Halfan (halofantrine) / SRI International, GSK - LARVOL DELTA

Primary Small Intestinal Epithelia Are Physiological Alternatives to the Caco-2 Lymphatic Transport Model. (PubMed, Mol Pharm) - "Monolayers were assessed for changes in (Ia) lipoprotein secretion, (Ib) re-esterification enzyme expression, and (II) CM transport of the model lipophilic compounds halofantrine (HF; logP 7.34) and navitoclax (NX; logP 7.93). Drug appearance in secreted lipoproteins was higher in stimulated mIle than Caco-2 (4.6- vs 1.6-fold for HF; 14.9- vs 1.3-fold for NX), with the primary culture model transporting a larger proportion of the dose via CMs than the cell line standard. We concluded that pulse-chase in primary monolayer cultures is a promising New Approach Methodology (NAM) for measuring intestinal lymphatic transport of lipid-formulated drugs and could offer, with refinement and validation, an alternative to the lymph-cannulated animal model."

Journal • APOB

Drug Resistance Profiling of Malaria Isolates in the BEI Resources Repository (ASTMH 2025) - "SYBR® Green I-based IC₅₀ assays were used to determine the susceptibility of >100 isolates against a standard panel of drugs, including chloroquine (CQ), artemisinin (ART), quinine (QN), pyrimethamine (PYR), sulfadoxine (SDX), and cycloguanil (CYC). Additional antimalarial susceptibility testing was performed against a secondary panel of drugs, including halofantrine (HF) and lumefantrine (LM). Because standard IC₅₀ assays poorly capture in vitro parasite susceptibility to artemisinin drugs and piperaquine, ring-stage survival assays and piperaquine-survival assays were also performed on a subset of isolates (n = 22), which were primarily deposited into BEI Resources as showing sensitivity or resistance to these drugs. Our results reveal a range of drug susceptibility profiles for the different isolates and provide valuable information to assist current and prospective users of the BEI Resources repository in making data-driven requests of isolates to meet their..."

Late-breaking abstract • Infectious Disease • Malaria

Indirect Modeling of Post-Prandial Intestinal Lymphatic Uptake of Halofantrine Using PBPK Approaches: Limitations and Implications. (PubMed, Pharmaceutics) - "Moreover, the importance of integrating representative physicochemical factors for drugs, particularly in post-prandial conditions or lipid formulations, is evident. Overall, these findings contribute to advancing predictive regulatory and developmental considerations in drug development using post hoc analyses."

Journal

A novel cellular tool for screening human pan-coronavirus antivirals. (PubMed, Antiviral Res) - "We also compared two known 3C-like protease inhibitors and found that Nirmatrelvir is superior to Pomotrelvir in terms of pan-coronavirus antiviral activity. Furthermore, we tested 13 known antimalarial drugs and identified Halofantrine as having antiviral activity against SARS-CoV-2. Our findings suggest that this novel human cell model is a valuable and versatile tool for the screening and identification of pan-CoV antiviral drugs."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Leveraging Buprenorphine and Halofantrine as Tool Molecules to Develop a Novel Semi-Physiologically based Pharmacokinetic Model Accounting for Gastro-Intestinal Lymphatic Absorption and Enabling Cross-Species Translation. (PubMed, AAPS J) - "Incorporating the allometric scaled CLCE competing with the extensive gut metabolism, our model predicted Buprenorphine prodrugs remains effective in enabling substantial absorption boosts, with oral F% estimates ranging from 15.8% to 56.7% in humans. This study highlights the significant potential of GI-lymph-PBPK modeling in predicting intestinal lymphatic absorption and facilitating cross-species translation."

Journal • PK/PD data

Novel hydrazone compounds with broad-spectrum antiplasmodial activity and synergistic interactions with antimalarial drugs. (PubMed, Antimicrob Agents Chemother) - "Isobologram assays demonstrated synergistic interactions between CB-61 and the FDA-approved antimalarial drugs, clindamycin and halofantrine. Testing of six CB compounds showed no inhibition of Plasmodium glutathione S-transferase as a putative target and no cytotoxicity in HepG2 liver cells. CB compounds are promising candidates for further development as antimalarial drugs against multidrug-resistant parasites, which could also prevent malaria transmission."

Journal • CNS Disorders • Infectious Disease • Malaria • Psychiatry • Schizophrenia

Quantifying the Lymphatic Transport of Model Therapeutics from the Brain in Rats. (PubMed, Mol Pharm) - "Rats were administered 14C-ibuprofen (206.29 g/mol, logP 3.84), 3H-halofantrine HCl (536.89 g/mol, logP 8.06), or 3H-albumin (∼65,000 g/mol) via direct injection into the brain striatum at a rate of 0.5 μL/min over 16 min. Similar to other tissues, the lymphatics may thus play a significant role in the transport of macromolecules, including therapeutic proteins, from the brain but are unlikely to be a major transport pathway from the brain for small molecule drugs that are not lipophilic. Our rat cervical lymph cannulation model can be used to quantify the lymphatic drainage of different molecules and factors from the brain."

Journal • Preclinical • Anesthesia • Cervical Cancer

Halofantrine Hydrochloride Acts as an Antioxidant Ability Inhibitor That Enhances Oxidative Stress Damage to Candida albicans. (PubMed, Antioxidants (Basel)) - "In addition, the antifungal activity of HAL has been observed in the Galleria mellonella infection model. These findings provide evidence that targeting the oxidative stress response of C. albicans and augmenting the fungicidal capacity of oxidative damage agents hold promise as effective antifungal strategies."

Journal • Candidiasis • Infectious Disease

Development of a Novel In Vitro Model to Study Lymphatic Uptake of Drugs via Artificial Chylomicrons. (PubMed, Pharmaceutics) - "The model was validated using cannabidiol, halofantrine, quercetin, and rifampicin. Moreover, it can be employed to explore innovative drug formulations and excipients that either enhance or hinder lymphatic drug uptake. The insights gained from this study have significant implications for advancing drug delivery through the lymphatic system."

Journal • Preclinical

Characterization of Kenyan Plasmodium falciparum field isolates for use in Controlled Human Malaria Infection (ASTMH 2023) - "Of n=16, 10 were tested and had the following median drug concentration (IC50s) 14 ng/ml (7.946-14.78) for chloroquine, 29.04 ng/ml (21.71-57.17) for quinine, 4.955 ng/ml (3.631-6.173) for atovaquone, 870 ng/ml (622.6-900.1) for primaquine, 3824 ng/ml (1527-6569) for doxycycline, 5.796 ng/ml(3.941-8.531) for artemether, 3.627 ng/ml (3.299-6.829) for artesunic acid, 1.457 ng/ml (0.9395-1.666) for amodiaquine, 5.796 ng/ml (3.941-8.531) for artemisinin, 19.69 ng/ml (16.45-27.74) for halofantrine and 423.4 ng/ml (141.2-859.4) for tafenoquine. Of the 16 samples, 87.5% harbored gametocytes, 68.75% had falciparum only, and 12.5% had co-infection of either P.falciparum with P.malariae or P.falciparum with P. o.wallikeri respectively. These findings prequalify and support the identification of new isolates for consideration in future CHMI studies."

Infectious Disease • Malaria

CYP3A4gene variantsinresidents of LakeVictoriaregion,Kenya, 2013 (ASTMH 2023) - "Cytochrome P450 3A4 (CYP3A4) significantly contribute to inter-individual variation in drug metabolism and is involved in the metabolism of about 30% of clinically used drugs, including the antimalarials lumefantrine and halofantrine...In addition, we mapped an introgenic SNP, rs3735451, involved in hydroxychloroquine metabolism. To our knowledge this is the first study in Kenya to genotype the entire CYP3A4 variation which provides a foundation for future pharmacogenetic studies. Our work contributes to the data needed to improve precision medicine approaches in Africa."

Infectious Disease • Malaria • CYP3A4

Comparative cardiac effects of antimalarial drug halofantrine with or without concomitant administration of kolanut or fluconazole in healthy volunteers. (PubMed, Afr Health Sci) - "Pre-treatment PR interval (PR) correlated well with post-treatment PR, and with PR r= 0.519, p= 0.014; r=0.664, p=0.013. Concomitant intake of kolanut with halofantrine was significantly decrease cardiac effect of halofantrine."

Journal • Cardiovascular • Infectious Disease • Malaria

CRISPR/Cas9-Based Screening of FDA-Approved Drugs for NRF2 Activation: A Novel Approach to Discover Therapeutics for Non-Alcoholic Fatty Liver Disease. (PubMed, Antioxidants (Basel)) - "Our model was validated using a known NRF2 activator, after which we screened 1200 FDA-approved drugs, unearthing six compounds (Disulfiram, Thiostrepton, Auranofin, Thimerosal, Halofantrine, and Vorinostat) that enhanced NRF2 activity and antioxidant response. These compounds demonstrated protective effects against oxidative stress induced by hydrogen peroxide and lipid droplets accumulation in vitro with hepatoma HUH-7 cells. Our study underscores the utility of CRISPR/Cas9 tagging with Nanoluc luciferase in identifying potential NRF2 activators, paving the way for potential NAFLD therapeutics."

FDA event • Journal • Fibrosis • Gastrointestinal Cancer • Genetic Disorders • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Obesity • Oncology • Solid Tumor • HMOX1

Antimalarials and amphotericin B interact synergistically and are new options to treat cryptococcosis. (PubMed, Int J Antimicrob Agents) - "Cryptococcus gattii and C. neoformans are the main etiological agents of cryptococcosis, an invasive mycosis treated with amphotericin B, 5-fluorocytosine, and fluconazole...The antimalarials (ATMs) halofantrine (HAL) and amodiaquine (AQ) block Plasmodium heme polymerase, while artesunate (ART) induces oxidative stresses...Finally, HAL+AMB and AQ+AMB efficiently reduced lethality and fungal burden in the lungs and brain, in murine cryptococcosis. These findings provide perspectives for further studies with ATMs against cryptococcosis and other fungal infections."

Journal • Dermatology • Infectious Disease • Malaria

Drug-induced torsades de pointes: Disproportionality analysis of the United States Food and Drug Administration adverse event reporting system. (PubMed, Front Cardiovasc Med) - "Amiodarone (464 cases) was associated with most cases of TdP. According to the disproportionality analysis, the top five drugs with the highest ROR and PRR were tolazoline (ROR 1615.11, 95% confidence interval [CI] 455.59-5725.75, PRR 969.46, χ 2960.10), levomethadyl (ROR 1211.01, 95% CI 302.75-4844.04, PRR 807.67, χ 1677.03), ibutilide (ROR 1118.74, 95% CI 425.00-2944.91, PRR 765.77, χ 3845.27), halofantrine (ROR 660.55, 95% CI 184.21-2368.69, PRR 519.22, χ 1076.31), and isoproterenol (ROR 352.20, 95% CI 227.19-546.00, PRR 307.82, χ 6692.53)...Notably, potential risks are of great importance and should be closely monitored in clinical practice. Also, further research is needed to investigate the association between these drugs and TdP."

Adverse events • Journal

Evaluation of in vitro and molecular antimalarial susceptibility prior to and during Covid-19 pandemic 2018-2019 to 2021-2022 (ASTMH 2022) - "A total of 400 clinical samples from individual presenting with uncomplicated malaria enrolled under our ongoing malaria drug resistance surveillance study in 2018-2022 were screened against a panel of antimalarials namely chloroquine (CQ), quinine (QN), atovaquone (AV), primaquine (PQ) and artemisinin (ART), halofantrine (HAL) artemether (AR) and dihydroartemisinin (DHA)...While Lumefantrine, Artesunic acid and tafenoquine medians remained unchanged prior and during Covid-19 period...Pfcrt codons 72 and 76 were predominantly wild type before and during the pandemic period. Analysis of other markers that could have resulted in elevated median (IC50) is still under way."

Preclinical • Infectious Disease • Malaria • Novel Coronavirus Disease • Respiratory Diseases • ABCB1

Functional evidence that Plasmodium vivax mdr1 haplotypes confer multidrug resistance (ASTMH 2022) - "We found that certain pvmdr1 alleles, in addition to overexpression, confer resistance (2- to 4-fold) to dihydroartemisinin, mefloquine, halofantrine and lumefantrine, while other haplotypes conferred no change in, or increased, sensitivity. Our results suggest major pvmdr1 alleles alone do not confer high-grade chloroquine resistance. Instead specific pvmdr1 alleles and overexpression of pvmdr1 confer resistance to artemisinin and its partner drugs, mefloquine and lumefantrine, with implications for guiding P. vivax treatment policy and the molecular surveillance of drug resistance alleles."

Late-breaking abstract • ABCB1

Evaluation of Compound A as a novel antiplasmodial lead against multiple parasitic stages (ASTMH 2022) - "Compound A exhibited synergistic matches with Lumefantrine, Clindamycin, Atovaquone, Dihydroartemisinin, and Halofantrine. The drug interaction assay validates the ML-SyPred’s predictions. This study supports the notion that Compound A is a promising candidate for further drug development."

Late-breaking abstract • Infectious Disease • Malaria

Small-volume in vitro lipid digestion measurements for assessing drug dissolution in lipid-based formulations using SAXS. (PubMed, Int J Pharm X) - "The digestibility of infant formula with the poorly-water-soluble drugs halofantrine and clofazimine dispersed into it was measured as an exemplar paediatric-friendly lipid formulation. The dissolution of the two forms of clofazimine during the digestion of infant formula were then measured using synchrotron SAXS, which revealed complete and partial solubilisation over 30 min of digestion for the powdered drug and nanoparticle formulations, respectively. The main challenge in reducing the volume of the measurements was in ensuring that thorough mixing was occurring in the smaller digestion vessel to provide uniform sampling of the dispersion medium."

Journal • Preclinical • Pediatrics

Resistance to Antimalarial Monotherapy Is Cyclic. (PubMed, J Clin Med) - "The antimalarial drugs that exhibit cyclic resistance are quinine, chloroquine, mefloquine, amodiaquine, artesunate, artemether, sulfadoxine, doxycycline, halofantrine, piperaquine, pyrimethamine, atovaquone, artemisinin, and dihydroartemisinin. Furthermore, cyclic resistance is clinically relevant and discourages routine monotherapy, in particular, while resistance is on the rise. Finally, cyclic resistance encourages the combination of antimalarial drugs at distinct phases of resistance."

Journal • Monotherapy • Infectious Disease • Malaria

Impact of chemoprophylaxis immunisation under halofantrine (CPS-HF) drug cover in Plasmodium yoelii Swiss mice malaria model. (PubMed, Folia Parasitol (Praha)) - "CPS-HF immunisation results in a significant up-regulation of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-12 and iNOS) and down-regulation of anti-inflammatory cytokines (IL-10 and TGF-β) mRNA expression in hepatic mononuclear cells (HMNC) and spleen cells in the immunised CPS-HF mice (after 6th sporozoite challenge) compared to control. Overall, our study suggests that the repetitive sporozoite inoculation under HF drug treatment develops a strong immune response that confers protection against subsequent challenges with sporozoites of P. yoelii."

Journal • Preclinical • Infectious Disease • Malaria • IFNG • IL10 • IL12A • TGFB1 • TNFA

A 3D-Printed Polymer-Lipid-Hybrid Tablet towards the Development of Bespoke SMEDDS Formulations. (PubMed, Pharmaceutics) - "Application to a range of drug molecules was demonstrated by incorporating the model lipophilic drugs; halofantrine, lumefantrine and clofazimine into the multicompartmental scaffolded tablets. Fenofibrate was used as the model drug in the single compartment scaffolded tablets for comparison with previous studies...At the extremes of SA:V studied here, within 20 min of dissolution time, formulations with an SA:V of 0.8 had dispersed to between 90 and 110%, and completely released the drug, where as an SA:V of 0 yielded 0% dispersion and drug release. Therefore, this study presents opportunities to develop new dose forms with advantages in a polypharmacy context."

Journal • Gastrointestinal Disorder

Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine. (PubMed, R Soc Open Sci) - "Combining HCQ with the antibacterial moxifloxacin or the anti-malarial halofantrine (HAL) increased the degree of human ventricular action potential duration prolongation at some or all concentrations investigated, and was predicted to increase risk compared to HCQ alone. The combination of HCQ/HAL was predicted to be the riskiest for the free C values investigated, whereas azithromycin administered individually was predicted to pose the lowest risk. Our simulation approach highlights that the torsadogenic potentials of HCQ, CQ and other QT-prolonging anti-infectives used in COVID-19 prevention and treatment increase with concentration and in combination with other QT-prolonging drugs."

Journal • Atrial Fibrillation • Cardiovascular • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Malaria • Novel Coronavirus Disease • Rheumatoid Arthritis • Rheumatology • Systemic Lupus Erythematosus

Diagnostic and therapeutic values of PMEPA1 and its correlation with tumor immunity in pan-cancer. (PubMed, Life Sci) - "This study integrated existing data to explore PMEPA1 potential function in cancers, provided insights for the future cancer-related studies."

Journal • Pan tumor • Immune Modulation • Inflammation • Oncology • Prostate Cancer • MSI • TMB

Mechanistic Oral Absorption Modeling of Halofantrine: Exploring the Role of Intestinal Lymphatic Transport. (PubMed, J Pharm Sci) - "The model simulated halofantrine fraction absorbed (f) via the lymph in the fed state was 0.26, representing 62% of the increase in f in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport."

Journal