofulvene drug CAP-0121.

e15120 Background: Irofulven is an anticancer agent derived from illudin S initially investigated due to its unique mechanism of action and potential to overcome multi-drug resistance. This study investigates the pharmacokinetics/pharmacodynamics (PK/PD) and efficacy and safety of the second-generation drug, CAP-0121 (Califia Pharma). Methods: 24-hour comprehensive PK was performed at two different intravenous (IV) doses in canines for irofulven (0.2 mg/kg and 1 mg/kg; MTD) and CAP-0121 (1 mg/kg and 3 mg/kg). Plasma concentrations were measured by LC-MS/MS and PK parameters were calculated for both drugs using noncompartmental methods (Phoenix WinNonlin, version 8.4). PK parameters included area under the concentration vs time curve (AUC), maximum observed concentration (Cmax), clearance (CL), volume of distribution (Vd), and elimination half-life (t1/2). Canine chemistry/hematology/coagulation/urine panels, were measured across 28 days to ascertain the maximum tolerated dose (MTD). Both platelet and neutrophil count reversibility was also assessed. Mice xenograft models implanted with a drug resistant human ovarian cancer (A2870), or a drug-resistant human metastatic lung cancer (MV522), were dosed with irofulven (9 mg/kg; MTD) and CAP-0121 (15, 20, and 25 mg/kg) and resulting tumor mass, % change in body weight, and platelet counts were compared relative to vehicle only. Results: Systemic exposure, CL, Vd, and t1/2 were similar between irofulven and CAP-0121 at a 1 mg/kg IV dose. For irofulven, AUC increased approximately proportionally at doses of 0.2 mg/kg and 1 mg/kg. For CAP-0121, exposure also increased proportionally at doses of 1 mg/kg and 3 mg/kg. MTD of CAP-0121 was found to be 3-fold higher in canines compared to irofulven as 3-fold more CAP-0121 was required to match the platelet reduction observed with irofulven; platelet and neutrophil nadir was rapidly reversible for CAP-0121. Canine nadir platelets and neutrophil counts were 3-fold higher for CAP-0121 vs irofulven at the same dose (1 mg/kg). There was no evidence of any canine systemic organ toxicity (gross, histologic, blood and urine analysis) for CAP-0121 at either dose. CAP-0121 was superior to irofulven (p &lt; 0.02) with regards to final tumor weights in mice xenograft models, even though MTD was not reached for CAP-0121; a change in body weight and platelet loss was not observed for CAP-0121 at up 25 mg/kg in mice. With regards to in vitro anticancer cytotoxic activity, the two drug-resistant xenograft models confirm the superiority of CAP-0121 over irofulven. This study demonstrates that CAP-0121 has favorable PK parameters and a wider therapeutic window in humans compared to irofulven, emphasizing the potential anticancer utility of CAP-0121 for solid cancers without prolonged thrombocytopenia. Conclusions: Further investigation in clinical trials is warranted to confirm these preclinical observations.

Preliminary results of a phase 1, first-in-human, dose escalation study of the anti-CCR8 cytolytic antibody, CHS-114 (formerly SRF114) in patients with advanced solid tumors.

2664 Background: Depletion of intratumoral regulatory T cells (itTregs) represents an attractive therapeutic strategy to enhance antitumor responses. The chemokine receptor CCR8 is preferentially expressed on itTregs compared to peripheral Tregs and other immune cell types, and CCR8 expressing itTregs are highly immune suppressive. Our preclinical studies have demonstrated that treatment of a PD-1 resistant mouse tumor model with an anti-CCR8 monoclonal antibody (mAb) depletes itTregs, reduces tumor growth, and enhances anti-PD-1 antitumor activity. CHS-114 an afucosylated mAb that binds CCR8, depletes itTregs, and enhances toripalimab- (tori; anti-PD-1 mAb) mediated T cell activation. Here, we present preliminary results of the first-in-human phase 1 study of CHS-114. Methods: This phase 1, multicenter, single agent and combination (combo) dose escalation study (NCT05635643) of CHS-114 is enrolling patients (pts) ≥18 years of age with advanced solid tumors who progressed during or after standard therapy. CHS-114 dose escalation guided by the Bayesian optimal interval (BOIN) design will evaluate doses ranging from 5 to 1500 mg q3w. Five additional pts with advanced head and neck squamous cell carcinoma (HNSCC) will be enrolled at each of 2 selected dose levels (DLs) with required biopsies. Combo dose escalation will evaluate 2 DLs of CHS-114 combined with tori 240 mg q3w in pts with HNSCC using a standard 3+3 design. Primary objectives are to determine the recommended dose(s) for expansion of CHS-114 and the safety and tolerability of CHS-114 + tori. Secondary objectives are to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of CHS-114 alone and in combination with tori. Tumor and immune biomarkers are being evaluated as exploratory endpoints. Results: As of 15Dec2023, 15 pts received CHS-114 at doses ranging from 5 to 700 mg q3w. No dose-limiting toxicities (DLTs) were reported. Treatment-related adverse events occurred in 33% of pts; all were CTCAE grade 1-2, with pyrexia (13%) being the most common. Preliminary PK analysis indicates that CHS-114 exposure increases with dose with an elimination half-life between 9-17 days across the dose range of 10-700 mg. Preliminary receptor occupancy analysis using an immune profiling assay in peripheral blood at 100, 300, and 700 mg DLs revealed minimal detection of CCR8+ Tregs and a modest concomitant decrease in overall Treg frequency at the end of cycle 1, consistent with strong receptor occupancy. Conclusions: CHS-114 has an acceptable safety profile to date in heavily pretreated pts at doses up to 700 mg. CHS-114 administration at 100 to 700 mg shows robust decreases in peripheral CCR8+ Tregs following the first dose (cycle 1). Dose escalation is ongoing. Clinical trial information: NCT05635643 .

Enhanced Pharmacokinetics of Celastrol via Long-Circulating Liposomal Delivery for Intravenous Administration.

Rheumatoid Arthritis (RA) involves prolonged inflammation of the synovium, damaging joints and causing stiffness and deformity. Celastrol (Cel), derived from the Chinese herbal medicine Tripterygium wilfordii Hook F, offers immunosuppressive effects for RA treatment but is limited by poor solubility and bioavailability. In this study, long-circulating Cel-loaded liposomes (Cel-LPs) were used to increase the pharmacokinetics of Cel, thereby improving drug delivery and efficacy for the treatment of RA. Cel-LPs were prepared and administered orally and intravenously to compare the elimination half-life of drugs and bioavailability of Cel. Cel-LPs were prepared using the lipid thin-layer-hydration-extrusion method. Human rheumatoid arthritis synovial (MH7A) cells were used to investigate the compatibility of Cel-LPs. The pharmacokinetic studies were performed on male Sprague-Dawley (SD) rats. The Cel-LPs had an average size of 72.20 ± 27.99 nm, a PDI of 0.267, a zeta potential of -31.60 ± 6.81 mV, 78.77 ± 5.69% drug entrapment efficiency and sustained release (5.83 ± 0.42% drug loading). The cytotoxicity test showed that liposomes had excellent biocompatibility and the fluorescence microscope diagram indicated that liposome entrapment increased intracellular accumulation of Rhodamine B by MH7A cells. Furthermore, the results exhibited that Cel-LPs improved the pharmacokinetics of Cel by increasing the elimination half-life (t1/2) to 11.71 hr, mean residence time (MRT(0-∞)) to 7.98 hr and apparent volume of distribution (Vz/F) to 44.63 L/kg in rats, compared to the Cel solution. In this study, liposomes were demonstrated to be effective in optimizing the delivery of Cel, enabling the formulation of Cel-LPs with prolonged blood circulation and sustained release characteristics. This formulation enhanced the intravenous solubility and bioavailability of Cel, developing a foundation for its clinical application in RA and providing insights on poorly soluble drug management.

A phase 1/1b, first-in-human, multi-part study of DF6215, an engineered IL-2Rα-active agonist, to investigate the safety, tolerability, pharmacokinetics, and biological and clinical activity in patients with advanced solid tumors.

TPS2704 Background: IL-2 is a pleiotropic cytokine that stimulates strong anti-tumor responses by promoting expansion and activation of cytotoxic tumor-infiltrating immune cells including CD8 + T cells and NK cells (1). Aldesleukin is an approved rhIL-2; however, it has clinical limitations due to short half-life, requirement for 5 days of hospitalization per cycle, and high toxicity [eg, cytokine-related toxicity, capillary leak syndrome (CLS)] that limits its use [aldesleukin USPI]. DF6215 is a modified monovalent human IL-2 that binds to the IL2R. Preclinically, DF6215 administration results in sustained and modulated IL-2 pharmacology, leading to protracted pharmacodynamic (PD) effects and enhanced anti-tumor activity without observation of CLS in murine and primate toxicology studies. In response to the limitations of previous IL-2 therapeutics, DF6215 was designed as an IL-2Rα-active agonist with increased IL-2Rβγ stimulation to improve the benefit-to-risk ratio of historic IL-2 drugs. An additional design element is a prolonged elimination half-life due to Fc fusion, allowing for less frequent dosing. Methods: This is a first-in-human, open-label, multipart, Phase 1/1b clinical trial to characterize the initial safety, tolerability, pharmacokinetics, and preliminary efficacy of DF6215 in patients with advanced solid tumors. The Phase 1 dose escalation (DE) starting dose is 10 ug/kg IV every 2 weeks (up to 42 subjects expected to be enrolled), and the Safety/PK/PD will be explored at doses already characterized as safe in dose escalation and potentially efficacious (max of 40 subjects). Phase 1b includes an efficacy expansion (EE) cohort in subjects with advanced melanoma who have received prior anti-PD-1 agents and, if the tumor harbors a BRAF-activating mutation, a BRAF inhibitor. Key inclusion criteria include ≥ 18 years of age; ECOG PS of 0 or 1; adequate organ function, and locally advanced or metastatic solid tumors for which standard therapy options have been exhausted; and availability of baseline tumor biopsy. Primary objectives include determination of the MTD of DF6215 in DE and demonstration of clinical activity of DF6215 in the EE. Secondary objectives include assessment of safety and tolerability, pharmacokinetics, and immunogenicity of DF6215. This study plans to enroll up to 102 subjects across ~30 global centers in the US, European, and the Asia/Pacific regions, and is currently open to enrollment. 1. Arenas-Ramirez N, et al. 2015. Trends Immunol. Clinical trial information: NCT06108479 .

Pharmacokinetic (PK) and pharmacodynamic (PD) findings from a phase 1b study of ATR inhibitor tuvusertib + anti-PD-L1 avelumab in patients with advanced unresectable solid tumors.

2614 Background: Ataxia telangiectasia and Rad3-related protein (ATR) kinase is critical in the DNA damage response, and its inhibition modulates antitumor immunity. The combination of ATR inhibitor (ATRi) + immune checkpoint inhibitor (ICI) has shown activity in patients with ICI-resistant tumors and may have the potential to overcome ICI resistance and induce antitumor immune responses. Methods: Part B1 of the open-label, multicenter study DDRiver Solid Tumors 320 investigated safety, tolerability, PK, and PD, including effects on immune cells, of ATRi tuvusertib in combination with the ICI avelumab (anti-PD-L1) in patients with advanced unresectable solid tumors. Flow cytometry was used to analyze tuvusertib target inhibition via γ-H2AX modulation in the CD45+ fraction of ex-vivo stimulated peripheral blood mononuclear cells, and to explore the effect on the peripheral immunophenotype. Tuvusertib PK samples were analyzed by a validated bioanalytical liquid chromatography/mass spectrometry method. Results: 22 patients were enrolled and treated with tuvusertib 180 mg once daily on a schedule of 2 weeks (w) on treatment followed by a treatment break of 1 or 2 w, and avelumab 800 mg once every 2 weeks (Q2W). The 2 w on/1 w off schedule, corresponding to the recommended dose for expansion (RDE) for tuvusertib monotherapy, was chosen for further exploration. At this schedule, 2 of 9 patients evaluable for dose-limiting toxicity (DLT) experienced DLTs: Grade 3 ALT and Grade 3 AST increase (n=1), and Grade 3 anemia requiring transfusion (n=1). A patient with chordoma experienced a RECIST v1.1 partial response. Preliminary PK data for tuvusertib suggested rapid absorption with median Tmax range of ~2–3 h and mean elimination half-life range of ~2.93 to 4.23 h, with ~2-fold accumulation of steady-state area-under-the-curve following multiple doses. Exposure of tuvusertib in combination with avelumab was consistent with tuvusertib monotherapy exposure (1). PD showed complete or almost complete target inhibition at 1–6 h after tuvusertib 180 mg followed by rebound above baseline after 24 h on days 1 and 8 of cycle 1. No clear trend of variation in absolute counts of myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cell subtypes was detected. Conclusions: Tuvusertib and avelumab were combined at established monotherapy doses with no new safety findings. Tuvusertib PD and exposure data were in line with monotherapy observations. The combination did not cause any consistent change of the immunophenotype. Given the accumulating evidence of ATRi as an immunosensitiser (2), further evaluation of this combination in patients with ICI-resistant advanced solid tumors is warranted. 1. Yap T et al., Ann Oncol 2022;33(suppl_7):S197–S224. 2. Besse B et al., JTO 2022;17(suppl_9):S41–S42. Clinical trial information: NCT05396833 .

Tramadol intoxication in children: An emerging issue

Background: Prescribing tramadol in children raises safety concerns. In Europe, tramadol is still approved and licensed for use in children over 1-3 years of age, depending on the country. In this context, the authors report a case of a tramadol overdose in a 5-year-old-child with a medical history of homozygous sickle cell disease.Methods: Tramadol and M1 were quantified using liquid chromatography with a diode array detection method. CYP2D6 genotype was determined using a Next Generation Sequencing platform (MISeq, Illumina).Results: Tramadol and M1 were quantified in blood respectively at 5.48 and 1.32 µg/mL at admission, at 0.77 and 0.35 µg/mL 12 hours later, and at 0.32 and 0.18 µg/mL 20 hours later. The patient was predicted as a CYP2D6 normal metabolizer (*35/*29).Conclusion: One of the most important difficulties with the use of tramadol in children relates to its pharmacokinetic (PK) properties. Indeed, tramadol’s PK is characterized by a great variability related to: i) anatomical/physiological factors that impact the volume of distribution (Vd); ii) CYP2D6 genetic polymorphisms. Considering such an issue is particularly relevant to prevent poisoning. In the reported case, the plasma elimination half-life was estimated at 6.3 h, significantly more than those reported in 2-8 year-old children (about 3 h). This discrepancy does not seem related to genetic polymorphisms but rather to the Vd. Indeed, the patient was predicted to be a CYP2D6 normal metabolizer (*35/*29). The case presented here highlights the risk associated with the tramadol use in children and emphasizes the importance of considering PK variability among this population. Such variability necessitates greater caution in prescribing tramadol in children and highlights the importance of therapeutic education for families of children treated with this painkiller.

Diltiazem Hydrochloride Floating Matrix Tablet: Formulation and in vitro-in vivo Evaluation.

Diltiazem hydrochloride is a calcium channel-blocker with a plasma elimination half-life of 4.4 ± 1.3 h and has a narrow absorption window. So, this work aimed to prepare a gastro-retentive floating matrix tablet. The direct compression method was used to manufacture tablets. 32 factorial design was applied for optimization, taking Hydroxypropyl Methylcellulose K100M (HPMC K 100M) and the amount of sodium bicarbonate as independent factors and cumulative percentage release at 1 h, at 6 h, and at 12 h and floating lag time as dependent variables. The high amount of HPMC K100M and sodium bicarbonate shows good results. The optimized preparation was evaluated for differential scanning calorimetry, in-vivo gastric retention in male albino rabbits, kinetic modeling, and stability study. An in vivo study revealed gastric retention of tablets up to 6 h in healthy male Albino rabbits. The stability study indicated no significant change in the buoyancy and release profiles of the drug. From this study, it can be concluded that the gastro-retentive diltiazem hydrochloride floating matrix tablet was successfully prepared and retained inside the rabbit stomach for up to 6 h and was stable under accelerated stability study.

Preliminary safety and efficacy of TQB2930, a HER2-targeted bispecific antibody in patients with advanced breast cancer: Results from a phase 1b study.

1026 Background: TQB2930 is a HER2-targeted bispecific antibody, binding to two distinct HER2 epitopes, the same domain as trastuzumab (ECD4) and pertuzumab (ECD2). This study aims to evaluate the safety and efficacy of TQB2930 for patients with advanced breast cancer after failure of standard therapy. Methods: This phase 1b, dose-escalation and expansion trial included patients preferred HER2-expressing or HER2-amplified breast cancer who had received standard therapy. In the dose-escalation phase, TQB2930 was given weekly (10mg/kg, QW), biweekly (20mg/kg, Q2W), or triweekly (30mg/kg, Q3W). After the dose-escalation phase, eligible patients were enrolled and dosed biweekly or triweekly in the expansion cohort. The primary endpoints were safety, maximum tolerated or maximum administered dose, and the secondary endpoints were immunogenicity, pharmacokinetics, and tumor response per RECIST v1.1. Results: As of Dec 20, 2023, 34 patients(pts) have received TQB2930 weekly (n=3), biweekly (n=16), and triweekly (n=15). All pts were female, the median age was 59. 22 pts had HER2 expression of ICH3+ or ICH2+ with FISH+, and the others had ICH2+ with FISH- or ICH1+. The median prior lines of therapies were 3 (range: 0-8), with one pt intolerance to first-line treatment enrolled, and the median prior lines of HER2-targeted therapies were 2 (range: 0-8). No dose-limited toxicity was observed. The main treatment-related adverse events (TRAEs) were infusion reaction, occult blood of urine, leukopenia, and neutropenia. 3 pts were reported grade≥3 TRAEs, including neutropenia, anemia, and hypokalemia. Of 31 response-evaluable pts, the objective response rate (ORR) was 25.8% with 8 partial responses (PRs) were observed (including 5 confirmed PRs and 3 PRs awaiting confirmation). The disease control rate was 80.6%. Moreover, 5 pts achieved PR at 30mg/kg (ORR 41.7%), including one with prior exposure to trastuzumab, pyrotinib, tucatinib, ARX788, and the other one prior to trastuzumab, pertuzumab, lapatinib, MRG002. The median progression-free survival for all pts was 5.5 months (95%CI 3.58-NE). Additionally, Pharmacokinetic analysis showed exposure (Cmax and AUC0-t) of TQB2930 increased linearly with doses within 10~30mg/kg. After dosing, the mean peak concentration reached at 2.5-4.3 h, and the elimination half-life of TQB2930 was 109-161 h. Conclusions: TQB2930 is well tolerated and has demonstrated promising single-agent anti-tumor activity in HER2-positive breast cancer who have failed standard anti-HER2 therapies, including multiple lines of prior HER2 targeted agents. These early signs of activity support the further exploration of combination therapy of TQB2930 and the study is ongoing. Clinical trial information: NCT06202261 .

First-in-human study of ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.

3001 Background: SEZ6 is a transmembrane protein expressed in small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NENs), and central nervous system (CNS) tumors. These malignancies have a high unmet need for novel effective therapies. ABBV-706 is an ADC targeting SEZ6 conjugated to a topoisomerase 1 inhibitor payload at a drug-to-antibody ratio of 6, and is highly efficacious in preclinical models of SCLC, NENs, and CNS tumors. Here, results from ABBV-706 monotherapy dose escalation (DE) are presented. Methods: Phase 1, open-label, multicenter, DE and dose-expansion study (NCT05599984) of ABBV-706 as monotherapy or in combination with budigalimab (a programmed cell death 1 inhibitor), carboplatin, or cisplatin. Primary objectives are to determine the safety, PK, preliminary efficacy, and recommended phase 2 dose of ABBV-706. Exploratory objectives are to assess SEZ6 expression retrospectively and its association with safety, PK, and efficacy. DE enrolled adults (≥18 yr) with relapsed/refractory SCLC, high-grade CNS tumors, and high-grade NENs, following the Bayesian optimal interval design. ABBV-706 was administered IV at 1.3–3.5 mg/kg doses Q3W in 21-d cycles. Results: As of data cutoff on Nov 15, 2023, 49 pts (SCLC: n=22 [45%]; CNS tumors: n=5 [10%]; NEN: n=22 [45%]) were enrolled and treated with ABBV-706 in DE and backfill cohorts. Median age was 64 yr (range 32–81) and median prior lines of therapy was 2.5 (range 1–6). 2 pts had a dose-limiting toxicity: 1 G4 leukopenia and neutropenia lasting &gt;7 d at 3.0 mg/kg and 1 G4 thrombocytopenia at 3.5 mg/kg. TEAEs occurred in 45 (92%) pts, the most frequent being anemia (51%), fatigue (41%), neutropenia (31%), and leukopenia (31%). G≥3 TEAEs occurred in 28 (57%) pts and were mainly hematologic: neutropenia (29%), anemia (27%), and leukopenia (25%). No pneumonitis/interstitial lung disease was observed. Gastrointestinal TEAEs (all G1/2) were seen in 55% of pts, with the most common being nausea (27%) and vomiting (18%). There were no ABBV-706–related deaths. The maximum tolerated dose was 3 mg/kg IV Q3W. ABBV-706 ADC showed an approximate dose-proportional increase in exposure with an elimination half-life of approximately 7 d across doses. For 33 RECIST-evaluable pts, the confirmed (c) objective response rate was overall 21% (7 partial responses [PRs]); 40% (6/15) for SCLC and 6% (1/18) for NEN. The overall response (c and unconfirmed [u]) rate without confirmation was 45% (7 cPRs/8 uPRs); 73% (6 cPRs/5 uPRs) for SCLC, and 22% (1 cPR/3 uPRs) for NEN. 8 uPRs are pending confirmation and will be reported in the final presentation. The clinical benefit rate was 91% (7 PR, 23 stable disease). No activity was observed in 3/3 pts with high-grade gliomas. Conclusions: ABBV-706 demonstrated a manageable safety profile with promising efficacy in SCLC and NENs. Further evaluation of ABBV-706 is ongoing. Clinical trial information: NCT05599984 .