Study In Healthy Volunteers Research Articles

Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections

In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20–5.32) mg/L p < 0.001, 180 min 2.2 (1.58–3.25) mg/L p < 0.001; free: 45 min 1.15 (0.88–1.42) mg/L p < 0.001, 180 min 0.5 (0.35–0.76) mg/L p < 0.001). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

Respiratory physiological exploration during self-induced cognitive trance

Background and methodsLittle is known about self-induced cognitive trance (SICT) on respiratory function. The aims of this prospective, single-center, non-randomized, open-label study of healthy volunteers, were to characterize spirometry changes during SICT, confirm the safety of this technique, and investigate the potential clinical benefits of SICT. ResultsNine people participated. There were no significant difference in FEV1 FVC or FEF 25–75 before, during, and after SICT. There were significant improvements in grip strength during SICT (+2.2 kg/5.7 %, p<0.05) and in self-efficacy score related to physical activity at the end of the trance. One participant had a significant worsening of FEV1 during SICT in the context of a recent upper airway infection. ConclusionSICT does not significantly modify spirometry data in healthy volunteers and can improve self-efficacy related to physical activity. SICT should probably be performed with caution during upper airway infections.

Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

Development of a population pharmacokinetic model for the novel long-acting injectable antipsychotic risperidone ISM®.

The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg.

A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam.

Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity. Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction. Mean midazolam values of maximum plasma concentration (Cmax) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in Cmax of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon. Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.

Oxygenation and Carbon Dioxide Rebreathing of a Well-fitting Non-rebreathing EcoLite™ Mask with a Reservoir: A Single-center Prospective Observational Study in Healthy Volunteers.

The fitting of oxygen mask affects the performance of it such as oxygenation or CO₂ elimination. The intersurgical EcoLite™ adult high-concentration oxygen mask (EcoLite with a reservoir, Intersurgical, UK) was developed to give well-fitting. The purpose of this study is to evaluate the performance of EcoLite with a reservoir compared to the conventional mask. Ten healthy volunteers were included in this study. EcoLite with a reservoir and conventional mask were given to patients at different oxygen flow rates (5, 8, 10, 12, and 15 L/min). Fraction of inspiratory O₂ (FIO₂) and partial pressure of inspiratory CO₂ (PICO₂) were measured by a sampling tube at the middle pharynx inserted via nose. The EcoLite with a reservoir had a significantly higher FIO₂ than the control reservoir mask. However, the PICO₂ was significantly higher in the EcoLite with a reservoir than in the control reservoir mask, especially when the oxygen flow rate was low. The EcoLite with a reservoir provided improved oxygenation and a better fit than the conventional reservoir masks in healthy volunteers. However, the EcoLite with a reservoir might cause higher CO₂ rebreathing at low oxygen flow rates.

A double-blind, randomized, two-arm, single-dose, parallel-group study in healthy participants to compare the pharmacokinetics, pharmacodynamics, and immunogenicity of FKS518 proposed biosimilar to denosumab with the originator (LUMIADE-1 study).

e15097 Background: Denosumab is a RANKL inhibitor used in patients with bone metastases from solid tumors. FKS518 is a proposed biosimilar to denosumab originator product. Biosimilars offer similar efficacy, quality, safety, and favorable economic impact. Once the analytical and functional similarity of a biosimilar has been shown, a comparative human pharmacokinetics (PK) study is conducted to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference product. The present study assessed the PK equivalence of FKS518 to the originator product and provided data on the similarity of the pharmacodynamic, safety and immunogenicity profiles. Methods: A randomized, controlled, double-blind, parallel-group study in healthy volunteers was performed to compare denosumab biosimilar candidate FKS518 versus the originator product. Subjects received a single subcutaneous denosumab 60 mg injection and were followed up for 40 weeks. Primary endpoints PK parameters (Cmax, AUC0-last and AUC0-inf) were natural log transformed and analyzed using analysis of covariance methods; results were then transformed back to the original scale. Safety data were collected throughout the study and analyzed descriptively. Results: 213 male subjects 28-55 years of age, with a baseline BMI between 18.2 and 31.7 kg/m2, were randomized to the originator denosumab (n = 106) or FK518 (n = 107). Results of the primary PK analysis demonstrated bioequivalence between FKS518 and the originator denosumab product since the 90% confidence intervals (CIs) for the geometric least squares mean (LSM) ratios for the 3 primary PK parameters were completely included within the predefined 80.00% to 125.00% equivalence margin (point estimate [90%CI for the ratio]): Cmax: 104.79% [97.04%,113.15%], AUC0-last: 112.29% [104.17%,121.04%] and AUC0-inf : 112.65% [104.27%,121.70%]. Secondary PK parameters were similar as well between FKS518 and the originator: tmax (median: 217.45 hrs. vs. 216.03 hrs. respectively), t1/2 (median: 235 hrs. vs 337 hrs. respectively). The nature, frequency, severity, or resolution of adverse events were comparable across treatments. For immunogenicity, there was no difference between the 2 treatment groups in ADA and Nab incidence at each timepoint. Conclusions: PK equivalence of FKS518 and denosumab originator product was demonstrated with similar PD, safety and immunogenicity profile for the two products. This study adds to the totality of evidence supporting FKS518 as a proposed biosimilar to denosumab.

Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel in first-line patients with advanced pancreatic cancer (ACCENT trial): Interim analysis.

e16337 Background: Narmafotinib (AMP945) is a highly potent and selective, orally bioavailable inhibitor of Focal Adhesion Kinase (FAK). FAK is a non-receptor tyrosine kinase over-expressed in pancreatic cancer, where it contributes to cell survival, proliferation, migration and chemoresistance and thus plays a key role in tumor growth, FAK also contributes to multiple mechanisms underlying fibrosis and immunosuppression in the tumor microenvironment. Narmafotinib has successfully completed a Phase 1 study in healthy volunteers where the drug was safe and well tolerated with pharmacokinetics consistent with once-a-day dosing. A Phase 1b/2a trial of narmafotinib, in combination with gemcitabine and Abraxane, in advanced pancreatic cancer patients – the ACCENT trial – is currently underway in Australia and South Korea. Methods: The ACCENT trial (NCT05355298) is a Phase 1b/2a, open label study of the pharmacokinetics, safety and tolerability, and efficacy of narmafotinibin combination with gemcitabine and Abraxane (nab-paclitaxel) standard of care as first-line therapy in patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. In Part A, patients were enrolled in a 3+3 design to determine the narmafotinib recommended Phase 2 dose (RP2D), with narmafotinibdose-escalation (100, 200 and 400 mg). Safety and tolerability were assessed according to incidence and severity of adverse events. Narmafotinibplasma PK samples were collected on Days -8, -7, 1, 3, 8, and 10 of Run-In/Cycle 1. Imaging was conducted every 2 months. Part B of the trial is a Simon’s two stage design, with the primary objectives of assessing safety, tolerability, and efficacy of the combination using RECIST v1.1. Results: Preliminary analysis across all doses (14 patients) showed narmafotinib to be generally safe and well-tolerated and showed promising signs of efficacy. All patients who completed their first 28-day cycle of treatment elected to stay on narmafotinib and 9/14 patients have remained on trial for 5 months or more. There have been 6 confirmed PRs (4 in 400 mg cohort; 2 in 200 mg cohort) as best response. A single DLT was reported: uncontrolled grade 3 nausea (400 mg cohort). Fatigue, grade 3 or below related to narmafotinib occurred in more than one participant. The PK for narmafotinib is dose-proportional across the dose range tested, and the chemotherapy regimen used in this study did not impact narmafotinib PK. Safety, tolerability and efficacy data continues to be collected and will be presented. Conclusions: Based on this promising Phase 1b data, 400 mg of narmafotinib has been selected for the RP2D and Part B of the trial is now underway and recruiting patients in Australia and South Korea. The trial will enrol up to 50 patients as part of the Phase 2 expansion cohort. Clinical trial information: NCT05355298 .

Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies.

TPS6591 Background: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs promote production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. IRAK1/4 is a potential target for inhibition for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the study supported the further evaluation of R289. An open-label, phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The R289 phase 1b open label, single arm, multi-center study (NCT05308264) includes a dose escalation phase (up to 24 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases: patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 1 g qd with dose limiting toxicity (DLT) assessed at each dose level. The DLT evaluation period will be 28 days. After completion, patients without DLTs may remain at their respective dose levels if clinical benefit continues without toxicity. Dose Expansion Phase: R289 will be administered to up to 10 additional patients with LR-MDS at a dose not exceeding the MTD in the dose escalation phase. The primary endpoint is safety and tolerability of R289. Secondary endpoints include preliminary efficacy and pharmacokinetics of R289. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites. Clinical trial information: NCT05308264 .

Pharmacokinetics and Bioequivalence of Two Formulations of Azithromycin Tablets: A Randomized, Single-Dose, Three-Period, Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers. This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented. In a fasting state, the bioequivalence of maximum plasma concentration (Cmax) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, SWR >0.294), and the bioequivalence of area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC0-t) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) were evaluated by the average bioequivalence (ABE) method (SWR < 0.294). The geometric mean ratio (GMR) of T/R for Cmax was 106.49%, while the 95% upper confidence bound was < 0. The GMRs of AUC0-t and AUC0-∞ were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90-111.35%/94.85-108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of Cmax (SWR >0.294), and the ABE approach was applied to estimate the bioequivalence of AUC0-t and AUC0-∞ (SWR < 0.294). The GMR for Cmax was 99.80%, while the 95% upper confidence bound value was < 0. The GMRs of AUC0-t and AUC0-∞ were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02-104.68% and 90.66-106.25%, respectively. All adverse events were mild and transient. The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers under both fasting and fed conditions. Clinicaltrials, ChiCTR2300071630 (retrospectively registered in 19/05/2023).

Nanocomposite Gels Loaded with Flurbiprofen: Characterization and Skin Permeability Assessment in Different Skin Species.

Nanocomposite gels consist of nanoparticles dispersed in a gel matrix. The main aim of this work was to develop nanocomposite gels for topical delivery of Flurbiprofen (FB) for humans and farm animals. Nanocomposite gels were prepared stemming from nanoparticles (NPs) freeze-dried with two different cryoprotectants, D-(+)-trehalose (NPs-TRE) and polyethylene glycol 3350 (NPs-PEG), sterilized by gamma (γ) irradiation, and gelled with Sepigel® 305. Nanocomposite gels with FB-NPs-TRE and FB-NPs-PEG were physiochemically characterized in terms of appearance, pH, morphological studies, porosity, swelling, degradation, extensibility, and rheological behavior. The drug release profile and kinetics were assessed, as well as, the ex vivo permeation of FB was assessed in human, porcine and bovine skin. In vivo studies in healthy human volunteers were tested without FB to assess the tolerance of the gels with nanoparticles. Physicochemical studies demonstrated the suitability of the gel formulations. The ex vivo skin permeation capacity of FB-NPs nanocomposite gels with different cryoprotectants allowed us to conclude that these formulations are suitable topical delivery systems for human and veterinary medicine. However, there were statistically significant differences in the permeation of each formulation depending on the skin. Results suggested that FB-NPs-PEG nanocomposite gel was most suitable for human and porcine skin, and the FB-NPs-TRE nanocomposite gel was most suitable for bovine skin.

#2341 WS016, a novel potassium binder: safety, tolerability and pharmacodynamics in first-in-human phase 1 healthy volunteer study

Abstract Background and Aims Hyperkalemia is a common and potentially serious medical condition in patients with chronic kidney disease and is associated with high rates of mortality. Partiromer and Lokelma are available recently, however, edema is the common adverse event resulted from the exceed sodium exchanged by Lokelma and constipation, hypomagnesemia are frequently found using Partiromer because of the basic structure of them. WS016 is a highly selective, non-absorbed, cation-exchange polymer binder with the potential characteristics of no edema and hypomagnesemia. The objective of the trials was to assess the safety/tolerability and pharmacodynamics (PD) profiles of WS016. Method This is a randomized, double-blind, placebo-controlled phase 1 clinical trial. 40 healthy volunteers were randomized (6:2 randomization within a cohort) into five different cohorts administered with 6 g, 12 g, 24 g, 36 g, 48 g WS016 orally once daily for only one dose during the single dose ascending (SAD) stage and 24 healthy volunteers were randomized (6:2 randomization within a cohort) into three different cohorts administered with 12 g, 36 g, 48 g orally once daily for consecutive seven days during the multiple dose ascending(MAD) stage. Adverse events (AE) were collected, and physical examination, laboratory tests were done at baseline and different visits according to the protocol. Urinary potassium and fecal potassium were collected, tested and calculated per 24 hour. Serum potassium was evaluated alone with the timing after administration of WS016 in different cohort. Results Data of subjects from different placebo cohorts were pooled together for analysis in SAD and MAD stage. 40 healthy volunteers, including 6 in different WS016 cohorts and 10 in placebo cohort completed the SAD trial. 9, 5, 6, 7, 12 grade 1 AEs were reported from 12-48 g WS016 cohorts, respectively; 11 AEs were reported from placebo cohort and 1 is grade 2 AE. Totally, 5 cases with hypertriglyceridemia, 4 cases with prolonger activated partial thromboplastin time (APTT), 4 cases with decreased blood fibrinogen, 3 cases with sinus bradycardia were reported from WS016 cohort and 2 cases with hypertriglyceridemia, 1case with prolonged APTT, 1 case with decreased fibrinogen were reported from placebo cohort. 24 healthy volunteers, 6 from different WS016 cohorts and 6 from placebo cohort completed the MAD trial. 12, 10, 12 AEs were reported from 12 g, 24 g, 48 g cohort, respectively and 6 AEs were from placebo cohort. Only 1 AE as hypertriglyceridemia from 24 g cohort is grade 2, while others are grade 1. 5 cases with sinus bradycardia, 4 cases with hypertriglyceridemia, 3 cases with hyperuricacidemia, 3 cases with hypotension, 3 cases with prolonged APTT were reported from all WS016 cohort totally and 1 cases with hyperuricacidemia,1 cases with hypotension, 1 cases with prolonged APTT were reported from placebo cohort. There is no AE related to gastrointestinal tract and no side effects on the other electrolytes such as magnesium, calcium, sodium and phosphorus, reported from both SAD and MAD. It was found that fecal potassium excretion increased and urinary potassium decreased on D2 in SAD (Fig. 1) and on D7 in MAD (Fig. 2) compared to baseline. The serum potassium decreased quickly at about 1-2 hour after first administration of WS016 both in SAD and MAD (Figs 1 and 2) and the mean serum potassium of placebo cohort is higher than that in other WS016 cohorts during MAD (Fig. 2). Conclusion WS016 was generally well-tolerated following single doses and multiple doses. The AEs like constipation, hypomagnesemia commonly found in Patiromer and edema commonly found in Lokelma were not reported in WS016 cohorts. In accordance to the results from pre-clinical studies, the clinical pharmacodynamics characteristics was the increased fecal potassium along with the decreased urinary potassium, meanwhile the serum potassium decreased, especially during the first 4 hours after administration of WS016 although in the normal range among the healthy volunteers.

#1003 Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of AZD2373, an antisense oligonucleotide targeting APOL1

Abstract Background and Aims APOL1 mediated kidney disease (AMKD) is associated with toxic gain of function variants in people of African ancestry carrying the high-risk APOL1 genotypes (G1 and G2). APOL1 protein is part of the innate immune system but not considered essential. AZD2373, an antisense oligonucleotide that targets APOL1 mRNA to reduce its protein synthesis, is in development for AMKD. In genomic APOL1-transgenic mice, AZD2373 reduced APOL1 expression in kidney and liver, reduced plasma APOL1 protein concentration, and prevented development of IFN-γ induced proteinuria in high-risk genotype mice. In a single ascending dose study (NCT04269031), AZD2373 was well tolerated. We assessed the safety and tolerability of AZD2373 in a multiple ascending dose study including pharmacokinetics, and pharmacodynamic effect on APOL1 plasma protein levels. Method In this phase 1, randomized, single-blind, placebo-controlled study (NCT05351047) in healthy male volunteers of West African ancestry, participants were enrolled after a pre-screening study where they were genotyped for APOL1 prospectively; 18 participants had either 1 copy or 2 copies of the G1/G2 APOL1 high-risk allele. Low, medium and high dose cohorts each with 8 participants each receiving six weekly subcutaneous injections of either AZD2373 (n = 6) or placebo (n = 2) and were subsequently followed up for 9-weeks post-last dose. The primary objective was safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD2373. Results In total, 24 participants were randomized and completed the study. No major safety and tolerability concerns were reported up to the highest dose of AZD2373 administered. The most common adverse event was injection site reactions which were dose-dependent, mild to moderate in severity and did not lead to treatment discontinuation. After dosing, AZD2373 had a rapid distribution phase (hours) and prolonged elimination phase (days to weeks). Clearance was similar across dose levels after single and repeated dosing, and the renal contribution to overall clearance was minimal. Exposure generally increased in a dose proportional manner. Plasma APOL1 was knocked down in a dose dependent manner (Figure). Conclusion Repeated doses of AZD2373 were safe and well tolerated, reducing plasma APOL1 concentrations in a dose- and time-dependent manner in healthy males of West African ancestry.

Phase I Study of Tivozanib Eye Drops in Healthy Volunteers and Patients with Neovascular Age-Related Macular Degeneration

PurposeTo evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD). DesignThis multicenter, group-sequential dose escalation phase 1 study consisted of a placebo-controlled, double-masked study of healthy volunteers (Cohorts 1 and 2) and an open-label study of nAMD patients (Cohort 3). ParticipantsHealthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye. MethodsIn the single-dose cohort of healthy men (Cohort 1: Steps 1–5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (Cohort 2: Steps 1–6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily (TID) in 1 eye for 21 days. In the multiple-dose cohort of nAMD patients (Cohort 3, Steps 1–3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered TID in 1 affected eye for 21 days. Main Outcome MeasuresThe safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, central subfield thickness (CST) was evaluated. ResultsIn total, 40, 48, and 28 participants were enrolled in Cohorts 1, 2, and 3, respectively. Serious AEs did not occur in Cohorts 1–3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to Day 22 were −27.6 ± 54.88 (0.5 w/v%; 1 drop, TID), −35.6 ± 49.64 (1.0 w/v%; 1 drop, TID), and −43.7 ± 55.19 μm (1.0 w/v%; 2 drops, TID). ConclusionsTivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.

Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers.

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150mg) or placebo. Pharmacokinetic samples were collected over 24hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411ng/mL) associated with the recommended therapeutic doses (25mg twice-monthly), even at the highest supratherapeutic concentration (2425ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.

Pharmacokinetics and Bioequivalence of Fixed-Dose Combination of Simvastatin and Ezetimibe Tablets: A Randomized, Crossover, Open-Label Study in Healthy Volunteers.

The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open-label, randomized, 3-period, 3-sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20mg of simvastatin and 10mg of ezetimibe as a single-dose tablet, separated by a minimum of 2-week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography-tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin β-hydroxy acid determination was done via a validated ultra-performance liquid chromatography-tandem mass spectrometry. Each assay was preceded by a liquid-liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration-time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log-transformed under the concentration-time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%-125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation.

Quantification of water exchange across the blood-brain barrier using noncontrast MR fingerprinting.

A method is proposed to quantify cerebral blood volume ( ) and intravascular water residence time ( ) using MR fingerprinting (MRF), applied using a spoiled gradient echo sequence without the need for contrast agent. An in silico study optimized an acquisition protocol to maximize the sensitivity of the measurement to and changes. Its accuracy in the presence of variations in , , and was evaluated. The optimized protocol (scan time of 19 min) was then tested in a exploratory healthy volunteer study (10 volunteers, mean age 24 3, six males) at 3 T with a repeat scan taken after repositioning to allow estimation of repeatability. Simulations show that assuming literature values for and , no variation in , while fitting only and , leads to large errors in quantification of and , regardless of noise levels. However, simulations also show that matching , , , and , simultaneously is feasible at clinically achievable noise levels. Across the healthy volunteers, all parameter quantifications fell within the expected literature range. In addition, the maps show good agreement between hemispheres suggesting physiologically relevant information is being extracted. Expected differences between white and gray matter (p < 0.0001) and (p < 0.0001) are observed, and show no significant differences, p = 0.4 and p = 0.6, respectively. Moderate to excellent repeatability was seen between repeat scans: mean intra-class correlation coefficient of , , , and . We demonstrate that regional simultaneous quantification of , , , and using MRF is feasible in vivo.

Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability.

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.

Heatmap Evaluation of Facial Hydration Using a Novel Python Program.

Evaluating cleansers and moisturizers provides important information to guide clinicians in the recommendation of these products. This project was performed to visualize skin hydration via heatmap after the use of a gentle skin cleanser (GSC) and moisturizing lotion (ML). Half-face, intra-individual open-label study in healthy volunteers. Cleanser was administered in a single application that was then wiped off the face. Moisturizing lotion was applied at least once-daily for one week. Hydration measurements were made at 30 pre-defined points on half of the face, at baseline, and 30 minutes post-application; an additional assessment at week 1 was made for the moisturizing lotion. Heatmaps were generated using Python programming software to interpolate hydration values to colors that were then superimposed onto the volunteer's facial image.&nbsp; Results: Five subjects completed the cleanser assessments, and 5 subjects completed the 30-minute evaluation for the lotion, with 4 completing the week 1 assessment. There was a visible shift in skin hydration post-GSC application from values approximately in the 12-42 AU (arbitrary unit) range to 30-60 AU at 30 minutes. Similarly, there was a shift in hydration from baseline to 30 minutes that continued to increase through week 1 of ML use. This innovative heatmap data generation showed a clear, visual change in hydration over time. There was a visible shift in hydration values from baseline to 30 minutes after application of cleanser; hydration also improved after use of moisturizing lotion at 30 minutes and increased after week 1 application.&nbsp; J Drugs Dermatol. 2024;23(6):463-465.&nbsp; &nbsp;&nbsp; doi:10.36849/JDD.8221.

A genetic algorithm-based approach for the prediction of metabolic drug-drug interactions involving CYP2C8 or CYP2B6

Background and objectivesA genetic algorithm (GA) approach was developed to predict drug-drug interactions (DDIs) caused by cytochrome P450 2C8 (CYP2C8) inhibition or cytochrome P450 2B6 (CYP2B6) inhibition or induction. Nighty-eight DDIs, obtained from published in vivo studies in healthy volunteers, have been considered using the area under the plasma drug concentration–time curve (AUC) ratios (i.e., ratios of AUC of the drug substrate administered in combination with a DDI perpetrator to AUC of the drug substrate administered alone) to describe the extent of DDI. MethodsThe following parameters were estimated in this approach: the contribution ratios (CRCYP2B6 and CRCYP2C8, i.e., the fraction of the dose metabolized via CYP2B6 or CYP2C8, respectively) and the inhibitory or inducing potency of the perpetrator drug (IRCYP2B6, IRCYP2C8 and ICCYP2B6, for inhibition of CYP2B6 and CYP2C8, and induction of CYP2B6, respectively). The workflow consisted of three main phases. First, the initial estimates of the parameters were estimated through GA. Then, the model was validated using an external validation. Finally, the parameter values were refined via a Bayesian orthogonal regression using all data. ResultsThe AUC ratios of 5 substrates, 11 inhibitors and 19 inducers of CYP2B6, and the AUC ratios of 19 substrates and 23 inhibitors of CYP2C8 were successfully predicted by the developed methodology within 50–200% of observed values. ConclusionsThe approach proposed in this work may represent a useful tool for evaluating the suitable doses of a CYP2C8 or CYP2B6 substrates co-administered with perpetrators.