Cancer Chemotherapy and Pharmacology最新文献

Purpose: Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics.

Methods: This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL).

Results: Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0.

Conclusion: We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.

Purpose: To explore the possibility of treating patients with alternative imatinib formulations.

Methods: Two patients were treated with different enteral en rectal imatinib formulations. During treatment plasma concentrations where measured to assure adequate exposure.

Results: The first patient received imatinib suspension through the duodenum tube. With a dose of 400 mg BID the patient had an imatinib plasma concentration of 750 µg/L. After increasing the dose to 600 mg BID the imatinib plasma concentration was 1500 µg/L (target GIST treatment > 1100 µg/L). Rectal administration of the tablet did not lead to sufficient plasma concentrations. The second had adequate exposure of imatinib both when the suspension was taken orally and through the tube (target CML treatment are > 1000 µg/L).

Conclusion: For patients able to swallow liquids, we prefer the suspended imatinib tablets (comparable to drug label). If patients have a duodenum tube the use of a suspension base with pulverized tablets could be an alternative. Based on the extremely low exposure found in case 1, we do not recommend rectal administration of tablets. We recommend the monitor plasma concentrations when off label dosing forms are used.

Purpose: Folinic acid (FA) rescue protocols to counter the adverse effects of high-dose methotrexate (HDMTX) vary widely, and the risk of over-rescue and potential adverse effects of excessive FA (e.g., hypercalcemia) are under-recognized issues when providing augmented rescue in cases of delayed methotrexate elimination (DME). This opinion summary defines over-rescue, describes its potential adverse impacts, highlights the risk of hypercalcemia associated with excessive FA dosing in patients with acute kidney injury (AKI) from HDMTX, and provides recommendations to improve safety and efficacy of FA rescue in patients receiving HDMTX.

Methods: A multidisciplinary panel of experts with clinical experience in HDMTX treatment convened in three roundtable meetings to coalesce expert opinion and best published evidence on the pharmacology and clinical effects and interactions of FA and HDMTX.

Results: The type of FA (calcium folinate, calcium levofolinate, sodium levofolinate), dose, and frequency of FA administration may be factors for over-rescue and the development of hypercalcemia due to their respective pharmacokinetic characteristics, especially in cases of DME requiring augmented FA rescue.

Conclusion: Clinicians are reminded of the possibility of over-rescue with FA and its impact on subsequent HDMTX courses, types of FA available and their durations of action, and avoid providing too frequent doses. In the setting of AKI and DME requiring high doses of FA, use of sodium levofolinate or calcium levofolinate may be considered to reduce the risk of hypercalcemia associated with calcium folinate.

In recent years, assessing dihydropyrimidine dehydrogenase (DPD) activity has become crucial for cancer patients undergoing 5-fluorouracil (5FU)-based chemotherapy due to the life-threatening toxicity associated with reduced DPD function. The methods for evaluating DPD activity have evolved, with the analysis of DPYD polymorphisms in blood samples becoming the preferred approach. As the indications for liver transplantation are increasing-particularly due to a rise in cases of cholangiocarcinoma (CCA) and non-resectable colorectal liver metastasis-more cancer patients with a history of liver transplantation may experience disease relapse. Furthermore, 5-fluorouracil chemotherapy is a standard treatment for both cancers. This growing need to evaluate DPD activity in transplanted livers arises because standard tests conducted on blood samples reflect the activity of native liver tissue and may produce misleading results. This paper presents two clinical cases from 2022 to 2023 involving patients who underwent successful liver transplants but were later diagnosed with intrahepatic CCA in the explanted liver. Both patients were subsequently prescribed capecitabine as adjuvant chemotherapy, making it essential to assess DPD activity in donor liver tissue to ensure safe treatment protocols. However, there are currently no established guidelines for this specific patient group. If we follow standard clinical practice, this critical analysis will be insufficient, as it only describes the DPD activity of the native liver. It is imperative to determine the DPD activity of the transplanted liver. In summary, this case report highlights the importance of managing this complex situation effectively.

Purpose: To evaluate alternative ibrutinib dosing regimens that maintain Bruton's tyrosine kinase (BTK) receptor occupancy over the entire dosing interval for CLL patients using a model-based approach.

Methods: Ibrutinib inhibits B-cell proliferation via irreversible binding of BTK. As IC₅₀ is not an appropriate parameter to describe the potency of the inhibition in the presence of a covalent binding inhibitor. A BTK covalent binding model was developed using k_inact/K_I as key parameter to account for covalent binding. The ibrutinib-BTK covalent binding model was used to describe the effect of daily doses of 140, 280, 420 and 560 mg on the proportion of subjects with more than 90% BTK inhibition at steady state trough concentrations. Predictive performance of the model was assessed using the available ibrutinib BTK inhibition data following QD dosing. Model-based predictions were used to identify the minimum ibrutinib QD dose that provides more than 90% inhibition in more than 90% of the subjects.

Results: The covalent binding model was able to describe the data and predicted that ibrutinib QD dose reduced from 420 mg to 280 mg or 140 mg may inhibit de novo synthetized BTK efficiently in a CLL population.

Conclusion: Using a model-based approach showed that reducing the ibrutinib dosing regimen to 280 mg QD or even 140 mg in case of adverse events could maintain BTK inhibition over the entire dosing interval.

Background: The original population pharmacokinetics (popPK) model for asciminib in patients with chronic myeloid leukemia in chronic phase (CML-CP) was refined to address drug development needs in support of drug submission, namely, attainment of target drug exposure in specific patient populations, populating individual daily exposures for exposure-response analyses of key efficacy and safety endpoints, confirmation of comparability in exposure between 40 mg b.i.d. and 80 mg q.d., and assessment of ethnic insensitivity.

Methods: Participants from two organ dysfunction studies, patients with CML in blast and acute phases and acute lymphoblastic leukemia and patients from a phase III efficacy study in newly diagnosed Ph + CML-CP, and data from a dedicated phase II study in the Chinese patients previously treated with at least two prior tyrosine kinase inhibitors, and a phase IIIb study comparing two dose regimens of asciminib (40 mg b.i.d. and 80 mg q.d.) were included in the revised popPK model. Covariates evaluated were line of therapy, baseline renal and hepatic functions, Chinese or Japanese ethnicity.

Results: The apparent clearance and steady-state volume of distribution of asciminib were 6.84 L/h and 110 L, respectively, for a typical individual of 70 kg weight and 90 mL/min absolute glomerular filtration rate. Both the 40 mg b.i.d. and 80 mg q.d. resulted in a steady-state daily AUC of 12,600 ng.h/mL, and there was no difference between lines of therapy. Effects of renal or hepatic impairment on clearance were not clinically relevant. Chinese and Japanese exhibited similar PK as that of the global population.

Conclusions: The 40 mg b.i.d. and 80 mg q.d. regimens are comparable in their daily exposure, supporting the use of the two dosing regimens in newly diagnosed and previously treated CML-CP patients. The PK of asciminib is insensitive to ethnic differences and no dose adjustment is required for severe renal and hepatic impaired patients.

Purpose: Trametinib, a MEK1/2 inhibitor, has emerged as a promising treatment for pediatric patients with low-grade gliomas (LGG). However, trametinib exhibits significant inter-individual pharmacokinetic (PK) variability, and studies in adults demonstrated an exposure-efficacy relationship. This study aimed to evaluate the PK profile of trametinib in pediatric routine care and explore potential exposure-outcome relationships.

Methods: We analyzed PK data from 65 blood samples from 19 children receiving trametinib, either as single agent or in combination with dabrafenib. A trough concentration (Cmin) range of 8-15 ng/mL was considered, based on average exposure reported in the largest pediatric study.

Results: The mean Cmin was 8.82 ng/ml, with 64.6% of samples falling within the predefined target range, while 35.4% were below it. Regarding tolerance, 84.2% of patients experienced treatment-related toxicities, predominantly skin and subcutaneous tissue disorders. Efficacy data were limited.

Conclusion: These findings underscore the necessity of therapeutic drug monitoring in pediatric patients to optimize treatment efficacy and minimize toxicity, highlighting trametinib's potential for personalized dosing strategies in this population.

Purpose: To determine the, safety, tolerability and recommended phase 2 dosing of the combination of navitoclax, a dual Bcl-2/xL inhibitor, and vistusertib, a TORC1/2 inhibitor.

Methods: Patients with advanced solid tumors received navitoclax plus vistusertib following a 3 + 3 dose escalation design. To mitigate thrombocytopenia, a known toxicity of navitoclax, all patients received lead-in dosing of navitoclax alone at 150 mg orally daily for a minimum of 7 days. In addition to safety and tolerability, pharmacokinetics of navitoclax and vistusertib were evaluated.

Results: 14 patients received combination treatment which was well-tolerated at dose level 1 (navitoclax 150 mg orally daily plus vistusertib 35 mg orally twice daily). The main dose-limiting toxicity, grade 3 serum aminotransferase elevation, occurred in two of five patients at dose level 2 (navitoclax 250 mg orally daily plus vistusertib 35 mg orally twice daily). Navitoclax and vistusertib exposures appeared consistent with levels reported in prior studies of each agent. No responses were observed among the 8 response evaluable patients.

Conclusions: A tolerable dose of navitoclax at 150 mg orally daily plus vistusertib at 35 mg orally twice daily was identified in patients with advanced solid tumors and established as the recommended phase 2 dose (RP2D). Further efficacy assessment of this combination, in a planned phase 2 expansion in patients with relapsed small cell lung cancer, was terminated due to discontinuation of vistusertib.

Trial registration: NCT03366103 (First posted December 8, 2017).