Effects of triclabendazole and its metabolite exposure on the heart-rate-corrected QT intervals: A randomized, placebo- and positive-controlled thorough QT study in healthy individuals.

Triclabendazole is an effective and well-tolerated treatment for human fascioliasis. A placebo- and positive-controlled, four-sequence by four-period crossover study was conducted in 45 healthy participants to assess the effect of therapeutic (10 mg/kg twice daily [b.i.d.] for 1 day) and supratherapeutic (10 mg/kg b.i.d. for 3 days) oral doses of triclabendazole on corrected QT (QTc) interval prolongation. Moxifloxacin (400 mg, oral) was used as a positive control. The highest mean placebo-corrected change from baseline in QTcF (ΔΔQTcF) on day 4 with triclabendazole was 9.2 at therapeutic dose ms and 21.7 ms at supratherapeutic dose, at 4 h postdose. The upper limit of the two-sided 90% confidence interval exceeded 10 ms across all timepoints, except at predose timepoint on day 4 in the therapeutic group indicating that an effect of triclabendazole on cardiac repolarization could not be excluded. However, triclabendazole had no clinically significant effects on heart rate and cardiac conduction at the studied doses. In the moxifloxacin group, the mean ΔΔQTcF peak value was 13.7 ms at 3 h on day 4. The assay sensitivity was confirmed. Maximum plasma concentration of triclabendazole, sulfoxide metabolite, and sulfone metabolite occurred at ~3-, 4-, and 6-h postdose, respectively. No deaths, serious adverse events, study discontinuations due to treatment-emergent adverse events, or clinically relevant abnormalities in laboratory evaluations and vital sign values were observed. This study showed that triclabendazole had no clinically relevant effects on heart rate and cardiac conduction; however, an effect on cardiac repolarization (ΔΔQTcF >10 ms) could not be excluded.

Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). METHODS: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. CONCLUSIONS: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03334747).

Triclabendazole in the treatment of human fascioliasis: a review.

Fascioliasis occurs on all inhabited continents. It is caused by Fasciola hepatica and Fasciola gigantica, trematode parasites with complex life cycles, and primarily affects domestic livestock. Humans become infected after ingestion of contaminated food (typically wild aquatic vegetables) or water. Fascioliasis may be difficult to diagnose as many symptoms are non-specific (e.g. fever, abdominal pain and anorexia). Treatment options are limited, with older effective therapies such as emetine and bithionol no longer used due to safety issues and unavailability, and most common anthelminthics having poor efficacy. Clinical trials conducted over a 25-year period, together with numerous case reports, demonstrated that triclabendazole has high efficacy in the treatment of human fascioliasis in adults and children and in all stages and forms of infection. Triclabendazole was approved for human use in Egypt in 1997 and in France in 2002 and a donation program for the treatment of fascioliasis in endemic countries was subsequently established by the manufacturer and administered by the World Health Organization. Here the published data on triclabendazole in the treatment of human fascioliasis are reviewed, with a focus on more recent data, in light of the 2019 US Food and Drug Administration approval of the drug for use in human infections.

ß-Hydroxybutyric acid grafted solid lipid nanoparticles: a novel strategy to improve drug delivery to brain.

Delivery of drugs to brain is an elusive task in the therapy of many serious neurological diseases. With the aim to create a novel formulation to enhance the drug uptake to brain, betreliesoxybutyric acid (HBA) grafted docetaxel loaded solid lipid nanoparticles (HD-SLNs) were explored. Transportation of HD-SLNs relies on the transport of novel ligand, HBA, by monocarboxylic acid transporter (MCT1). Expression of MCT1 transporter on brain endothelial cells (bEnd cells) was studied using immunocytochemistry. Stearylamine-HBA conjugate was used to modify the surface of SLNs and it was confirmed using XPS (X-Ray Photon Spectroscopy) analysis. In vitro release studies revealed the controlled release of drug from HD-SLNs. Cytotoxicity and cell uptake studies revealed the increased uptake of docetaxel with HD-SLNs. Mechanism involved in the uptake of HD-SLNs was studied in bEnd cells by saturating MCT1 with excess HBA. Pharmacokinetic and brain distribution demonstrated increased docetaxel concentrations in brain compared with Taxotere®. FROM THE CLINICAL EDITOR: The authors of this study demonstrate enhanced drug delivery to the brain using a novel formulation of beta-hydroxybutyric acid grafted docetaxel loaded solid lipid nanoparticles. The results show increased uptake of docetaxel compared with Taxotere.

Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles.

Docetaxel is used in the treatment of many types of cancer, but its entry into the brain is restricted by p-glycoprotein (p-gp) efflux. A potential drug-drug interaction exists between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system, and ketoconazole can inhibit p-gp efflux of docetaxel at blood brain barrier. Hence, these two drugs were loaded in solid lipid nanoparticles (SLNPs) and surface of these NPs were modified with folic acid for brain targeting. These NPs were characterized for particle size, zeta potential, entrapment efficiency, in vitro drug release, cytotoxicity, and cell uptake in brain endothelial cell lines. Plasma and brain pharmacokinetics have shown increased brain uptake of docetaxel with surface-modified dual drug-loaded SLNPs. Brain permeation coefficient (K(in)) of folate-grafted docetaxel and ketoconazole loaded SLNPs was 44 times higher than that of Taxotere. Hence, these NPs were suitable for the delivery of lipophilic anticancer drugs to the brain. FROM THE CLINICAL EDITOR: In this paper, successful delivery of docetaxel and ketoconazole is reported using solid lipid nanoparticles surface modified with folic acid for brain targeting, which may pave the way to optimized clinical applications of lipophilic anticancer drugs to the brain.

Design and evaluation of polymer coated carvedilol loaded solid lipid nanoparticles to improve the oral bioavailability: a novel strategy to avoid intraduodenal administration.

Solid lipid nanoparticles are most promising delivery systems for the enhancement of bioavailability of highly lipophilic drugs those prone to the first pass metabolism. But burst release of drug from solid lipid nanoparticles in acidic environment such as gastric milieu precludes its usage as oral delivery system. Studies on SLN revealed intraduodenal administration as an alternative route for SLN administration. But clinically it is an inappropriate route for repeated administration of drugs to patients. Hence, we prepared N-carboxymethyl chitosan (MCC) coated carvedilol loaded SLN to protect the rapid release of carvedilol in acidic environment. Positively charged carvedilol loaded SLN were developed using monoglyceride as lipid and soya lecithin and poloxamer 188 as surfactants and stearylamine as charge modifier. These SLN were characterized for particle size, zeta potential, entrapment efficiency, crystallinity and stability studies. Further these SLN were coated with N-carboxymethyl chitosan and confirmed by change in zetapotential and X-ray Photon Spectroscopic analysis. Effect of polymer coating on drug release profiles were studied simulated gastric and intestinal fluids. Effect of polymer coating on oral bioavailability of carvedilol loaded SLN were studied in rats after oral administration. MCC coated SLN improved the bioavailability of carvedilol compared uncoated SLN after oral administration. Insignificant difference in bioavailability was observed compared to intraduodenal administration of SLN. Hence, MCC coated SLN is a novel strategy to avoid intrduodenal administration.

Application of validated RP-HPLC method for simultaneous determination of docetaxel and ketoconazole in solid lipid nanoparticles.

Docetaxel has significant single agent activity in prostate cancer and ketoconazole also has activity as a second line hormonal agent. In vitro, ketoconazole is synergistic with some chemotherapy agents by enhancing the intracellular retention of the cytotoxic agent. A potential drug-drug interaction exists though between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system. Hence, a nanoparticulate system was formulated by loading both drugs for tumor targeting. Assay and in vitro release of the formulation were conducted by developing simple, precise, accurate, and validated analytical method for simultaneous determination docetaxel and ketoconazole using reversed-phase high-performance liquid chromatography (RP-HPLC). The RP-HPLC method was developed using Waters Symmetry C(18) column (25 cm × 4.5 mm, 5 µm) with a mobile phase consisting of acetonitrile and 0.2% triethylamine pH adjusted to 6.4 (48:52, v/v) at flow rate of 1 mL/min. Intra-day and inter-day variations were less than 2% over the linearity range, 0.5-20 µg/mL. The proposed two methods were successfully applied for the determination of docetaxel and ketoconazole in solid lipid nanoparticles.

Development and validation of a reversed-phase HPLC method for determination of nitrendipine in rat plasma: application to pharmacokinetic studies.

A simple and sensitive method for the determination of nitrendipine in rat plasma was developed using high-performance liquid chromatography (HPLC). The procedure involves extraction of nitrendipine in dichloromethane/sodium hydroxide, followed by reversed phase HPLC using a Waters, Spherisorb ODS2 (250 x 4.6 mm, 5 microm) column and UV detection at 238 nm. The retention times of nitrendipine and internal standard (felodipine) were 5.0 min and 7.5 min, respectively. The calibration curves were linear over the range of 5 ng/mL (lower limit of quantification, LOQ) to 200 ng/mL for nitrendipine. The intra- and inter-day coefficients of variation for all criteria of validation were less than 15% over the linearity range. The sensitivity and precision of the method were within the accepted limits (< 15%) throughout the validation period. The present method was also successfully applied for the study of plasma pharmacokinetics of nitrendipine loaded solid lipid nanoparticles (SLN) in rats.