Cancer Chemotherapy and Pharmacology最新文献

Purpose: S-equol is an intestinal bacterial metabolite of soy isoflavones. S-equol-containing supplements have been demonstrated to alleviate menopausal symptoms, including hot flashes and joint pain, because of decreasing estrogen levels. Hence, some patients with hot flashes and joint pain induced by hormone therapy drugs are taking S-equol-containing supplements with expectation of reducing their symptoms. However, there is little information of pharmacokinetic interaction between S-equol and drugs. Therefore, we investigated the potential of S-equol to affect the pharmacokinetics of hormone therapy drugs.

Methods: This open-label, crossover study was performed at a single center. Twenty-four healthy postmenopausal women were enrolled and divided into four groups containing six subjects (three equol-producers and three equol-nonproducers). Each group received either anastrozole, letrozole, exemestane, or tamoxifen at standard doses on days 1 and 15. All subjects received S-equol-containing supplement at a standard dose of 10 mg on days 9-15. Blood samples for pharmacokinetic assessment were drawn at predefined time points.

Results: No significant differences were observed in the geometric mean area under the concentration-time curve from 0 h to 24 h of anastrozole (269.0 vs. 289.3 ng‧h/mL; P = 0.14), letrozole (496.5 vs. 523.5 ng‧h/mL; P = 0.07), exemestane (54.1 vs. 53.8 ng‧h/mL; P = 0.69), and tamoxifen (638.4 vs. 578.8 ng‧h/mL; P = 0.22) without and with S-equol-containing supplement on days 1 and 15.

Conclusion: S-equol-containing supplement has no clinically significant effects on the exposure of oral hormone therapy drugs for breast cancer. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: jRCTs031200084, August 13th, 2020.

Purpose: Standard dosing of infusional 5-FU results in subtherapeutic drug exposure for up to half of all patients. We evaluated plasma uracil concentration and DPYD rs4294451 genotype as candidate predictors of individual-level 5-FU exposure.

Methods: We conducted a prospective study of drug exposure in patients with gastrointestinal cancer receiving infusional 5-FU. Participants were evaluated by measurement of fasting pretreatment plasma uracil concentration, DPYD gene sequence (including genotyping of rs4294451) and 5-FU area under the curve (5-FU AUC). We used a linear mixed-effects model to evaluate the association of 5-FU AUC with uracil concentration and rs4294451 genotype, adjusting for cycle number, sex, serum creatinine, and 5-FU dose.

Results: There were 29 evaluable participants with a median age of 64 years (range 41-81); nine (31%) were female. The median plasma uracil concentration was 10.4 ng/mL (IQR 7.2, 12.6). Nine participants carried the DPYD rs4294451 T-allele (7 with T/A, 2 with T/T.) Among all participants the median 5-FU AUC was 22.0 mg*h/L in cycle 1 and 19.3 mg*h/L in cycle 2. In the mixed-effects model, higher rs4294451 T-allele count (0, 1, or 2) was significantly associated with lower 5-FU AUC (-4.0 mg*h/L per T-allele [95% CI -8.0, 0.0], p = 0.049), as was male sex (-7.5 mg*h/L [95% CI -13.8, -1.3], p = 0.021). Pretreatment plasma uracil concentration was not significantly associated with 5-FU AUC (p = 0.57). The subject with the highest uracil concentration (23.1 ng/mL) had a rare DPYD missense variant (c.2185G > A [p.A729T]) and experienced early 5-FU-related toxicity.

Conclusions: DPYD rs4294451 T-allele count and male sex were significantly associated with reduced 5-FU drug exposure. DPYD rs4294451 and male sex merit further evaluation as candidate biomarkers to inform initial dosing of infusional 5-FU.

Purpose: Among cancer patients treated with fluoropyrimidine chemotherapeutics, approximately 30% of individuals experience severe fluoropyrimidine-associated toxicity. Dihydropyrimidine dehydrogenase (DPD, gene DPYD) is the main enzyme responsible for fluoropyrimidine metabolism; genetic variation in the DPYD gene that reduce enzyme function may contribute to increased risk for fluoropyrimidine toxicity. Routine pre-emptive genotype testing and dose adjustments for c.1905 + 1G > A (rs3918290, DPYD*2A), c.2846 A > T (rs67376798, p.D949V), c.1679T > G (rs55886062, DPYD*13, p.I560S), and c.1129-5923 C > G (rs75017182, HapB3) according to the guidelines established by international consortia predicts 20-30% of toxicity cases. However, the majority of severe adverse events are not captured by the currently recommended panel of four variants. There is a paucity of data regarding novel and rare (minor allelic frequency < 1%) DPYD genetic variants associated with chemotherapy-related toxicity.

Methods: Whole-exome next generation sequencing was carried out in a retrospective study of 334 fluoropyrimidine-treated cancer patients to identify DPYD variants and potential association with severe toxicity.

Results: We identified 10 rare DPYD variants among 334 fluoropyrimidine-treated cancer patients that were wildtype for the pre-emptively tested variants. Four nonsynonymous rare DPYD variants, c.257 C > T (rs568132506, p.P86L), c.601 A > C (rs72549308, p.S201R), c.1850 C > T (rs753707032, p.T617M), and c.2324T > G (rs200643089, p.L775W), were found in patients that experienced severe toxicity.

Conclusions: The discovery of rare DPYD variants followed by functional characterization may aid in further optimization of fluoropyrimidine dosing.

Purpose: Isatuximab, an immunoglobulin G monoclonal antibody that targets a specific CD38 epitope, is approved in combination with dexamethasone plus either pomalidomide or carfilzomib for treatment of adults with relapsed or refractory (R/R) multiple myeloma. Isatuximab demonstrated significant anti-leukemic activity in preclinical models. In the phase 2 ISAKIDS study (NCT03860844), isatuximab was tested as combination therapy for pediatric patients with R/R acute lymphoblastic leukemia and acute myeloid leukemia. Here, we use population pharmacokinetics (PopPK) to select the appropriate isatuximab dose for infants aged 1-24 months in ISAKIDS.

Methods: An initial PK modeling and simulation strategy was applied to the first 18 tested patients to confirm the isatuximab 20-mg/kg dose administered to patients aged 24 months or older and to explore the dose needed for the youngest patients. The PK of isatuximab in children was characterized by pooling data from ISAKIDS with adult data from the phase 2 ISLAY study (NCT02999633).

Results: The PopPK model predicted a slight drug underexposure (median decrease of about 30%) in pediatric patients aged 10-24 months (9-12 kg) compared with reference adults (51-100 kg), which did not require a dose adjustment, as no isatuximab exposure versus efficacy relationships were observed in these clinical settings.

Conclusion: The modeling and simulation strategies in this study support the previous selection of a 20-mg/kg dose for all age groups and enabled both de-risking of dose selection and the ability to pursue additional pediatric investigation of isatuximab in the youngest age group of patients with acute leukemias.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a common gastrointestinal side effect in cancer treatment. 6-gingerol, a bioactive component of ginger, demonstrates efficacy in attenuating CINV. This study aimed to explore the effects of 6-gingerol on inhibiting ferroptosis and to clarify its potential antiemetic mechanisms in a cisplatin-induced rat pica model.

Methods: We established the rat pica model by intraperitoneal injection of cisplatin (6 mg/kg). The histopathological damage in gastrointestinal (GI) tissues was assessed by hematoxylin-eosin staining. The levels of serum IL-6, IL-1β, TNF-α, and hepcidin were measured by ELISA. The occurrence of ferroptosis was confirmed by measuring the levels of ROS, GSH, SOD, MDA, and iron in GI tissues. Furthermore, iron deposition was visualized with Perls + DAB staining, and the lipid peroxidation product 4-HNE was detected via immunohistochemistry. The expression levels of iron homeostasis-related proteins in GI tissues were examined by western blotting.

Results: The results showed that 6-gingerol improved pica behavior and mitigated GI inflammation in cisplatin-treated rats. Additionally, 6-gingerol mitigated oxidative stress, lipid peroxidation, and reduced iron accumulation. Molecular docking analysis showed that iron homeostasis-related proteins (TfR1, DMT1, ferritin, Fpn, and hepcidin) might be the potential regulatory targets of 6-gingerol. Mechanistically, 6-gingerol restored iron homeostasis by downregulating the expression levels of TfR1 and DMT1 to reduce iron uptake and transport, and upregulating the expression levels of ferritin and Fpn to enhance iron storage and export.

Conclusion: Overall, this study indicates that regulating iron homeostasis to inhibit ferroptosis is related to the therapeutic effect of 6-gingerol against CINV.

Background: CDK4/6 inhibitors have transformed treatment for HR + HER2 - advanced breast cancer (aBC). However, adverse events (AEs) often lead to dose adjustments or discontinuation, potentially impacting outcomes. This study assessed AE incidence and its effect on survival in patients receiving abemaciclib (AB), ribociclib (RB), or palbociclib (PB).

Methods: A retrospective study of 162 h + HER2 - aBC patients treated with CDK4/6 inhibitors as first-line therapy (July 2017-September 2024) was conducted. AE incidence, progression-free survival (PFS), and overall survival (OS) were analyzed.

Results: Most patients (91.4%) were postmenopausal, with a median follow-up of 24.6 months. AEs occurred in 87% of patients, with grade 3-4 neutropenia most common in PB (79.3%) and RB (80%), while AB caused more diarrhea (66.7%). Dose reductions due to AEs were linked to significantly longer PFS (38.5 vs. 16.3 months, p < 0.001) and OS (NR vs. 32.4 months, p = 0.024). Treatment discontinuation was highest for PB (19.6%), followed by RB (16.9%) and AB (14.9%).

Conclusions: CDK4/6 inhibitors have distinct toxicity profiles. Effective AE management and dose adjustments are crucial for maintaining efficacy, emphasizing the need for AE prediction models to optimize CDK4/6i use in HR + HER2 - aBC.

Purpose: Castration and enzalutamide induce BCL-2 to drive therapy resistance in prostate cancer (PCa). We conducted a phase Ib trial to test that metastatic castration-resistant PCa (mCRPC) can be effectively targeted by combining enzalutamide with the BCL-2 inhibitor venetoclax.

Experimental design: This phase Ib single-arm trial of enzalutamide (160 mg/d) with venetoclax in patients with progressive mCRPC assessed dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Three dose levels (DL) of venetoclax (DL1 at 400 mg/d; DL2 at 600 mg/d; and DL3 at 800 mg/d) were evaluated using a 3 + 3 design. We also analyzed enzalutamide and venetoclax pharmacokinetics and conducted pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) to determine the impact of venetoclax on BCL-2 expression.

Results: A total of 10 patients were enrolled across 3 DL and no DLT was observed. Mean duration on treatment was 29 weeks (range: 8-140 weeks). Treatment-related adverse events (TRAEs) were mostly grade 1-2, and Grade 3 TRAEs included fatigue (10%) and thrombocytopenia (10%). 1/10 (10%) attained PSA50 response and 4/10 (40%) had stable disease. Estimated median overall survival (OS) was 19 months (95% CI 5-28 months) and median time to next systemic therapy (TNST) was 5 months (95% CI 1-35 months). Pharmacokinetic results revealed sub-optimal plasma levels of venetoclax. Pharmacodynamic studies demonstrated that venetoclax enhanced BCL-2β generation and promoted BCL-2 degradation.

Conclusions: Enzalutamide with venetoclax has an acceptable toxicity profile in patients with mCRPC. Despite sub-optimal venetoclax levels, the treatment elicited pharmacodynamic and clinical response in a subset of patients.

Clinical trial id: NCT03751436.

Purpose: Chemotherapy-Induced Nausea and Vomiting (CINV) has a significant negative impact on cancer chemotherapy and patients' quality of life (QOL). Purpose of this study is to establish the safety, tolerability and pharmacokinetics of novel Ondansetron Extended Release Injectable Suspension (OERIS) through preclinical and clinical studies. Antiemetic medications, especially 5-HT3 antagonists like ondansetron, granisetron, neurokinin1 antagonists (aprepitant, fosaprepitant etc.) have proven to be effective in the prevention and control of CINV. However, ondansetron is currently available as oral tablet/solutions or IM/IV formulations requiring multiple dosing 3-5 days during chemotherapy. Novel OERIS formulation is developed with an aim to provide a single dose treatment strategy for an effective prophylaxis of acute and delayed phases of CINV.

Methods: Preclinical studies in rats and dogs viz. maximum tolerated dose, sub-acute toxicity and pharmacokinetic studies were conducted to support safety and pharmacokinetic assessments and before initiating human studies. Subsequently, a Phase I study was conducted in 24 healthy male human volunteers to evaluate safety, tolerability and pharmacokinetics. Study involves 4 arms with 6 subjects in each arm administered with either one of the 3 doses of OERIS (35, 70 and 100 mg, IM) or reference (24 mg, IV in 3 divided doses).

Results: No Observed Adverse Effect Level (NOAEL) was found to be 150 mg/kg, i.m. in rats, which is approximately 160 times that of recommended ondansetron human dose (0.15 mg/kg, i.v.). Phase I study of OERIS demonstrated optimal PK exposures for efficacy up to 5-days within therapeutic window along with good safety (no QT prolongation and no hypokalemia) and tolerability (no injection site reactions) in healthy subjects at a dose of 100 mg.

Conclusion: OERIS is a promising, convenient, safe anti-emetic therapy effective for acute and delayed phases (lasts for 5-days) of CINV in patients receiving chemotherapy with a single dose.

Trial registration: The trial is registered at Clinical Trial Registry of India (CTRI) with registration number: CTRI/2022/07/043886 (Registered on: 11/07/2022).