Predicting drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors and forward planning.

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors are cornerstones in the treatment of Hormone Receptor (HR) positive and Human Epidermal Growth factor (HER2) negative metastatic breast cancer. Given their widespread use in the metastatic setting and emerging use in the adjuvant setting, studying drug-drug interactions (DDI) of these medications is of utmost importance. AREAS COVERED: This review provides key background information on the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. We discuss drug-drug interactions including those with proton pump inhibitors as well as CYP3A substrates, inhibitors, and inducers. We describe the effect of these drugs on membrane transporters and their substrates as well as those drugs that increase risk of CDK4/6 toxicities. Finally, we explore future directions for strategies to minimize drug-drug interactions. EXPERT OPINION: It is crucial to be mindful of medications that may interfere with drug absorption, such as proton pump inhibitors, as well as those that interfere with drug metabolism, such as CYP3A4 inhibitors and inducers. Additionally, special consideration should be given to populations at higher risk for polypharmacy, such as older patients with greater comorbidities. These interactions and patient characteristics should be considered when developing individual treatment plans with CDK4/6 inhibitors.

Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity.

The activation of Homo sapiens Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone ONC201. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC50 = 0.79 ± 0.03 µM) and antitumor activity in vitro (IC50 = 0.038 ± 0.003 µM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo. This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.

Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F = 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.

Discovery of Novel Heterotricyclic Compounds as DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Enhanced Chemosensitivity, Oral Bioavailability, and the Ability to Potentiate Cancer Immunotherapy.

In this work, a novel series of heterotricyclic DNA-PK inhibitors were rationally designed, synthesized, and assessed for their biological activity. In the DNA-PK biochemical assay, most compounds displayed potent enzymatic activity, with IC50 values between 0.11 and 71.5 nM. Among them, SK10 exhibited the most potent DNA-PK-inhibitory activity (IC50 = 0.11 nM). Studies of the mechanism of action indicated that SK10 could lower γH2A.X expression levels and demonstrate optimal synergistic antiproliferative activity against Jurkat cells (IC50 = 25 nM) when combined with doxorubicin. Importantly, in CT26 and B16-F10 tumor-bearing mouse models, the combination therapies of SK10 with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1 (a potent PD-L1 small-molecule inhibitor) demonstrated superior synergistic anticancer and potential immunomodulatory effects. Furthermore, SK10 possessed favorable in vivo pharmacokinetic properties [e.g., oral bioavailability (F) = 31.8%]. Taken together, SK10 represents a novel heterotricyclic DNA-PK inhibitor with antitumor immune effects and favorable pharmacokinetics.

Discovery of a Novel CSF-1R Inhibitor with Highly Improved Pharmacokinetic Profiles and Superior Efficacy in Colorectal Cancer Immunotherapy.

Blocking CSF-1/CSF-1R pathway has emerged as a promising strategy to remodel tumor immune microenvironment (TME) by reprogramming tumor-associated macrophages (TAMs). In this work, a novel CSF-1R inhibitor C19 with a highly improved pharmacokinetic profile and in vivo anticolorectal cancer (CRC) efficiency was successfully discovered. C19 could effectively reprogram M2-like TAMs to M1 phenotype and reshape the TME by inducing the recruitment of CD8+ T cells into tumors and reducing the infiltration of immunosuppressive Tregs/MDSCs. Deeper mechanistic studies revealed that C19 facilitated the infiltration of CD8+ T cells by enhancing the secretion of chemokine CXCL9, thus significantly potentiating the anti-CRC efficiency of PD-1 blockade. More importantly, C19 combined with PD-1 mAb could induce durable antitumor immune memory, effectively overcoming the recurrence of CRC. Taken together, our findings suggest that C19 is a promising therapeutic option for sensitizing CRC to anti-PD-1 therapy.

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

Regulating Tumor-Associated Macrophage Polarization by Cyclodextrin-Modified PLGA Nanoparticles Loaded with R848 for Treating Colon Cancer.

Purpose: This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-ß-CD). Methods: R848-loaded PLGA nanoparticles modified with 2-HP-ß-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo. Results: The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-ß-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival. Conclusion: The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.

Pharmacology and pharmacokinetics of tazemetostat.

Tazemetostat, a novel oral selective inhibitor of enhancer of zeste homolog 2 (EZH2), was approved by the Food and Drug Administration (FDA) in 2020 for use in patients with advanced epithelioid sarcoma or relapsed/refractory (R/R) EZH2-mutated follicular lymphoma. These indications were approved by the FDA trough accelerated approval based on objective response rate and duration of response that resulted from phase 2 clinical trials. Tazemetostat competes with S-adenosylmethionine (SAM) cofactor to inhibit EZH2, reducing the levels of trimethylated lysine 27 of histone 3 (H3K27me3), considered as pharmacodynamic marker. Tazemetostat is orally bioavailable, characterized by rapid absorption and dose-proportional exposure, which is not influenced by coadministration with food or gastric acid reducing agents. It highly distributes in tissues, but with limited access to central nervous system. Tazemetostat is metabolized by CYP3A in the liver to 3 major inactive metabolites (M1, M3, and M5), has a short half-life and is mainly excreted in feces. Drug-drug interactions were shown with moderate CYP3A inhibitors as fluconazole, leading the FDA to recommend a 50% dose reduction, while studies investigating coadministration of tazemetostat with strong inhibitors/inducers are ongoing. No dosage modifications are recommended based on renal or hepatic dysfunctions. Overall, tazemetostat is the first-in-class EZH2 inhibitor approved by the FDA for cancer treatment. Current clinical studies are evaluating combination therapies in patients with several malignancies.

Metabolism, toxicity and management of fruquintinib: a novel drug for metastatic colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most diagnosed cancer globally and despite therapeutic strides, the prognosis for patients with metastatic disease (mCRC) remains poor. Fruquintinib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) targeting VEGFR -1, -2, and -3, and has recently received approval by the U.S. Food and Drug Administration for treatment of mCRC refractory to standard chemotherapy, anti-VEGF therapy, and anti-epidermal growth factor receptor (EGFR) therapy. AREAS COVERED: This article provides an overview of the pre-clinical data, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib, as well as the management of clinical toxicities associated with fruquintinib. EXPERT OPINION: Fruquintinib is a valuable additional treatment option for patients with refractory mCRC. The pivotal role of vigilant toxicity management cannot be understated. While fruquintinib offers a convenient and overall, well-tolerated treatment option, ongoing research is essential to determine its efficacy in different patient subsets, evaluate it in combination with chemotherapy and immunotherapy, and determine its role in earlier lines of therapy.

Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study.

PURPOSE: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population. METHODS: Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 - 2, pre-dose and 2 h post-dose on D15 of C1 - 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously. RESULTS: PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease). CONCLUSION: Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma. CLINICAL TRIAL REGISTRATION: NCT02989857 Registered February 20, 2017.

Macrophage derived Exosomal Docetaxel (Exo-DTX) for pro-metastasis suppression: QbD driven formulation development, validation, in-vitro and pharmacokinetic investigation.

Exosomes, biogenic nano-vesicles, are renowned for their ability to encapsulate diverse payloads, however the systematic development and validation of exosomal formulation with significant biological implications have been overlooked. Herein, we developed and validated Exo-DTX, a QbD-driven optimized RAW 264.7 cell derived exosomal anti-cancer formulation of docetaxel (DTX) and evaluate its anti-metastatic and apoptotic efficacy in TNBC 4T1 cells. RAW264.7-derived exosomes were having particle size (112.5 ± 21.48 nm) and zeta-potential (-10.268 ± 3.66 mV) with polydispersity (PDI:0.256 ± 0.03). The statistical optimization of exosomes (200 µg) with Exo: DTX ratio 4:1 confirmed encapsulation of 23.60 ± 1.54 ng DTX/ µg exosomes. Exo-DTX (∼189 nm, -11.03 mV) with 100 ng/ml DTX as payload exhibited ∼5 folds' improvement in IC50 of DTX and distinct cytoskeletal deformation in TNBC 4T1 cells. It also has shown enormous Filamentous actin (F-actin) degradation and triggered apoptosis explained Exo-DTX's effective anti-migratory impact with just 2.6 ± 6.33 % wound closure and 4.56 ± 1.38 % invasion. The western blot confirmed that Exo-DTX downregulated migratory protein EGFR and ß1-integrin but raised cleaved caspase 3/caspase 3 (CC3/C3) ratio and BAX/BCL-2 ratio by about 2.70 and 4.04 folds respectively. The naive RAW 264.7 exosomes also contributed positively towards the effect of Exo-DTX formulation by suppressing ß1-integrin expression and increasing the CC3/C3 ratio in TNBC 4T1 cells as well. Additionally, significant improvement in PK parameters of Exo-DTX was observed in comparison to Taxotere, 6-folds and 3.04-folds improved t1/2 and Vd, proving the translational value of Exo-DTX formulation. Thus, the Exo-DTX so formulated proved beneficial in controlling the aggressiveness of TNBC wherein, naive exosomes also demonstrated beneficial synergistic anti-proliferative effect in 4T1.

Discovery, Optimization, and Evaluation of Potent and Selective DNA-PK Inhibitors in Combination with Chemotherapy or Radiotherapy for the Treatment of Malignancies.

Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with the susceptibility of DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in the pursuit of clinical potential for DNA-PK inhibitors as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although substantial progress has been made with the discovery of potent inhibitors of DNA-PK, the clinical trial landscape requires even more potent and selective molecules. This necessitates further endeavors to expand the repertoire of clinically accessible DNA-PK inhibitors for the ultimate benefit of patients. Described herein are the obstacles that were encountered and the solutions that were found, which eventually led to the identification of compound 31t. This compound exhibited a remarkable combination of robust potency and exceptional selectivity along with favorable in vivo profiles as substantiated by pharmacokinetic studies in rats and pharmacodynamic assessments in H460, BT474, and A549 xenograft models.

Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents.

An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.

Pharmacokinetics and tissue distribution study of two novel quinazoline PI3K/mTOR dual-inhibitors, potential anticancer agents.

S1 and S2, two structurally similar quinazoline derivatives, are novel anticancer drugs targeting the PI3K/AKT/mTOR signaling pathway channel. However, their pharmacokinetic and tissue distribution characteristics are unknown, which has hindered further development and in-depth studies. In this study, a simple, rapid and sensitive method using high performance liquid chromatography was established and validated to quantitatively study the pharmacokinetics and tissue distribution profiles of S1 and S2 in rats following intravenous injection. The results indicated that after intravenous injection, the elimination of S1 and S2 fit the two-compartment model and linear pharmacokinetics characteristics were observed. Furthermore, S1 and S2 were widely distributed and found in high concentrations in liver and kidney tissues and a small proportion of S1 and S2 could cross the blood-brain barrier and be distributed in the brain. The current findings will contribute to interpretation and understanding the relationship between dosage and pharmacodynamic effects of S1 and S2.

Key Pharmacokinetic Parameters of 74 Pediatric Anticancer Drugs Providing Assistance in Preclinical Studies.

Novel drug treatments for pediatric patients with cancer are urgently needed. Success of drug development in pediatric oncology has been promising, but many drugs still fail in translation from preclinical to clinical phases. To increase the translational potential, several improvements have been implemented, including the use of clinically achievable concentrations in the drug testing phase. Although pharmacokinetic (PK) parameters of numerous investigated drugs are published, a comprehensive PK overview of the most common drugs in pediatric oncology could guide preclinical trial design and improve the translatability into clinical trials. A review of the literature was conducted for PK parameters of 74 anticancer drugs, from the drug sensitivity profiling library of the INdividualized Therapy FOr Relapsed Malignancies in Childhood (INFORM) registry. PK data in the pediatric population were reported and complemented by adult parameters when no pediatric data were available. In addition, blood-brain barrier (BBB)-penetration assessment of drugs was provided by using the BBB score. Maximum plasma concentration was available for 73 (97%), area under the plasma concentration-time curve for 69 (92%), plasma protein binding for 66 (88%), plasma half-life for 57 (76%), time to maximum concentration for 54 (72%), clearance for 52 (69%), volume of distribution for 37 (49%), lowest plasma concentration reached by the drug before the next dose administration for 21 (28%), and steady-state concentration for 4 (5%) of drugs. Pediatric PK data were available for 48 (65%) drugs. We provide a comprehensive review of PK data for 74 drugs studied in pediatric oncology. This data set can serve as a reference to design experiments more closely mimicking drug PK conditions in patients, and may thereby increase the probability of successful clinical translation.

Magnetically controlled drug delivery and hyperthermia effects of core-shell Cu@Mn3O4 nanoparticles towards cancer cells in vitro.

Recent increase in the integration of nanotechnology and nanosciences to the biomedical sector fetches the human wellness through the development of sustainable treatment methodologies for cancerous tumors at all stages of their initiation and progression. This involves the development of multifunctional theranostic probes that effectively support for the early cancer diagnosis, avoiding non-target cell toxicity, controlled and customized anticancer drug release etc. Therefore, to advance the field of nanotechnology-based sustainable cancer treatment, we fabricated and tested the efficacy of anticancer drug-loaded magnetic hybrid nanoparticles (NPs) towards in vitro cell culture systems. The developed conjugate of NPs was incorporated with the functions of both controlled drug delivery and heat-releasing ability using Mn3O4 (manganese oxide) magnetic core with Cu shell encapsulated within trimethyl chitosan (TMC) biopolymer. On characterization, the Cu@Mn3O4-TMC NPs were confirmed to have an approximate size of 130 nm with full agglomeration (as observed by the HRTEM) and crystal size of 92.95 ± 18.38 nm with tetragonal hausmannite phase for Mn3O4 spinel structure (XRD). Also, the UV-Vis and FTIR analysis provided the qualitative and quantitative effects of 5-fluororacil (5-Fu) anticancer drug loading (max 68 %) onto the Cu@Mn3O4-TMC NPs. The DLS analysis indicated for the occurrence of no significant changes to the particle size (around 100 nm) of Cu@Mn3O4-TMC due to the solution dispersion thereby confirming for the aqueous stability of developed NPs. In addition, the magnetization values of Cu@Mn3O4-TMC NPs were measured to be 34 emu/g and a blocking temperature of 42 K. Further tests of magnetic hyperthermia by the Cu@Mn3O4-TMC/5-Fu NPs provided that the heat-releasing capacity (% ΔT at 15 min) increases with that of increased frequency, i.e. 28 % (440 Hz) > 22.6 % (240 Hz) > 18 % (44 Hz), and the highest specific power loss (SPL) value observed to be 488 W/g for water. Moreover, the 5-Fu drug release studies indicate that the release is high at a pH of 5.2 and almost all the loaded drug is getting delivered under the influence of the external magnetic field (430 Hz) due to the influence of both Brownian-rotation and Néel relaxation heat-mediated mechanism. The pharmacokinetic drug release studies have suggested for the occurrence of more than one model, i.e. First-order, Higuchi (diffusion), and Korsemeyer-Peppas (non-Fickian), in addition to hyperthermia. Finally, the in vitro cell culture systems (MCF-7 cancer and MCF-10 non-cancer) helped to differentiate the physiological changes due to the effects of hyperthermia and 5-Fu drug individually and as a combination of both. The observed differences of cell viability losses among both cell types are measured and discussed with the expression of heat shock proteins (HSPs) by the MCF-10 cells as against the MCF-7 cancer cells. We believe that the results generated in this project can be helpful for the designing of new cancer therapeutic models with nominal adverse effects on healthy normal cells and thus paving a way for the treatment of cancer and other deadly diseases in a sustainable manner.

Application of physiologically based pharmacokinetics modeling in the research of small-molecule targeted anti-cancer drugs.

INTRODUCTION: Physiologically based pharmacokinetics (PBPK) models are increasingly used in the drug research and development, especially in anti-cancer drugs. Between 2001 and 2020, a total of 89 small-molecule targeted antitumor drugs were approved in China and the United States, some of which already included PBPK modeling in their application or approval packages. This article intended to review the prevalence and application of PBPK model in these drugs. METHOD: Article search was performed in the PubMed to collect English research articles on small-molecule targeted anti-cancer drugs using PBPK modeling. The selected articles were classified into nine categorizes according to the application areas and further analyzed. RESULT: From 2001 to 2020, more than 60% of small-molecule targeted anti-cancer drugs (54/89) were studied using PBPK model with a wide range of application. Ninety research articles were included, of which 48 involved enzyme-mediated drug-drug interaction (DDI). Of these retrieved articles, Simcyp, GastroPlus, and PK-Sim were the most widely model building platforms, which account for 63.8%, 15.2%, and 8.6%, respectively. CONCLUSION: PBPK modeling is commonly and widely used to research small-molecule targeted anti-cancer drugs.

Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates.

While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.

Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs.

BACKGROUND AND OBJECTIVE: As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. METHODS: Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. RESULTS: The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. CONCLUSION: By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.

Bioanalytical Assays for Pharmacokinetic and Biodistribution Study of Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are produced by the chemical linkage of cytotoxic agents and monoclonal antibodies. The complexity and heterogeneity of ADCs and the low concentration of cytotoxic agent released in vivo poses big challenges to their bioanalysis. Understanding the pharmacokinetic behavior, exposure-safety, and exposure-efficacy relationships of ADCs is needed for their successful development. Accurate analytical methods are required to evaluate intact ADCs, total antibody, released small molecule cytotoxins, and related metabolites. The selection of appropriate bioanalysis methods for comprehensive analysis of ADCs is mainly dependent on the properties of cytotoxic agents, the chemical linker, and the attachment sites. The quality of the information about the whole pharmacokinetic profile of ADCs has been improved due to the development and improvement of analytical strategies for detection of ADCs, such as ligand-binding assays and mass spectrometry-related techniques. In this article, we will focus on the bioanalytical assays that have been used in the pharmacokinetic study of ADCs and discuss their advantages, current limitations, and potential challenges. SIGNIFICANCE STATEMENT: This article describes bioanalysis methods which have been used in pharmacokinetic study of ADCs and discusses the advantages, disadvantages and potential challenges of these assays. This review is useful and helpful and will provide insights and reference for bioanalysis and development of ADCs.