Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment.

Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.

Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg flucytosine: A randomized, open-label, crossover study in healthy volunteers.

The opportunistic fungal infection cryptococcal meningoencephalitis is a major cause of death among people living with HIV in sub-Saharan Africa. We report pharmacokinetic (PK) and safety data from a randomized, four-period crossover phase I trial of three sustained-release (SR) oral pellet formulations of 5-flucytosine conducted in South Africa. These formulations were developed to require less frequent administration, to provide a convenient alternative to the current immediate release (IR) formulation, A. Formulations B, C, and D were designed to release 5-flucytosine as a percentage of the nominal dose in vitro. We assessed their safety and PK profiles in a single dose (1 × 3000 mg at 0 h), relative to commercial IR tablets (Ancotil 500 mg tablets; 3 × 500 mg at 0 h and 3 × 500 mg at 6 h) in healthy, fasted participants. Forty-two healthy participants were included. All treatments were well-tolerated. The primary PK parameters, maximum observed plasma concentration (Cmax ) and area under the concentration-time profiles, were significantly lower for the SR formulations than for the IR tablets, and the geometric mean ratios fell outside the conventional bioequivalence limits. The median maximum time to Cmax was delayed for the SR pellets. Physiologically-based PK modeling indicated a twice-daily 6400 mg dose of SR formulation D in fasted condition would be optimal for further clinical development. This regimen is predicted to result in a rapid steady-state plasma exposure with effective and safe trough plasma concentration and Cmax values, within the therapeutic boundaries relative to plasma exposure after four times per day administration of IR tablets (PACTR202201760181404).

Effect of food on the pharmacokinetics of zoliflodacin granules for oral suspension: Phase I open-label randomized cross-over study in healthy subjects.

Gonorrhea is a sexually transmitted infection for which antibiotic treatment options have declined due to increasing antibiotic resistance. Zoliflodacin, an investigational oral spiropyrimidinetrione antibiotic with activity against Neisseria gonorrhoeae strains that are multidrug-resistant, including to third-generation cephalosporins, is in phase III development for uncomplicated gonorrhea. This phase I, parallel, open-label, randomized, crossover study in healthy adults evaluated the effect of food on the pharmacokinetics of single 3 or 4 g doses of zoliflodacin administered as granules for oral suspension in the fasted state or after consumption of a standardized high-fat meal. Forty-seven out of 48 randomized subjects completed the study. Oral administration of zoliflodacin with food delayed the absorption rate, compared with fasted state, with time to maximum concentration (Tmax ) increasing from 3 to 6 h for the 3 g dose, and 2.5 to 4 h for the 4 g dose, but had no impact on the elimination of zoliflodacin. The maximum concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-24) ) significantly increased with food by 52% and 94% for the 3 g dose, and by 89% and 108% for the 4 g dose. Forty-two percent of participants reported a total of 34 treatment-emergent adverse events (TEAEs), which were all considered mild in severity. Headache was the most common TEAE (22/48 subjects, 45.8%) and the only TEAE reported in more than one subject. In conclusion, administration of single 3 and 4 g doses of zoliflodacin as granules for oral suspension, with a high-fat meal was well-tolerated and resulted in statistically significant increases in peak and overall systemic exposure to zoliflodacin.

Safety, tolerability and pharmacokinetics of emodepside, a potential novel treatment for onchocerciasis (river blindness), in healthy male subjects.

AIMS: Emodepside is an anthelmintic, originally developed for veterinary use. We investigated in healthy subjects the safety, and pharmacokinetics of a liquid service formulation (LSF) and immediate release (IR) tablet of emodepside in 2 randomised, parallel-group, placebo-controlled, Phase I studies. METHODS: Seventy-nine subjects in 10 cohorts in the single ascending dose study and 24 subjects in 3 ascending-dose cohorts in the multiple ascending dose study were enrolled. Emodepside as LSF was administered orally as single 1-40-mg doses and for 10 days as 5 or 10 mg once daily and 10-mg twice daily doses, respectively. Pharmacokinetics and safety were assessed up to 21 and 30 days, respectively. In addition, IR tablets containing 5 or 20 mg emodepside were tested in the single ascending dose study. RESULTS: Emodepside as LSF was rapidly absorbed under fasting conditions, with dose-proportional increase in plasma concentrations at doses from 1 to 40 mg. Terminal half-life was > 500 hours. In the fed state, emodepside was absorbed more slowly but overall plasma exposure was not significantly affected. Compared to the LSF, the rate and extent of absorption was significantly lower with the tablets. CONCLUSIONS: Overall, emodepside had acceptable safety and tolerability profiles, no major safety concerns, after single oral administration of 20 mg as LSF and after multiple oral administration over 10 days at 5 and 10 mg OD and at 10 mg twice daily. For further clinical trials, the development of a tablet formulation overcoming the limitations observed in the present study with the IR tablet formulation is considered.

Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169).

The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampin, pyrazinamide, and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis Intensive efforts have been made to develop new antibiotics or to repurpose old drugs, and several of these are currently being evaluated in clinical trials for their antitubercular activity. Among the new candidate drugs is macozinone (MCZ), the piperazine-containing benzothiazinone PBTZ169, which is currently being evaluated in phase I/II clinical trials. Here, we determined the in vitro and in vivo activity of MCZ in combination with a range of anti-TB drugs in order to design a new regimen against active TB. Two-drug combinations with MCZ were tested against M. tuberculosis using checkerboard and CFU enumeration after drug exposure assays. MCZ was observed to have no interactions with all first- and second-line anti-TB drugs. At the MIC of each drug, MCZ with either bedaquiline (BDQ), clofazimine (CLO), delamanid (DMD), or sutezolid (STZ) reduced the bacterial burden by 2 logs compared to that achieved with the drugs alone, indicating synergism. MCZ also displayed synergism with clomiphene (CLM), a potential inhibitor of the undecaprenyl pyrophosphate synthase (UppS) in mycobacteria. For all the other drugs tested in combination with MCZ, no synergistic activity was observed. Neither antagonism nor increased cytotoxicity was found for most combinations, suggesting that MCZ could be added to different TB treatment regimens without any significant adverse effects.

MMP-12 induces IL-8/CXCL8 secretion through EGFR and ERK1/2 activation in epithelial cells.

Macrophage metalloelastase (MMP-12) is described to be involved in pulmonary inflammatory response. To determine the mechanisms linking MMP-12 and inflammation, we examined the effect of recombinant human MMP-12 (rhMMP-12) catalytic domain on IL-8/CXCL8 production in cultured human airway epithelial (A549) cells. Stimulation with rhMMP-12 resulted in a concentration-dependent IL-8/CXCL8 synthesis 6 h later. Similar results were also observed in cultured BEAS-2B bronchial epithelial cells. In A549 cells, synthetic matrix metalloproteinase (MMP) inhibitors prevented rhMMP-12-induced IL-8/CXCL8 release. We further demonstrated that in A549 cells, rhMMP-12 induced transient, peaking at 5 min, activation of ERK1/2. Selective MEK inhibitors (U0126 and PD-98059) blocked both IL-8/CXCL8 release and ERK1/2 phosphorylation. IL-8/CXCL8 induction and ERK1/2 activation were preceded by EGF receptor (EGFR) tyrosine phosphorylation, within 2 min, and reduced by selective EGFR tyrosine kinase inhibitors (AG-1478 and PD168393) by a neutralizing EGFR antibody and by small interfering RNA oligonucleotides directed against EGFR, implicating EGFR activation. In addition, we observed an activation of c-Fos in A549 cells stimulated by rhMMP-12, dependent on ERK1/2. Using small interfering technique, we showed that c-Fos is involved in rhMMP-12-induced IL-8/CXCL8 production. From these results, we conclude that one mechanism, by which MMP-12 induces IL-8/CXCL8 release from the alveolar epithelium, is the EGFR/ERK1/2/activating protein-1 pathway.

Control of death receptor and mitochondrial-dependent apoptosis by c-Jun N-terminal kinase in hippocampal CA1 neurones following global transient ischaemia.

c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is activated in response to a number of extracellular stimuli, including inflammatory cytokines, UV irradiation and ischaemia. A large body of evidence supports a role for JNK signalling in stress-induced apoptosis. It has been hypothesized that JNK may contribute to the apoptotic response by regulating the intrinsic cell death pathway involving the mitochondria. Here, we examined the role of the JNK signalling pathway in hippocampal CA1 apoptotic neurones following transient ischaemia in gerbils. We showed early activation of death receptor-dependent apoptosis (caspase-8 activation 2 days after ischaemia) and a biphasic activation of caspase-3 and caspase-9 after ischaemia. Activation of the mitochondrial pathway, as measured by cytochrome c release, appeared as a late event (5-7 days after ischaemia). AS601245, a novel JNK inhibitor, antagonized activation of both pathways and significantly protected CA1 neurones from cell death. Our results suggest a key role of JNK in the control of death receptor and mitochondrial-dependent apoptosis after transient ischaemia.