Multiple-dose Study Research Articles

Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study

ObjectiveThis phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day),...

A Critical Review of the Pharmacokinetics, Pharmacodynamics, and Safety Data of Antibiotics in Avian Species.

In avian medicine, the use of antibiotic dosing regimens based on species-specific pharmacological studies is ideal. However, due to a lack of such studies, dose extrapolation, which may cause inefficacy and toxicity, is common practice. Multiple searches were performed using the PubMed and Web of Science databases to extract relevant pharmacological studies performed in exotic avian species. The pharmacokinetics (PK), pharmacodynamics (PD), and safety data of the selected antibiotics (enrofloxacin, marbofloxacin, gentamicin, amikacin, ceftiofur, doxycycline, and amoxicillin/clavulanate) from these studies were reviewed. This review aimed to identify trends amenable for safe inter-species dose extrapolation and provide updated findings on dosing regimens that are safe and efficacious for various exotic avian species. We observed that the half-life of antibiotics appears to be shorter in the common ostrich and that amikacin may be amenable to inter-species dose extrapolation as it is safe and shows little inter-species PK and PD variation. Species-specific enrofloxacin dosing regimens that were not listed in the Exotic Animal Formulary (5th ed.) were found for Caribbean flamingos, African penguins, southern crested caracaras, common ostriches, and greater rheas. Specific dosing regimens recommended for psittacine birds (doxycycline 130 mg/kg medicated water) and ratites (PO doxycycline 2–3.5 mg/kg q12 h, PO enrofloxacin 1.5–2.5 mg/kg q12 h and IM enrofloxacin 5 mg/kg q12 h) in the formulary may not be effective in budgerigars and common ostriches, respectively. Apart from the lack of species-specific pharmacological studies, a lack of multiple dose studies was also noted.

0453 Lemborexant Exposure Is Independent of Race

Abstract Introduction Some hypnotic treatments for insomnia require dosing consideration due to exposure differences based on patient characteristics. Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adult insomnia. LEM is not associated with exposure differences based on sex, age, or BMI that impact dosing. The potential impact of race on exposure was determined in two stand-alone pharmacokinetic (PK) studies and by modeling data from studies comprising the LEM clinical development program, which included healthy subjects and insomnia patients. Methods Study 003 (NCT02039089) was a single-center, multiple-dose, randomized, double-blind, placebo-controlled, parallel-group study in healthy Japanese and White subjects. Study 014 (NCT04555733) was a phase 1, single center, open-label, single and multiple oral dose study in healthy Chinese subjects. Additionally, effect of race on LEM exposure was independently examined as part of a population PK analysis incorporating LEM data from 9 Phase 1 studies (n=407), and Studies 201 (NCT01995838; n=235), 303 (NCT02952820; n=726) and 304 (NCT02783729; n=524) (Lalovic et al., 2020). Plasma concentrations of LEM were quantified from plasma by validated liquid chromatography with tandem mass spectrometry. Adverse events (AE) were recorded. Results Exposure of LEM increased in an approximately dose-proportional manner across the dose range (2.5 mg to 25 mg) in studies 003 and 014. There were no significant exposure differences between Japanese and White subjects following single LEM10 administration on Day 1 in Study 003 (maximum concentration [Cmax] mean[SD], ng/mL: Japanese, 46.5[25.8]; White, 47.3[28.1]; area under the curve from time zero to 24h [AUC0-24] mean[SD], ng·h/mL: Japanese, 231[40.2]; White, 208[83.4]) or when comparing PK data from Chinese subjects in Study 014 following single dose administration on Day 1 (Cmax mean[SD], ng/mL: LEM5, 29.8[12.8]; LEM10, 56.2[16.9]; LEM25, 116[46.8]; AUC0-24 mean[SD], ng·h/mL: LEM5, 106[29.9]; LEM10, 205[35.6]; LEM25, 549[116]) to Japanese and White subjects in Study 003. These results are supported by the cross-study, population PK model-based analysis, indicating no significant clinical or statistical differences in LEM PK attributable to the intrinsic factor race. Conclusion LEM exposure is not significantly affected by race. Therefore, dosing of LEM can be consistent across patient populations from different racial groups. Support (If Any) Eisai Inc.

Pharmacokinetics and Tolerability of Intraperitoneal Chloroprocaine After Fetal Extraction in Women Undergoing Cesarean Delivery.

Intraperitoneal chloroprocaine has been used during cesarean delivery to supplement suboptimal neuraxial anesthesia for decades. The short in vitro half-life of chloroprocaine (11-21 seconds) has been cited to support the safety of this approach. However, there are no data regarding the rate of absorption, representing patient drug exposure, through this route of administration. Accordingly, we designed a study to determine the in vivo half-life of intraperitoneal chloroprocaine and assess clinical tolerability. We designed a single-center, prospective, cohort, multiple-dose escalation study of women 18 to 50 years of age undergoing cesarean delivery with spinal anesthesia. Chloroprocaine (40 mL) was administered after delivery of the newborn and before uterine closure. The first cohort (n = 5) received 1%, the second cohort (n = 5) received 2%, and the third cohort (n = 5) received 3% chloroprocaine solution. Maternal blood samples were obtained before administration and 1, 5, 10, 20, and 30 minutes after dosing. The primary objective was to define the pharmacokinetic profile of intraperitoneal chloroprocaine, including in vivo half-life. The secondary objective was to evaluate tolerability through determination of peak plasma concentration and prospective assessment for local anesthetic systemic toxicity. The peak plasma concentration occurred 5 minutes after intraperitoneal administration in all 3 cohorts: 64.8 ng/mL (6.5 µg/kg), 28.7 ng/mL (2.9 µg/kg), and 799.2 ng/mL (79.9 µg/kg) for 1%, 2%, and 3% chloroprocaine, respectively. The in vivo half-life of chloroprocaine after intraperitoneal administration was estimated to be 5.3 minutes (95% confidence interval, 4.0-6.6). We did not detect clinical signs of local anesthetic systemic toxicity in any of the 3 cohorts. The in vivo half-life of intraperitoneal chloroprocaine (5.3 minutes) is more than an order of magnitude greater than the in vitro half-life (11-21 seconds). However, maximum plasma concentrations of chloroprocaine (C max range, 0.05-79.9 µg/kg) were not associated with local anesthetic systemic toxicity and remain well below our predefined safe level of exposure (970 µg/kg) and levels associated with clinical symptoms (2.6-2.9 mg/kg). Therefore, our study suggests that intraperitoneal chloroprocaine, in a dosage ≤1200 mg, administered after fetal extraction, is well tolerated during cesarean delivery.

PREPARATION, CHARACTERIZATION AND SAFETY ASSESSMENT OF COMBINATORIAL NANOPARTICLES OF CARVEDILOL AND SERICIN

Objective: The objective of the study is to prepare and evaluate the safety assessment of novel combinatorial Nanoparticle formulation. Methods: Chitosan nanoparticles were prepared by the ionic gelation method with slight modification. Drug-drug interaction was evaluated by Fourier Transform Infra-Red Spectroscopy. Size, Polydispersity Index, Zeta potential, Transmission Electron Microscopy Characterizations were performed as per standard procedures. Acute and subacute toxicity assessments were done by the standard protocol of OECD guideline number 425 and 407, respectively. Results: Size and zeta-potential were found to be 186.7 nm and-12.0mV, respectively. TEM analysis showed uniform, smooth, and spherical-sized particles. FTIR analysis of carvedilol, sericin, and physical mixture showed no interaction between them. The safety evaluation of prepared nanoparticle which was found to be safe at a dose of up to 1000 mg/kg body weight in single-dose acute toxicity and multiple-dose subacute toxicity study. Biochemical estimations were statistically evaluated and no significant differences were found that the mean P-value is greater than 0.05 and Histopathological examination has shown no marked disparity when compared to the normal control group. Conclusion: It can be concluded that the prepared Nanoparticles are safe in rodents and can be preceded for further evaluation for its preclinical cardioprotective potential.

Pharmacokinetics of the Anti-Inflammatory Drug Meloxicam after Single 1.5 mg/kg Intramuscular Administration to Undulate Skates (Raja undulata).

The therapy database currently used in elasmobranchs is still mostly based on empirical data, and there are few efficacy and safety studies supporting clinical practice. In this study, meloxicam pharmacokinetics (PK) were evaluated after a single 1.5 mg/kg IM administration to a group of seven clinically healthy adult undulate skates (Raja undulata Lacepède, 1802). Blood samples were collected before administration and at 15, 30, 60 and 90 min and 2, 4, 8, 12, 24 and 48 h after the IM injection. The meloxicam concentrations in plasma were determined using high-performance liquid chromatography, and PK parameters were calculated using a non-compartmental model approach. The mean ± SEM values of the main PK values were 1.84 ± 0.31 μg/mL for peak plasma concentration, 1.5 ± 0.24 h for time to maximum plasma concentration, 11.43 ± 2.04 h·µg/mL for area under the plasma concentration vs. time curve, 3.55 ± 0.65 h for elimination half-life, and 5.37 ± 0.94 h for mean residency time. No adverse reactions were detected. The relatively high plasma concentration and short time to maximum plasma concentration suggest that meloxicam could turn into an efficient analgesic and anti-inflammatory candidate drug to be used in skates. Further efficacy, pharmacodynamic, and multiple-dose studies with meloxicam are needed in elasmobranchs.

Dose-dependent glucosuria of DWP16001, a novel selective sodium-glucose cotransporter-2 inhibitor, in healthy subjects.

DWP16001 is a novel sodium-glucose cotransporter-2 inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics, pharmacodynamics and safety of DWP16001 after single and multiple doses in healthy subjects. A randomized, double-blind, placebo- and active-controlled, single- and multiple-dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0 or 5.0mg) or multiple doses (0.1, 0.3, 0.5, 1.0 or 2.0mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10mg or placebo at a ratio of 8:2:2. Serial blood and interval urine samples were collected for the pharmacokinetic and pharmacodynamic analyses. The safety and tolerability of DWP16001 were also assessed. A dose-dependent increase in the urinary glucose excretion was observed after a single dose, and the steady state urinary glucose excretion was 50-60 g/d after multiple doses in the dose range of 0.3-2.0mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0-3.0hours, and it exhibited a mean elimination half-life of 13-29hours. The systemic exposure to DWP16001 increased proportionally with multiple dose administrations in the range of 0.1-2.0mg. DWP16001 was well tolerated in all dose groups. DWP16001 induced glucosuria in a dose-dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated in single oral doses of up to 5.0mg and in multiple oral doses of up to 2.0mg.

Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years

Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6months to 17years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11years who received voxelotor treatment for up to 48weeks are reported. Hemoglobin (Hb) response, defined as a >1.0g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5g/dl increase and a >2.0g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4years.

Postmarketing pharmacovigilance: Remdesivir and cardiovascular events.

Postmarketing pharmacovigilance: Remdesivir and cardiovascular events.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers

ApTOLL is an aptamer that antagonizes Toll-like receptor 4 and improves functional outcomes in models of ischemic stroke and myocardial infarction. The aim of this study was to characterize the safety and pharmacokinetics of ApTOLL in healthy volunteers. A first-in-human dose-ascending, randomized, placebo-controlled phase I clinical trial to assess safety and pharmacokinetics of ApTOLL (30-min infusion intravenously) was performed in 46 healthy adult male volunteers. The study was divided into two parts: part A included seven single ascending dose levels, and part B had one multiple dose cohort. Safety and pharmacokinetic parameters were evaluated. No serious adverse events or biochemistry alterations were detected at any dose nor at any administration pattern studied. Maximum concentration was detected at the end of the infusion and mean half-life was 9.3 h. Interestingly, exposure increased in the first four levels receiving doses from 0.7 mg to 14 mg (AUC of 2,441.26 h∗ng/mL to 23,371.11 h∗ng/mL) but remained stable thereafter (mean of 23,184.61 h∗ng/mL after 70 mg). Consequently, the multiple dose study did not show any accumulation of ApTOLL. These results show an excellent safety and adequate pharmacokinetic profile that, together with the efficacy demonstrated in nonclinical studies, provide the basis to start clinical trials in patients.

Hypericum Perforatum L. Hairy Root Extracts – Regulation of Glycemic, Metabolic, Serum Enzyme and Lipid Profile in STZ - Induced Diabetic Rats

Abstract Apart from currently available therapeutics for the treatment of diabetes mellitus, much attention has been paid to discover phytochemicals from natural resources, mainly due to their low side-effects. Hypericum perforatum hairy root (HR) transformed with Agrobacterium rhizogenes A4 represent prospective experimental system enriched in xanthones, known as potent antidiabetic agents. Thus, the aim of this study was to evaluate HR extracts for their potential antihyperglycemic activity in streptozotocin (STZ)-induced diabetic rats, also compared to the effects of wild-growing Hyperici herba (HH). We conducted an acute-toxicity study, multiple dose study, and 24h blood glucose measurements after a single dose administration of HH and HR (200 mg/kg) in diabetic rats. Furthermore, we examined the effects of 14-days administration of HH and HR extracts on blood glucose levels, metabolic parameters, enzyme, and lipid status in healthy and diabetic rats. Both extracts produced a fall of about 70% in blood glucose level after 24h of administration. Two-week treatment with HH and HR induced a significant decrease (70-72%) in blood glucose levels. Moreover, we found an improvement of the dysregulated metabolic parameters (body weight, food, and water consumption and urine output). Serum enzyme (AST, ALT, and γ-GT) and lipid profile parameters (CHOL, TAG, and HDL) were also improved by both extracts. These findings might provide a new insight for managing diabetic hyperglycemia and dysregulated serum enzyme and lipid profile, using extracts from transgenic roots cultures from H. perforatum.

BIO89-100 Demonstrated Robust Reductions in Liver Fat, Improved Metabolic Parameters, Favorable Tolerability and Potential for Weekly (QW) or Every 2 Weeks (Q2W) Dosing in a Phase 1b/2a Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study in NASH

Background:

Oxygenator impact on peramivir in extra-corporeal membrane oxygenation circuits.

This study aims to determine the oxygenator impact on alterations of peramivir (PRV) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extra-corporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. 1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of PRV was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5-min and 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24-h time points. PRV was also maintained in a glass vial, and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. For the 1/4-in. circuit with an oxygenator, there was < 15% PRV loss, and for the 1/4-in. circuit without an oxygenator, there was < 3% PRV loss during the study period. For the 3/8-in. circuits with an oxygenator, there was < 15% PRV loss, and for the 3/8-in. circuits without an oxygenator, there was < 3% PRV loss during the study period. There was no significant PRV loss over the 24-h study period in either the 1/4-in. or 3/8-in circuit, regardless of the presence of the oxygenator. The concentrations obtained pre- and post-oxygenator appeared to approximate each other, suggesting there may be no drug loss via the oxygenator. This preliminary data suggests PRV dosing may not need to be adjusted for concern of drug loss via the oxygenator. Additional single and multiple dose studies are needed to validate these findings.

AZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosis

BackgroundEpithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibrosis (CF); however, data are limited. We report the outcomes of a Phase I (NCT02679729) and a Phase Ib (NCT02950805) study of AZD5634, a novel inhaled ENaC inhibitor. MethodsA Phase I, first-in-human, single-blind, placebo-controlled, single ascending dose, sequential dose group study assessed the safety, tolerability, and pharmacokinetics of AZD5634 in healthy subjects (n=53) in part A following inhaled doses up to 1700 µg, and, in part B, following administration of single inhaled (1700 µg) and intravenous (65 µg) doses. A Phase Ib, randomized, double-blind, placebo-controlled, single-dose, 2-way cross-over study assessed the effects of a single dose (600 µg) of inhaled AZD5634 on mucociliary clearance (MCC), pharmacokinetics and safety and tolerability in patients with CF (n=11). Nasal potential difference (NPD) was assessed as an in situ target engagement exploratory biomarker. ResultsAbsolute bioavailability of AZD5634 after inhalation was approximately 3%, indicating minimal distribution into the systemic circulation. Urinary excretion was a minor elimination pathway. Administration of inhaled AZD5634 did not improve MCC in CF patients, but AZD5634 inhibited ENaC in the nasal epithelium, as measured by NPD. AZD5634 was safe and well tolerated in both studies. ConclusionsAZD5634 showed favorable pharmacokinetics and safety in healthy subjects and patients with CF. However, despite achieving target engagement, proof of mechanism was not achieved after a single dose in patients with CF. Further evaluation into multiple dose studies is warranted to explore its therapeutic potential.

Assessment of the impact of partial area under the curve in a bioavailability/bioequivalence study on generic prolonged-release formulations

The requirement for multiple-dose bioequivalence studies for the approval of generic prolonged-release (PR) formulations is not agreed upon by the EMA and FDA. While the EMA requests these studies, the FDA has no specific requirement, nor does ANVISA.Additional metrics are suggested for the assessment of prolonged-release products, and the partial Area Under the Curve (pAUC) metric has received increasing regulatory recognition.The objective of this work was to investigate whether the evaluation of the partial AUC in studies assessed by ANVISA can detect differences between 2 prolonged-release formulations that have demonstrated bioequivalence by the usual metrics.Twenty-four studies in a total of 117, which were already approved by ANVISA considering the usual metrics in the last 14 years, failed to demonstrate bioequivalence for partial AUC, which is related to 33.9% of evaluated PR products.For 76.92% of the studies, there was no significant increase in the intrasubject variability observed in the partial AUC analysis compared to the usual metrics, with a CV < 30% for both cases, calculated individually for each study, indicating that there is no need to increase the sample size to perform such analysis.The results of this paper demonstrate that the current criteria for assessing the bioequivalence of some prolonged-release formulations are insufficient and that the evaluation of partial AUC could be useful to assure the therapeutic parity of two products.

Pharmacodynamic assessment of gliclazide multiparticulate system: single-dose and multiple-dose studies

Background Conventional dosage forms of oral hypoglycemic drugs, including gliclazide (GLZ), may have a number of limitations, reducing their bioavailability. Thus, efforts are directed to design novel modified-release (MR) dosage forms for these drugs. The possible role of orally administered GLZ-MR multiparticulates in the treatment of hyperglycemia as well as improvement of impaired wound healing associated with type 2 diabetes mellitus was investigated.Objective This study aimed to evaluate the pharmacodynamics (PD) of GLZ-MR multiparticulate system against Diamicron MR tablets in nondiabetic (healthy) and streptozotocin-induced diabetic rats, by measuring blood glucose levels. For the first time, the hypothetical wound-healing capabilities of multiple doses of both treatments in diabetic rats were also studied by evaluating the wound diameter and histology.Materials and methods Novel cross-linked freeze-dried GLZ-alginate-gelatin beads were prepared. Two GLZ treatments at 4 mg/kg [test (T, MR beads) and reference (R, Diamicron MR 30 mg)] were administered to rats. A single-dose PD study was carried out on both healthy and diabetic rats, whereas the multiple-dose study was evaluated in diabetic rats. A single-dose pharmacokinetics (PK) study was conducted for assessment of the PK-PD relationship in healthy rats.Results and conclusion The single-dose study on nondiabetic rats showed that T beads exhibited a greater magnitude of blood glucose level reduction, with 1.5-fold increase in Cmax, compared with R. A direct linear relationship with high correlation was detected between GLZ glucose-lowering effect and its PK parameters, only for T beads. Multiple dosing of T beads was more efficient than R in managing hyperglycemia of wounded diabetic rats. T beads allowed almost complete wound closure, after multiple dosing for 17 days. The proposed GLZ beads could provide a promising therapeutic prospect for managing hyperglycemia as well as resolving impairment of wound healing associated with diabetes.

Population Pharmacokinetics of Intraperitoneal Gentamicin and the Impact of Varying Dwell Times on Pharmacodynamic Target Attainment in Patients with Acute Peritonitis Undergoing Peritoneal Dialysis.

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data were obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio > 10) and toxicity (plasma area under the concentration-time curve [AUC] < 120 mg·h/L) was determined for 0.3- to 1.2-mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 h and for the duration of a 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility breakpoint of 4 mg/L, only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. The probability of achieving exposure below the threshold of 120 mg·h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2-mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical breakpoint of 4 mg/L is likely to produce early toxic levels of exposure that are expected to be detrimental to the renal system.

628. Pharmacokinetics, Safety and Tolerability of Co-administration of Nacubactam and β-lactams after Multiple Doses in Japanese Healthy Subjects

BackgroundIncrease of carbapenem-resistant Enterobacterales (CRE) is a serious problem in the clinical setting and drugs which can treat patients with CRE are still limited. Nacubactam (OP0595) is a novel diazabicyclooctane-type β-lactamase inhibitor and being developed as a standalone drug to be co-administered with cefepime or aztreonam.MethodsA randomized, double-blind multiple dose study of nacubactam in co-administration with cefepime (Cohort 1) or aztreonam (Cohort 2) in Japanese healthy subjects was performed to assess pharmacokinetics, safety, and tolerability of co-administrations of nacubactam and cefepime or aztreonam. In each cohort, 6 subjects received 2 g of nacubactam and 2 g of concomitant drug (cefepime or aztreonam) and 2 subjects received placebo (saline) intravenously over 60 minutes, three times daily every 8 hours for 7 days. Plasma samples were collected and concentrations of each drug were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and the evaluation of changes from baseline in safety laboratory test results, 12-lead electrocardiograms (ECGs), vital signs, and physical examinations.ResultsProfiles of Cmax, tmax, AUC0-8, AUC0-∞ and t1/2 for nacubactam, cefepime and aztreonam are summarized in Table 1. Summary of Ctrough for nacubactam, cefepime and aztreonam are summarized in Table 2. Plasma concentrations of nacubactam, cefepime and aztreonam reached the steady-state by Day 4, and the mean accumulation ratios of Cmax and AUC0-8 on Day 7 to those of Day 1 were in the range of 0.91 to 1.10. As for the safety, no serious adverse event was observed in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the discontinuation in 1 subject in nacubactam/cefepime group, but it was judged as “Not related to study drug”.Table 1. PK profiles of nacubactam and concomitant drugs on Day 1 and Day 7 Table 2. Summary of Ctrough of nacubactam and concomitant drugs ConclusionIn conclusion, no remarkable change in pharmacokinetics was observed in each drug with multiple concomitant administration for 7 days and safety and tolerability of co-administrations of nacubactam and cefepime or aztreonam were confirmed. Based on these results, nacubactam is currently under further development.Disclosures All Authors: No reported disclosures

Brain target occupancy of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme, following administration of single and multiple doses to healthy volunteers

AbstractBackgroundLY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report on single dose (SD) and multiple dose (MD) clinical studies testing the effect of LY3372689 on brain OGA enzyme occupancy (EO).MethodA positron emission tomography (PET) radioligand, 18F‐LY3316612, was used to assess brain OGA EO in healthy volunteers (HV). In the SD study [NCT03944031], 0.25, 1 and 5 mg LY3372689 were evaluated across 4 cohorts (N = 4 HV per cohort). Each HV had PET scans at baseline and two post‐dose intervals. Post‐dose scans occurred at 2 and 24 hours at 0.25, 1, and 5 mg, with additional scans for 1 mg at 30 and 54 hours. The MD study [NCT04392271] consisted of 1 cohort (N = 4 HV) given 1 mg LY3372689 once daily for 14 days. Each HV had a baseline PET scan, and PET scans at 24 hours post‐dose after the 1st and 14th administration of LY3372689. Plasma pharmacokinetics was assessed in these studies.ResultIn the SD study, the mean brain OGA EO at 5 mg was 98% at 2 hours and 93% at 24 hours. At 1 mg, the mean EO was 97% at 2 hours, 81% at 24 hours, 68% at 30 hours, and 30% at 54 hours. The EO at 0.25 mg was lower at 2 hours (26%) compared to 24 hours (46%). The Emax and EC50 values were estimated to be 97% and 0.1 ng/mL, respectively. In the MD study, the OGA EO at 24 hours after the 1st and 14th administration of 1 mg LY3372689 was 84%.ConclusionPET studies in healthy volunteers demonstrated that LY3372689 can achieve high brain target occupancy of the OGA enzyme. Brain OGA EO was maintained after multiple dosing, supporting the durability of target engagement for longer clinical trials. The human PET data will be used to support LY3372869 dose selection for efficacy trials in tauopathies.