Low Risk Of Drug-drug Interactions Research Articles

Design, synthesis and evaluation of novel LpxC inhibitors containing a hydrazone moiety as Gram-negative antibacterial agents

LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To enable the development of novel LpxC inhibitors with potent antibacterial activities, several series of compounds were designed and synthesized and their antibacterial activities were evaluated against E. coli ATCC25922, P. aeruginosa ATCC27853, P. aeruginosa clinical isolate PAE 22-1, K. pneumoniae ATCC700603, K. pneumoniae clinical isolate KPN+22-1 in vitro. Compound 6i exhibited significant antibacterial activities against above five Gram-negative bacteria except P. aeruginosa ATCC27853. Moreover, compound 6i exhibited moderate liver microsomal stability and a promising pharmacokinetic profile (AUC0-t = 1050 ng·h·mL-1, oral bioavailability of 13.3%) in Sprague-Dawley rats, acceptable PPB, low risk of drug-drug interactions and non-cytotoxic activity against hepatic cell. Collectively, compound 6i could be a promising Gram-negative antibacterial agent for further investigation.

Significant increases in detection capability for assessment of organic anion transporting polypeptide-mediated drug-drug interaction in cynomolgus monkeys by modifying pretreatment of Coproporphyrin I and III, and glycochenodeoxycholate-3-sulfate in plasma

BackgroundCoproporphyrin I (CP–I), Coproporphyrin III (CP-III), and glycochenodeoxycholate-3-sulfate (GCDCA-S) act as endogenous substrates of Organic Anion Transporting Polypeptide (OATP) 1B and have been considered for application in OATP1B-mediated drug‒drug interaction (DDI) risk assessments. Prior assays of the endogenous OATP substrates might exhibit reduced DDI detection capability and possibly overlook low DDI risk. We pioneered a simultaneous assay of the three substrates in monkey plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) and applied it to monkey studies to identify lower DDI risk. ResultsThe methodology development indicated that precursors of CP-I/III were oxidized to form CP-I/III, diminishing the detection capability in DDI risk assessments. A precursor eliminated analytical (PEA) method was developed to eliminate the precursors through solid-phase extraction. This method aimed to prevent the oxidation of CP-I/III precursors by incorporating edaravone. For comparison, a precursor oxidized analytical (POA) method was also developed, wherein the precursors of CP-I/III were fully oxidized to CP-I/III. The PEA method achieved high sensitivity for CP-I/III and GCDCA-S, with lower quantification limits of 0.01 ng mL−1 and 0.5 ng mL−1, respectively. Both methods ensured that the validation parameters met the acceptance criteria. The two methods were applied to a monkey study, with CP-I/III showcasing notably enhanced DDI detection capabilities through the novel PEA method in comparison to the POA method. SignificanceThis study's methodology has future implications for OATP-mediated DDI risk assessment using endogenous substrates. The novel PEA method can identify lower OATP-mediated DDI risks for drugs that the current methods cannot detect. Our method is likely applicable in clinical settings, and its utility should be assessed in clinical trials.

Discovery of a Novel Potent Tetrazole Antifungal Candidate with High Selectivity and Broad Spectrum.

Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 μg/mL against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K+ channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans-infected mice. Taken together, compound D2 will be further investigated as a promising candidate.

Discovery of Novel and Potent Prolyl Hydroxylase Domain-Containing Protein (PHD) Inhibitors for The Treatment of Anemia.

Stabilization of hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase domain enzymes (PHDs) represents a breakthrough in treating anemia associated with chronic kidney disease. Here, we identified a novel scaffold for noncarboxylic PHD inhibitors by utilizing structure-based drug design (SBDD) and generative models. Iterative optimization of potency and solubility resulted in compound 15 which potently inhibits PHD thus stabilizing HIF-α in vitro. X-ray cocrystal structure confirmed the binding model was distinct from previously reported carboxylic acid PHD inhibitors by pushing away the R383 and Y303 residues resulting in a larger inner subpocket. Furthermore, compound 15 demonstrated a favorable in vitro/in vivo absorption, distribution, metabolism, and excretion (ADME) profile, low drug-drug interaction risk, and clean early safety profiling. Functionally, oral administration of compound 15 at 10 mg/kg every day (QD) mitigated anemia in a 5/6 nephrectomy rat disease model.

832P Characterisation of EXS73565: A potent and selective MALT1 inhibitor with low drug-drug interaction risk and potential in lymphoma

832P Characterisation of EXS73565: A potent and selective MALT1 inhibitor with low drug-drug interaction risk and potential in lymphoma

Efficacy and tolerability of desvenlafaxine in the real-world treatment of patients with major depression: a narrative review and an expert opinion paper

ABSTRACT Introduction Major depressive disorder (MDD) is a common severe mental disorder, requiring a tailored and integrated treatment. Several approaches are available including different classes of antidepressants various psychotherapeutic approaches, and psychosocial interventions. The treatment plan for each patient with MDD should be differentiated on the basis of several clinical, personal, and contextual factors. Areas covered Desvenlafaxine – a serotonine-noradrenergic reuptake inhibitor (SNRI) antidepressant – has been approved in the United States in 2008 for the treatment of MDD in adults, and has been recently rediscovered by clinicians due to its good side-effect profile and its clinical effectiveness. A narrative review on efficacy, tolerability and use of desvenlafaxine in clinical practice was carried out. The keywords: ‘major depression’, ‘depression,’ ‘desvenlafaxine,’ ‘efficacy,’ ‘clinical efficacy,’ ‘side effects’, ‘tolerability,’ ‘elderly patients’, ‘consultation-liaison’, ‘menopausal’, ‘young people’, ‘adolescent’ were entered in PubMed, ISI Web of Knowledge, Scopus and Medline. No time limit was fixed, the search strategy was implemented on May 10, 2023. Expert opinion Desvenlafaxine should be listed among the optimal treatment strategies for managing people with MDD, whose main strengths are: 1) ease of dosing; 2) favorable safety and tolerability profile, 3) absence of sexual dysfunctions, weight gain and low rate of discontinuation symptoms; 4) low risk of drug–drug interactions.

Discovery of novel triazoles containing benzyloxy phenyl isoxazole side chain with potent and broad-spectrum antifungal activity

As a continuation study, 29 novel triazoles containing benzyloxy phenyl isoxazole side chain were designed and synthesized based on our previous work. The majority of the compounds exhibited high potency in vitro antifungal activities against eight pathogenic fungi. The most active compounds 13, 20 and 27 displayed outstanding antifungal activity with MIC values ranging from <0.008 µg/mL to 1 µg/mL, and showed potent activity against six drug-resistant Candida auris isolates. Growth curve assays further confirmed the high potency of these compounds. Moreover, compounds 13, 20 and 27 showed a potent inhibitory activity on biofilm formation of C. albicans SC5314 and C. neoformans H99. Notably, compound 13 showed no inhibition of human CYP1A2 and low inhibitory activity against CYP2D6 and CYP3A4, suggesting a low risk of drug-drug interactions. With high potency in vitro and in vivo and good safety profiles, compound 13 will be further investigated as a promising candidate.

Effects of Genetic Polymorphisms of Drug Metabolizing Enzymes and co-Medications on Tamoxifen Metabolism in Black South African Women with Breast Cancer.

Clinical outcomes of tamoxifen (TAM) treatment show wide interindividual variability. Comedications and genetic polymorphisms of enzymes involved in TAM metabolism contributes to this variability. Drug-drug and drug-gene interactions have seldom been studied in African Black populations. We evaluated the effects of commonly co-administered medicines on TAM pharmacokinetics in a cohort of 229 South African Black female patients with hormone-receptor positive breast cancer. We also investigated the pharmacokinetic effects of genetic polymorphism in enzymes involved in TAM metabolism, including the variants CYP2D6*17 and *29, which have been mainly reported in people of African descent. TAM and its major metabolites, N-desmethyltamoxifen (NDM), 4-OH-tamoxifen, and endoxifen (ENDO), were quantified in plasma using the liquid chromatography-mass spectrometry. The GenoPharm open array was used to genotype CYP2D6, CYP3A5, CYP3A4, CYP2B6, CYP2C9, and CYP2C19. Results showed that CYP2D6 diplotype and CYP2D6 phenotype significantly affected endoxifen concentration (P < 0.001 and P < 0.001). CYP2D6*17 and CYP2D6*29 significantly reduced the metabolism of NDM to ENDO. Antiretroviral therapy had a significant effect on NDM levels and the TAM/NDM and NDM/ENDO metabolic ratios but did not result in significant effects on ENDO levels. In conclusion, CYP2D6 polymorphisms affected endoxifen concentration and the variants CYP2D6*17 and CYP2D6*29 significantly contributed to low exposure levels of ENDO. This study also suggests a low risk of drug-drug interaction in patients with breast cancer on TAM.

In-vitro metabolism of LXY18, an orally available, potent blocker of AURKB relocation in mitosis

This study investigated the metabolism of LXY18, a quinolone-based compound that suppresses tumorigenesis by blocking AURKB localization. Metabolite profiling of LXY18 in liver microsomes from six species and human S9 fractions revealed that LXY18 undergoes various conserved metabolic reactions, such as N-hydroxylation, N-oxygenation, O-dealkylation, and hydrolysis, resulting in ten metabolites. These metabolites were produced through a combination of CYP450 enzymes, and non-CYP450 enzymes including CES1, and AO. Two metabolites, M1 and M2 were authenticated by chemically synthesized standards. M1 was the hydrolyzed product catalyzed by CES1 whereas M2 was a mono-N-oxidative derivative catalyzed by a CYP450 enzyme. AO was identified as the enzyme responsible for the formation of M3 with the help of AO-specific inhibitors and LXY18 analogs, 5b and 5c. M1 was the intermediate of LXY18 to produce M7, M8, M9, and M10. LXY18 potently inhibited 2C19 with an IC50 of 290 nM but had a negligible impact on the other CYP450s, indicating a low risk of drug-drug interaction. Altogether, the study provides valuable insights into the metabolic process of LXY18 and its suitability as a drug candidate. The data generated serves as a significant reference point for conducting further safety assessments and optimizing drug development.

Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents

In an effort to develop novel azole antifungals with potent activity and high selectivity, a series of (2R,3R)-3-((3-substitutied-phenyl-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butan-2-ol derivatives were designed and synthesized based on our previously work. All compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and Cryptococcus neoformans H99, but inactive against Aspergillus fumigatus 7544. Among them, the most active compound 10h displayed outstanding antifungal activity against fluconazole-resistant C. albicans 103, C. glabrata 537 and C. auris 922 with MIC values of ≤0.008 μg/mL. In addition, compound 10h was superior to FLC in inhibiting the filamentation of FLC-resistant C. albicans 103. Notably, compound 10h showed no inhibition of human CYP3A4 with IC50 values of >100 μM, low cytotoxicity at 32 μg/mL and low hERG inhibition with IC50 values of 6.22 μM, suggesting a low risk of drug-drug interactions and good safety profiles. Furthermore, compound 10h exhibited excellent PK profiles and showed remarkable in vivo efficacy in a mouse model of C. albicans and C. neoformans infection. Taken together, compound 10h will be further investigated as a promising lead antifungal agent.

Discovery of novel 7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines as ATR inhibitors based on structure-based drug design

ATR kinase is essential to the viability of replicating cells responding to the accumulation of single-strand breaks in DNA, which is an attractive anticancer drug target based on synthetic lethality. Herein we design, synthesize, and evaluate a novel series of fused pyrimidine derivatives as ATR inhibitors. As a result, compound 48f, with an IC50 value of 0.0030 μM against ATR, displayed strong monotherapy efficacy in ataxia-telangiectasia mutated (ATM) kinase-deficient tumor cells LoVo, SW620, OVCAR-3 cell lines with IC50 values of 0.040 μM, 0.095 μM, 0.098 μM, respectively. More importantly, the combination of 48f with AZD-1390, cisplatin, oxaliplatin, and olaparib respectively resulted in synergistic activity against HT-29, HCT116, A549, MCF-7, MDA-MB-231 cells. Moreover, 48f showed a favorable pharmacokinetic profile with a bioavailability of 30.0% in SD rats, acceptable PPB, high permeability (Papp A to B = 8.23 cm s−1 × 10−6), and low risk of drug-drug interactions. Collectively, compound 48f could be a promising compound for further investigation.

252 (PB032) - DB-1303, a HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising safety profile and anti-tumor efficacy with differentiation from DS-8201a

Background: DB-1303 is a novel antibody-drug conjugate comprised of trastuzumab biosimilar, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have high plasma stability, low free payload in circulation and wide therapeutic index. Herein, we describe the preclinical profile of DB-1303, including efficacy, pharmacokinetics, and safety. Material and Methods: In vitro cell growth inhibition and in vivo antitumor activities of DB-1303 were evaluated in several Her2-low tumor cell lines and xenograft models. Tumor-bearing mice were used to assess pharmacokinetic and pharmacodynamic characteristic of DB-1303. The mechanism of action for the efficacy was also evaluated. Plasma stability of DB-1303 was determined with rat, monkey, and human plasma. Pharmacokinetic and safety profiles of DB-1303 were evaluated in cynomolgus monkeys. Results: In vitro, DB-1303 selectively binds to and is endocytosed into the lysosome of HER2-positive cells. DB-1303 causes G2/M cell cycle arrest, induces DNA damage, and inhibits cell proliferation in HER2-expressing cells. Importantly, DB-1303 showed inhibitory activity to Her2 low-expressing CAPAN-1 (pancreatic cancer) and Ishikawa (endometrial cancer) cell lines. Under a coculture condition of HER2-positive KPL-4 cells and HER2-negative MDA-MB-468 cells in vitro, DB-1314 inhibited the proliferation of both cells, demonstrating its bystander effect. In vivo, DB-1303 induced dose-dependent tumor growth inhibition and tumor regression in T-DM1-resistant JIMT-1 xenograft model, HER2 low-expressing Ishikawa xenograft and two HER2-low breast cancer PDX models. A single dosing of DB-1303 in NCI-N87 tumor-bearing mice induced significant DNA damage in tumors, and the Cmax of payload in tumor tissues was about 45-fold higher than that in peripheral blood. Pharmacokinetics and safety profiles of DB-1303 were favorable and the highest non-severely toxic dose was 80 mg/kg in cynomolgus monkey study with Q3W dosing of 3 repeated doses. It’s worth noting that, unlike DS-8201a, no interstitial pneumonia was observed in monkeys during the dosing period and recovery period. The payload P1003 poses very low risk of drug-drug interaction. Following administration of DB-1303, systemic P1003 exposure was low and P1003 was cleared rapidly. Conclusions: DB-1303 exhibited potent antitumor activity in both HER2 positive and HER2 low tumor models with a wide therapeutic window. The stable linker in circulation and fast clearance of P1003 may contribute to the superior safety profile of DB-1303. These studies suggest the potential of DB-1303 to address unmet medical needs in HER2 expressing cancers, especially in HER2 low cancers. At the time of presentation, a first-in-human phase 1/2 study in patients with advanced solid tumors is in progress (NCT05150691). No conflict of interest.

Structure-based discovery of 1-(3-fluoro-5-(5-(3-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-3-(pyrimidin-5-yl)urea as a potent and selective nanomolar type-II PLK4 inhibitor

Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase involved in regulating cell mitosis and centriole duplication, and has emerged as a therapeutic target for treating multiple cancers. At first, the design and in vitro validation of PLK4 inhibitors (12a-12e, 17a-17f, 22a-22e) bearing 1H-pyrazolo[3,4-b]pyridine scaffold was described and lead compound 22a (IC50 = 0.106 μM) was identified. Then, selectivity- and activity-guided development of a series of potent and selective type-II PLK4 inhibitors using a homology model approach was carried out. Further structure-based optimization resulted in a potent type-II PLK4 inhibitor 29u (IC50 = 0.026 μM), which exhibited outstanding selectivity in a panel of 47 kinases at a single concentration of 1.0 μM. Furthermore, compound 29u significantly inhibited the proliferation of breast cancer cell line MCF-7 with an IC50 value of 1.52 μM, while it exhibited no inhibitory effect on normal cell lines (L02 and HUVECs). Meanwhile, the clone formation, senescence and migration abilities of compound 29u were evaluated using MCF-7 cells. The detailed biological evaluation revealed that compound 29u could arrest cell division in S/G2 phase by inhibiting PLK4, and then affect the expression of downstream signalling pathway proteins regulated by PLK4. Moreover, the in vitro preliminary evaluation of the drug-like properties of compound 29u exhibited outstanding plasma stability, moderate liver microsomal stability, and low risk of drug-drug interactions (DDIs). The current discovery will support the further development of compound 29u as a lead compound for PLK4-targeted anticancer drug discovery and as a useful chemical probe for the further biological research of PLK4.

In vitro inhibition of human UDP-glucuronosyltransferase (UGT) 1A1 by osimertinib, and prediction of in vivo drug-drug interactions

Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a Ki,u of 0.87 ± 0.12 μM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a Ki,u of 3.32 ± 0.25 μM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [I]gut/Ki,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.

A physiologically based pharmacokinetic/pharmacodynamic modeling approach for drug-drug interaction evaluation of warfarin enantiomers with sorafenib

Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs.PBPK models of warfarin enantiomers were constructed by Simcyp software. A mechanistic PK/PD model was built in NONMEM software. PBPK model of sorafenib was fitted via a top-down method. The final PBPK/PD model of warfarin enantiomers was verified and validated by different dosing regimens, ethnicities and genetic polymorphisms, and used to perform DDI simulations between warfarin racemate and sorafenib among general populations and sub-populations with various CYP2C9 and VKORC1 genotypes. Results suggested low DDI risk between warfarin and sorafenib for general populations. Potentially serious consequence was seen for those carrying both CYP2C9 ∗2 and ∗3 and VKORC1 A/A genotypes.This PBPK/PD modeling approach for warfarin enantiomers enabled DDI evaluation with sorafenib. Close monitoring and warfarin dosage adjustment were recommended for patients carrying mutant genotypes. The novel model could be applied to investigate other drugs that may interact with warfarin.

Rezafungin Prevention of Pneumocystis Pneumonia and Pneumocystis Reactivation Using Different Doses and Durations of Prophylaxis in a Mouse Model

Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal disease caused by <i>Candida, Aspergillus</i>, and <i>Pneumocystis</i> species in patients undergoing blood and marrow transplantation. RZF has a favorable safety and tolerability profile, a low risk of drug-drug interactions and with its stability, pharmacokinetics that allow for once-weekly dosing with broad distribution to the lung and other fungal target organs. We previously demonstrated RZF efficacy in preventing <i>Pneumocystis</i> infection in an immunosuppressed mouse model. The present study addressed whether <i>Pneumocystis</i> infection in a similar immunosuppressed mouse model could re-activate after 2 to 8 wks of prophylactic therapy using different dosing regimens of RZF. C3H/HeN mice were infected with <i>P. murina</i> intranasally at 2 × 10⁶/50 µl after immunosuppression with dexamethasone. Mice were administered vehicle as a negative control (C/S), trimethoprim/sulfamethoxazole (T/S) as a positive control, caspofungin (CASPO) as a comparator echinocandin or RZF intraperitoneally at time of challenge. Study drug administration was stopped at 2, 4, 6, and 8 weeks, at which time mice were immunosuppressed for an additional 6 weeks to allow any residual <i>P. murina</i> to re-activate. Mice were then euthanized and lungs were processed for analysis of nuclei and asci. All RZF dose regimens at all timepoints significantly reduced both nuclei and asci burdens versus the C/S group (Figure 1). After 4 weeks of RZF prophylaxis (plus 6 wks additional immunosuppression [week 10 timepoint]; Figure 1), both RZF 20 mg/kg groups (3x/wk and 1x/wk) had prevented <i>P. murina</i> organisms from activating an infection. After 6 and 8 weeks of RZF prophylaxis (week 12 and 14 timepoints; Figure 1), no re-activation of infection was present in any of the study groups. After 2 and 4 weeks of prophylaxis (week 8 and 10 timepoints), there was a significant reduction of nuclei and asci counts in all groups of RZF versus CASPO. After 2, 4, and 6 weeks of RZF prophylaxis, there was a significant reduction of nuclei and asci counts between all groups of RZF versus T/S 1x/week. There was a significant benefit in survival between the RZF group at 20 mg/kg/3x/week versus CASPO at week 14 (Figure 2). In this study, prophylaxis with RZF for as little as 4 weeks prevented <i>P. murina</i> organisms from developing infection after cessation of therapy and showed more efficacy than CASPO. These results in the mouse model of <i>Pneumocystis</i> pneumonia provide evidence that RZF can prevent <i>Pneumocystis</i> reactivation and that such regimens hold promise for prophylaxis against <i>Pneumocystis</i> in at-risk patients undergoing blood and marrow transplantation.

Pharmacological profile, clinical efficacy, and safety of esaxerenone (Minnebro&lt;sup&gt;®&lt;/sup&gt; tablets 1.25 mg, 2.5 mg, 5 mg)

Esaxerenone is a novel non-steroidal mineralocorticoid receptor antagonisit (MR blocker), whose unique binding to the MR-ligand domain yields a stronger MR antagonistic effect and higher selectivity than existing MR antagonisits. Esaxerenone was approved for the treatment of hypertension in Japan in January 2019. Esaxerenone suppresses the reduction of urinary Na+/K+ ratio in adrenalectomized rats and blood pressure increase, proteinuria, and renal tissue lesions in salt-sensitive hypertensive rats-all in a dose-dependent manner. Esaxerenone is rapidly absorbed and reaches intracellular targets because of its high membrane permeability, exhibits high bioavailability with small interindividual exposure variation, and is metabolized via several pathways (e.g., oxidation, glucuronidation, and hydrolysis), which is associated with low drug-drug interaction risk. As esaxerenone is slightly excreted into urine, its exposure is similar between elderly and non-elderly patients, and between patients with normal and moderately deteriorated renal function. Given its 19-hour half-life, once-daily administration would have a sustainable antihypertensive effect. The ESAX-HTN phase 3 study demonstrated the non-inferiority of esaxerenone's antihypertensive effect versus that of eplerenone in essential hypertension. Another study showed a stable antihypertensive effect for 52 weeks as monotherapy or combination therapy. In hypertensive patients with moderate impairment or both type 2 diabetes and albuminuria treated with a renin-angiotensin system inhibitor, esaxerenone elicited a stable antihypertensive effect and manageable hyperkalemia incidence with titration from a low dose and monitoring including serum potassium. Thus, with careful monitoring of serum potassium, esaxerenone can be administered to patients with moderate renal impairment or both diabetes and albuminuria.

Rezafungin Prevention of Pneumocystis Pneumonia and Pneumocystis reactivation Using Different Doses and Durations of Prophylaxis in a Mouse Model

Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis species in patients undergoing blood and marrow transplantation. RZF has a favorable safety and tolerability profile, a low risk of drug-drug interactions and, with its stability, pharmacokinetics that allow for once-weekly dosing with broad distribution to the lung and other fungal target organs. We previously demonstrated RZF efficacy in preventing Pneumocystis infection in an immunosuppressed mouse model. The present study addressed whether Pneumocystis infection in a similar immunosuppressed mouse model could re-activate after 2 to 8 wks of prophylactic therapy using different dosing regimens of RZF. C3H/HeN mice were infected with P. murina intranasally at 2 x 106/50 µl after immunosuppression with dexamethasone. Mice were administered vehicle as a negative control (C/S), trimethoprim/sulfamethoxazole (T/S) as a positive control, caspofungin (CASPO) as a comparator echinocandin or RZF intraperitoneally at time of challenge. Study drug administration was stopped at 2, 4, 6, and 8 weeks, at which time mice were immunosuppressed for an additional 6 weeks to allow any residual P. murina to re-activate. Mice were then euthanized and lungs were processed for analysis of nuclei and asci. All RZF dose regimens at all timepoints significantly reduced both nuclei and asci burdens versus the C/S group (Figure 1). After 4 weeks of RZF prophylaxis (plus 6 wks additional immunosuppression [week 10 timepoint]; Figure 1), both RZF 20 mg/kg groups (3x/wk and 1x/wk) had prevented P. murina organisms from activating an infection. After 6 and 8 weeks of RZF prophylaxis (week 12 and 14 timepoints; Figure 1), no re-activation of infection was present in any of the study groups. After 2 and 4 weeks of prophylaxis (week 8 and 10 timepoints), there was a significant reduction of nuclei and asci counts in all groups of RZF versus CASPO. After 2, 4, and 6 weeks of RZF prophylaxis, there was a significant reduction of nuclei and asci counts between all groups of RZF versus T/S 1x/week. There was a significant benefit in survival between the RZF group at 20 mg/kg/3x/week versus CASPO at week 14 (Figure 2). In this study, prophylaxis with RZF for as little as 4 weeks prevented P. murina organisms from developing infection after cessation of therapy and showed more efficacy than CASPO. These results in the mouse model of Pneumocystis pneumonia provide evidence that RZF can prevent Pneumocystis reactivation and that such regimens hold promise for prophylaxis against Pneumocystis in at-risk patients undergoing blood and marrow transplantation. Disclosures Cushion: Cidara Therapeutics: Consultancy, Research Funding.

Summary of Maribavir (SHP620) Drug–Drug Interactions Based on Accumulated Clinical and Nonclinical Data

Introduction Maribavir, a potent and orally bioavailable antiviral, is being evaluated in Phase 3 trials for the treatment of cytomegalovirus (CMV) infections in transplant patients. Often numerous concomitant medications are administered to these patients to manage their comorbidities. A thorough evaluation of maribavir potential for drug–drug interactions (DDIs) is warranted and required for the regulatory approval. Objectives To thoroughly evaluate potential DDIs for maribavir. Methods Extensive in vitro studies were conducted to evaluate the potential involvement of cytochrome P450s (CYPs), uridine diphosphate glucuronosyltransferases (UGTs) and transporters on the disposition of maribavir, as well as the inhibitory and induction effect of maribavir on these enzymes and transporters. Clinical Phase 1 studies included a human mass-balance study, two probe-cocktail studies, and five DDI studies with ketoconazole, rifampin, antacid, voriconazole, and tacrolimus. Results Maribavir is metabolized primarily in the liver through CYP3A4 (70–85%) and CYP1A2 (15–30%). Renal clearance is a minor route ( Conclusions Maribavir has low risk for DDI. Inhibitors of CYP3A4 and/or P-gp may increase maribavir exposure, but dose adjustment of maribavir is not necessary. Potent inducers of CYP3A4 and P-gp decrease maribavir exposure, necessitating maribavir dose increase. Maribavir may increase exposure of immunosuppressants, such as tacrolimus. Therefore, monitoring of concomitant immunosuppressants' blood concentration should be considered at initiation, co-administration, and discontinuation of maribavir. Maribavir is not expected to interact with other concurrent medications.

Rezafungin Prophylactic Efficacy in a Mouse Model of Pneumocystis Pneumonia

Background The risk of Pneumocystis pneumonia often warrants antifungal prophylaxis for bone marrow and solid organ transplantation patients. However, complications such as myelosuppression, nephrotoxicity, and intolerance with the existing standard, TMP/SMX, may hinder or interrupt prophylaxis. Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal infections caused by Candida, Aspergillus, and Pneumocystis species in patients at high risk of infection. RZF has a favorable safety and tolerability profile and a low risk of drug-drug interactions. Furthermore, the stability and pharmacokinetics of RZF allow for once-weekly dosing and broad distribution to the lung and other target organs. RZF was shown to prevent in vitro Pneumocystis biofilm formation and to reduce the viability of mature biofilms. A previous prophylactic study was conducted using a broader range of RZF doses. In the current study, the efficacy of RZF was evaluated to better understand the minimum doses necessary to prevent Pneumocystis growth in a mouse model. Methods C3H/HeN mice were immunosuppressed (dexamethasone 4 mg/L in acidified drinking water) and then infected intranasally with P. murina (2 × 106/50 µL). Given the slow growth of P. murina, test agents were administered at the same time mice were inoculated to test for prophylactic efficacy. Mice received intraperitoneal injections of either vehicle (control/steroid [C/S]), TMP/SMX 50/250 mg/kg/3x/week (wk), caspofungin 5 mg/kg once daily, or RZF 5 mg/kg or 0.5 mg/kg once daily, 1x, or 2x/wk. After a 6-week dosing period, mice were sacrificed and lung homogenates were processed for analysis to quantify the nuclei (trophic) and asci (cyst) forms of Pneumocystis. Prophylaxis efficacy was based on reduction of organism burden compared with C/S. Nuclei and asci counts were log transformed and analyzed by ANOVA; individual groups were compared by the Student-Newman-Keuls t test. Survival rates were compared using GraphPad Prism v5. Results All mice in the RZF groups had significantly reduced nuclei and asci burdens compared with the C/S group, and all but the lowest doses of RZF (0.5 mg/kg 1x or 2x/wk) worked as well as TMP/SMX at reducing nuclei levels (Fig 1). Similarly, all RZF groups except for the 0.5 mg/kg 1x/wk group showed reductions in asci levels comparable to that of TMP/SMX (Fig 1). The survival rates were not statistically different between treatment groups. Conclusions RZF demonstrated potent in vivo efficacy as prophylaxis against Pneumocystis in an in vivo mouse infection model at dose regimens much lower than the human equivalent Ph3 regimen. These data support the development of RZF for the prevention of invasive fungal infections including Pneumocystis pneumonia.