Multiple-dose Group Research Articles

Comparative Efficacy of Single-Dose versus Multiple-Dose Antibiotic Prophylaxis in Reducing Postoperative Infections in Elective Cesarean Deliveries

Cesarean Sections (CS) were common surgeries that may lead to complications like endometritis and Surgical Site Infections (SSIs). While prophylactic antibiotics reduce these risks, the ideal dosing regimen remains debated. Objective: To evaluates whether a single or multiple-dose antibiotic regimen offers better protection against infections in patients undergoing planned cesarean sections. Methods: A six-month quasi-experimental study was conducted from October 1, 2020, to March 30, 2021, at Lady Reading Hospital in Peshawar. Eighty-two women scheduled for elective CS were assigned into two groups: one received a single 1g dose of intravenous cefazolin before surgery, and the other received the same initial dose followed by two additional doses every eight hours. Primary outcomes assessed were the incidence of endometritis and SSIs within 30 days post-surgery. Results: Postpartum infections were significantly lower in the multiple-dose group (4.9%) compared to the single-dose group (19.5%, p = 0.039). The multiple-dose group also had fewer SSIs (4.9% vs. 14.6%, p = 0.140) and no cases of endometritis (0% vs. 4.9%, p = 0.154), though these differences were not statistically significant. There were no significant differences in adverse drug reactions, hospital stay duration, or antibiotic resistance development between the groups. Conclusions: Multiple-dose antibiotic regimens may reduce infection rates in planned CS without increasing adverse effects or antibiotic resistance. Further studies were needed to confirm these findings and optimize prophylactic strategies.

Pharmacokinetics and pharmacodynamics of intravenous delafloxacin in healthy subjects: model-based dose optimization.

Delafloxacin, a fluoroquinolone antibiotic to treat skin infections, exhibits a broad-spectrum antimicrobial activity. The first randomized, open-label phase I clinical trial was conducted to assess the safety and pharmacokinetics (PK) of intravenous delafloxacin in the Chinese population. A population pharmacokinetic (PopPK) model based on the clinical trial was conducted by NONMEM software. Monte Carlo simulation was performed to evaluate the antibacterial effects of delafloxacin at different doses in different Chinese populations. The PK characteristics of delafloxacin were best described by a three-compartment model with mixed linear and nonlinear clearance. Body weight was included as a covariate in the model. We simulated the AUC0-24h in a steady state at five doses in patient groups of various weights. The results indicated that for patients weighing 70 kg and treated with methicillin-resistant Staphylococcus aureus (MRSA) infections, a minimum dose of 300 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, suggesting an ideal bactericidal effect. For patients weighing less than 60 kg, a dose of 200 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, also suggesting an ideal bactericidal effect. Additionally, this trial demonstrated the high safety of delafloxacin in single-dose and multiple-dose groups of Chinese. Delafloxacin (300 mg, q12h, iv) was recommended for achieving optimal efficacy in Chinese bacterial skin infections patients. To ensure optimal efficacy, an individualized dose of 200 mg (q12h, iv) could be advised for patients weighing less than 60 kg, and 300 mg (q12h, iv) for those weighing more than 60 kg.

Predictive factors of early autologous blood pleurodesis for postoperative air leak.

The usefulness of autologous blood pleurodesis for air leak after pulmonary resection is well known; however, factors predicting the therapeutic efficacy are poorly understood. Herein, we aimed to examine the predictors of early autologous blood pleurodesis for air leak following pulmonary resection. Patients who underwent pulmonary resection and autologous blood pleurodesis with thrombin for postoperative air leak between January 2016 and October 2022 were retrospectively analyzed. Patients received 50-100 mL of autologous blood and 20,000 units of thrombin on postoperative days 1-4. If necessary, the same procedure or pleurodesis with other chemical agents was repeated until the air leak stopped. Patients were divided into single-dose and multiple-dose groups based on the number of times pleurodesis had occurred before the air leak stopped and were statistically analyzed. Logistic regression analysis was performed to identify predictors of treatment efficacy. Of the 922 patients who underwent pulmonary resection, 57 patients (6.2%) were included and divided into single-dose (n = 38) and multiple-dose (n = 19) groups. The amount of air leaks was identified as a significant predictor of multiple dosing, with a cutoff of 60 mL/min, in multivariate logistic regression analyses (odds ratio 1.13, 95% CI 1.03-1.24, p = 0.0065). The multiple-dose group showed a significantly higher recurrence of air leak (p = 0.0417). The amount of air leaks after pulmonary resection is the only significant factor predicting whether multiple autologous blood pleurodesis is required, and the recurrence rate of pneumothorax is significantly higher in such cases.

Pharmacokinetic/pharmacodynamic relationships of enrofloxacin against Klebsiella pneumoniae in an in vivo infection model in young chicks

Klebsiella pneumoniae is a serious pathogenic bacterium that poses a significant threat to young poultry and the cause of significant chick mortality and economic loss. We investigated the therapeutic efficacy of enrofloxacin in treating K. pneumoniae infections in chicks and employed an in vivo pharmacokinetic/pharmacodynamic (PK/PD) model. In vivo efficacy was evaluated using six multiple-dose groups (oral administration once a day for three days) and two single-dose groups (oral administration once only). The PK and PD parameters of plasma and lung were analyzed using PK/PD fitting analysis. K. pneumoniae administered intratracheally (108 CFU/mL in 0.4 mL saline) was used to establish a model for pulmonary infection. The plasma protein binding of enrofloxacin was 20.18%. Enrofloxacin displayed T1/2β values of 4.78 ± 0.69 h and 4.78 ± 1.02 h in plasma and lung of infected chicks, respectively. When the dosage in the multiple-dose group was ≥ 20 mg/kg, bactericidal activity was found and complete eradication was not achieved when the dosage was ≤ 40 mg/kg. When TMSW was set at 20%, the calculated dosage and bacterial reduction (E) based on plasma free drug data were 4.03 mg/kg and -1.982 Log10 CFU/mL, respectively. In the calculation of PK/PD parameters for reducing 3 log10 CFU/mL and using Cmax/MIC, AUC72h/MIC and TMSW of free drug in plasma values at 9.479, 379.691 and 44.395%, respectively, the value of AUC72h/MIC based on the concentration of drug in lung was 530.800. According to the fitting correlation R2, the PK/PD fitting results of free drug in plasma were better. The corresponding enrofloxacin dosage for AUC72h/MIC of the plasma free drug concentration was 14.16 mg/kg. The administration regimen corresponding to these dosages was once daily for 3 days. This dosage regimen (14.16 mg/kg) was relatively high compared to the clinically recommended dosage in China (7.5 mg/kg) when treating infections caused by K. pneumoniae with MIC ≥ 0.125 μg/mL, so careful consideration is needed.

The first selective VAP-1 inhibitor in China, TT-01025-CL: safety, tolerability, pharmacokinetics, and pharmacodynamics of single- and multiple-ascending doses.

Introduction: TT-01025-CL is an oral, irreversible small molecule that potently inhibits vascular adhesion protein-1 (VAP-1) for the treatment of inflammation associated with non-alcoholic steatohepatitis (NASH). The objectives of this study were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of TT-01025-CL, a VAP-1 inhibitor, in healthy Chinese volunteers. Methods: Double-blind, placebo-controlled, dose-escalation studies were conducted in subjects randomized to receive oral once-daily TT-01025-CL (ranges: 10-300mg [single dose]; 20-100mg for 7days [multiple doses]) or placebo under fasting conditions. Safety and tolerability were monitored throughout the study. Pharmacokinetic (PK) parameters were determined using non-compartment analysis. The activity of semicarbazide-sensitive amine oxidase (SSAO)-specific amine oxidase and the accumulation of methylamine in plasma were evaluated as pharmacodynamic (PD) biomarkers. Results: A total of 36 (single-dose group) and 24 (multiple-dose group) subjects were enrolled in the study. No serious adverse events (AEs) were reported, and no subject discontinued due to an AE. All treatment-emergent adverse events (TEAEs) were mild and moderate in intensity. No dose-dependent increase in the intensity or frequency of events was observed. TT-01025-CL was rapidly absorbed after administration. In the single-ascending dose (SAD) study, median Tmax ranged from 0.5 to 2h and mean t1/2z ranged from 2.09 to 4.39h. PK was linear in the range of 100-300mg. The mean Emax of methylamine ranged from 19.167 to 124.970ng/mL, with mean TEmax ranging from 13.5 to 28.0h. The complete inhibition (>90%) of SSAO activity was observed at 0.25-0.5h post-dose and was maintained 48-168h post-dose. In the multiple-ascending dose (MAD) study, a steady state was reached by day 5 in the 40mg and 100mg dose groups. Negligible accumulation was observed after repeated dosing. PK was linear in the range of 20-100mg. Plasma methylamine appeared to plateau at doses of 20mg and above, with mean Emax ranging from 124.142 to 156.070ng/mL and mean TEmax ranging from 14.2 to 22.0h on day 7. SSAO activity in plasma was persistently inhibited throughout the treatment period. No evident change in methylamine and SSAO activity was observed in the placebo groups. Conclusion: TT-01025-CL was safe and well-tolerated at a single dose of up to 300mg and multiple doses of up to 100mg once daily for 7 consecutive days. Absorption and elimination occurred rapidly in healthy volunteers. Linearity in plasma exposure was observed. TT-01025-CL inhibited SSAO activity rapidly and persistently in humans. The profile of TT-01025-CL demonstrates its suitability for further clinical development.

Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a)

Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities. To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a). Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023. Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval. The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations. Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, -30% (IQR, -51% to -18%) for the 300 mg of zerlasiran group, and -29% (IQR, -39% to -7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, -17 to 28) nmol/L for the placebo group, -258 (IQR, -289 to -188) nmol/L for the 200 mg of zerlasiran group, -310 (IQR, -368 to -274) nmol/L for the 300-mg dose group, and -242 (IQR, -343 to -182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, -4% to 21%), -97% (IQR, -98% to -95%), -98% (IQR, -99% to -97%), and -99% (IQR, -99% to -98%), respectively, attenuating to 0.3% (IQR, -2% to 21%), -60% (IQR, -71% to -40%), -90% (IQR, -91% to -74%), and -89% (IQR, -91% to -76%) 201 days after administration. Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration. ClinicalTrials.gov Identifier: NCT04606602.

First-in-human study on pharmacokinetics, safety, and tolerability of single and multiple escalating doses of PA9159 nasal spray, a highly potent glucocorticoid in healthy Chinese volunteers

ObjectivePA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated. MethodsThis was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10–80 μg and 20–40 μg, respectively. PA9159 was administered bilaterally via nasal spray once only or once daily for seven days. Pharmacokinetic, safety, and tolerability profiles were evaluated. ResultsA total of 60 participants completed the study. PA9159 doses of up to 80 μg in the SAD and up to 40 μg in the MAD were shown to be safe and tolerable. The most common treatment-related AEs were mild and transient local nasal AEs. Morning serum cortisol levels approximately remained unchanged in both the single-dose and multiple-dose groups. PA9159 was quantified in 41.8 % (368/880) of the samples in all treatment groups, including 25.2 % (105/416) of the SAD and 56.7 % (263/464) of the MAD. The majority (>80.0 %) of PA9159 plasma concentrations ranged from 0.5 to 2 pg/mL in determined samples. The mean AUC0-t of PA9159 in the SAD was 0.91, 1.39±0.68, 11.40±9.91, and 46.30±25.80 h*pg/mL in the 10 to 80 ug single group. The mean terminal half-life time (t1/2) was 8.43 h and 8.97±2.28 h in 40 ug and 80 ug single group, respectively. The mean AUCss of PA9159 in the MAD was 31.70±7.04, 44.20±20.60 h*pg /mL, and the t1/2 was 16.00±4.18 h, 21.20±10.20 h in the 20 ug and 40 ug multiple groups, respectively. The median Tmax was approximately 6 h in both the SAD and MAD cohorts. ConclusionsThe PA9159 nasal spray was generally safe and well tolerated, and the effects of PA9159 on serum cortisol levels were limited. The plasma concentration and systemic exposure to PA9159 were very low. These findings support the necessity for further clinical studies on PA9159 nasal spray in patients suffering from allergic rhinitis.

Nonlinear Pharmacokinetics of Topical Flurbiprofen Gel in a Phase I Study Among Chinese Healthy Adults.

PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.

Tissue distribution and pharmacokinetics of isoxanthohumol from hops in rodents.

Vegetables and fruits contain prenylflavonoids with biological functions that might improve human health. The prenylflavonoid isoxanthohumol (IXA) and its derivative, 8-prenylnaringenin (8-PN), have beneficial activities, including anti-cancer effects and suppression of insulin resistance. However, their pharmacokinetic profile is unclear. Previous studies suggested flavonoids have low systemic availability and are excreted via the feces. Therefore, this study investigated the tissue distribution dynamics of high-purity IXA (>90%) from hops administered orally, either singly (50 mg/kg body weight [BW]) or daily for 14 days (30 mg/kg BW), to mice. High-pressure liquid chromatography demonstrated that IXA was absorbed rapidly after a single administration and reached plasma maximum concentration (C max) (3.95 ± 0.81 μmol/L) by 0.5 h. IXA was present at high levels in the liver compared with the kidney, pancreas, lung, skeletal muscle, spleen, thymus, and heart. The highest IXA level after 14 days of IXA ingestion was observed in the liver, followed by the kidney, thymus, spleen, lung, and brain. There was no significant difference in IXA accumulation in tissues between the single and multiple dose groups. Analyses of the livers of rats treated with different concentrations of IXA (112.5-1500 mg/kg BW) once a day for 28 days demonstrated that IXA accumulated dose-dependently with a correlation coefficient of .813. The accumulation of 8-PN was dependent on the intake period but not the intake amount of IXA (correlation coefficient -.255). In summary, IXA and 8-PN were detected in tissues and organs up to 24 h after ingestion, suggesting that orally ingested IXA might have health benefits as a nutraceutical.

To study the planned surgical procedure in single-dose antibiotic prophylaxis

Background: Postoperative wound infection may be due to many causes, of which “microbial contamination” is the factor that is influenced by antibiotic administration. Since the concept of antimicrobial prophylaxis has emerged, several workers have searched for optimal antimicrobial drugs, their routes, and the timing of their administration, with the ultimate goal of achieving zero sepsis. The use of preoperative systemic antibiotics has brought down the incidence of wound infection considerably. Aims and Objectives: The aim is to identify which drug is the best option for single-dose antibiotic prophylaxis to prevent postoperative wound infection. Materials and Methods: This is a prospective study. The study was conducted in the surgical ward of J.A. Group of Hospitals, Gwalior, Madhya Pradesh, India, from May 2020 to April 2022. Patients of all sexes and ages were included in the study. Patients were divided into five groups according to a class of antibiotics. The study consisted of a total of 125 patients admitted to the surgical ward. Statistical Package for the Social Sciences–(10 systems) was applied for the study. P<0.05 was considered statistically significant. Results: A total of 125 patients were studied in five groups, depending on the antibiotics. The A, B, C, and D groups were given only a single dose of antibiotics, while group E was given a full course of antibiotics during preoperative, intraoperative, and postoperative periods. Out of 125 cases, only 5 patients had clinical and bacteriological evidence of wound sepsis in different groups of single-dose antibiotics, and one case in group E had multiple doses of antibiotic given. The wound infection rate in clean patients was 20% in ceftazidine, 12.5% with piperacillin tazobactum and cefoperazone sulbactum, and 21.1% in the multiple dose group. No infection was reported with amoxycillin-clavulanic acid. Staphylococcus, Escherichia Coli, and Klebsiella were the offending agents, and anaerobic infections were not found. Conclusion: A single dose of antibiotic prevents the suppression of normal, sensitive microbial flora, which is usually seen with multiple doses of antibiotics. In this way, it helps in keeping the patients infection-free without interfering with their naturally inherited immunological status of the patient.

Letrozole plus misoprostol versus misoprostol alone in the induction of anembryonic missed abortion: a randomized controlled trial conducted in Upper Egypt

BackgroundA missed abortion is a spontaneous abortion in which the embryo or fetus has already died but has remained in the uterus for days or weeks with a closed cervical ostium. Termination of pregnancy could be achieved either by surgical evacuation or medical or expectant management. Letrozole is a third-generation aromatase inhibitor. According to many recent studies, letrozole given for three days before the administration of misoprostol was more effective than misoprostol alone at inducing abortion. Our study compared the efficacy of various letrozole regimens (10 mg/d for three days and a single dose of 20 mg) combined with misoprostol vs. misoprostol alone in inducing abortion. To find the most efficient regimen of letrozole administered before misoprostol to induce an abortion.MethodologyThis prospective, parallel, three-arm, single-blinded, allocation-concealed randomized controlled trial was conducted in Sohag Teaching Hospital in Upper Egypt. We randomly divided 105 patients with anembryonic missed abortion (up to 63 days gestation) with no history of medical disorders or a history of allergies to misoprostol or letrozole into three equal groups (a single-dose letrozole group, a multiple-dose letrozole group, and a misoprostol-only group). The complete abortion rate, incomplete abortion rate, failure to abort rate, and induction-to-abortion interval were all collected. All statistical calculations were performed using the computer program SPSS (Statistical Package for the Social Science, SPSS Inc., Chicago, IL, USA).ResultsThe complete abortion rate was significantly higher in the single-dose letrozole and multiple-dose letrozole groups than in the misoprostol group (p values = 0.0455 and 0.001, respectively). On the other hand, there was no significant difference in the complete abortion rate between the single-dose group and the multiple-dose letrozole group (p-value = 0.1713). The time to complete abortion was significantly shorter in the single-dose and multiple-dose letrozole groups than in the misoprostol group (p values = 0.0036 and 0.0049, respectively). On the other hand, there was no significant difference in the time to complete abortion between the single-dose letrozole group and the multiple-dose letrozole group (P = 0.532).ConclusionSingle- and multiple-dose letrozole regimens followed by misoprostol had a higher rate and a shorter time to complete abortion than misoprostol alone.Trial registrationThe trial is registered at gov with the name “letrozole and abortion” and the identifier “NCT05198050”. The date of registration was April 1, 2022, registered prospectively. URL: https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0004GED&ts=25&sid=S000BPDQ&cx=43mobl.

A phase 1 study of dimdazenil to evaluate the pharmacokinetics, food effect and safety in Chinese healthy subjects.

Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects. Methods: In this phase 1 trial, 36 healthy subjects aged ≥18years were assigned to receive a single dose of 1.5, 2.5, or 5mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5mg daily dose of dimdazenil for 5days. Safety, tolerability, and pharmacokinetic characteristics were evaluated. Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5-5mg oral doses in humans. The median Tmax for dimdazenil was in the range of 0.5-1.5h, and the apparent terminal t1/2z ranged from 3.50 to 4.32h. Taking Dimdazenil with food may delay Tmax and decrease Cmax, without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46-1927 were observed in multiple-dose group. Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia. Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR20201978.

Pharmacokinetics of YK-1169 in healthy subjects and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation.

This study (NCT05588531) aimed to evaluate the safety and pharmacokinetics of cefepime-avibactam (YK-1169) in healthy Chinese subjects and explore the optimal regimen for treating carbapenem-resistant Klebsiella pneumoniae (CRKP) based on the pharmacokinetic/pharmacodynamic evaluation. YK-1169 single-ascending doses (0.5, 1.25, 2.5 or 3.75 g, 2-h infusion) and multiple doses (2.5 or 3.75 g every 8 h [q8h], 2-h infusion) given for 7 days were evaluated in pharmacokinetic studies. Subjects were randomized to receive cefepime (2 g), avibactam (0.5 g) or YK-1169 (2.5 g) to assess drug-drug interactions. The minimum inhibitory concentrations (MICs) of YK-1169 were determined by the broth microdilution method. Monte Carlo simulation was used to evaluate 10 different dose regimens. Cefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime Cmax,ss and AUC0-∞,ss were 9.20 and 16.0 μg/mL, 407.2 and 659.45 μg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. The avibactam Cmax,ss and AUC0-∞,ss were 0.545 and 0.837 μg/mL, 53.31 and 79.55 μg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. Cefepime and avibactam did not affect each other's pharmacokinetics. No serious adverse events occurred. All regimens achieved 90% probability of target attainment (PTA) goals when the MIC was ≤8 mg/L. The regimens of 2.5 (q8h, 2-h infusion), 3.75 (q8h, 2-, 3- and 4-h infusions) and 7.5 g (24-h continuous infusion) reached a 90% cumulative fraction of response. YK-1169 had good antibacterial activity against CRKP and could be an option for CRKP infections. The regimen of 2.5 g q8h intravenously guttae (ivgtt)2 h should be considered in future clinical trials.

Safety, pharmacokinetics and exploratory exposure-response analysis of CX3002, a novel inhibitor of Xa, in Chinese healthy subjects

Background and objectiveCX3002 is a structurally novel inhibitor of factor Xa, with promising prospects. This study aims to report the results of a first-in-human ascending-dose study of CX3002 in Chinese healthy subjects, and to establish an exploratory population pharmacokinetic/pharmacodynamic (PK/PD) model to investigate the exposure-response relationship of CX3002. MethodsThe randomized, double-blind, placebo-controlled study included six single-dose groups and three multiple-dose groups, with a dose range of 1–30 mg. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of CX3002 were evaluated. PK of CX3002 was analyzed using both non-compartment method and population modeling. PK/PD model was developed using nonlinear mixed effect modeling approach and was evaluated by prediction-corrected visual predictive check and bootstrap methods. ResultsA total of 84 subjects were enrolled and all participants completed the study. CX3002 exhibited satisfactory safety and tolerability in healthy subjects. Cmax and AUC of CX3002 increased with dose from 1 to 30 mg, but less-than-proportional increases were observed. There was no obvious accumulation with multiple doses. Anti-Xa activity showed dose-related increases after administration of CX3002 but not placebo. The PK of CX3002 was well described by a two-compartment model with a modification of bioavailability according to dose, and anti-Xa activity was described by a Hill function. No covariate was identified significant based on the limited data in this study. ConclusionsCX3002 was well tolerated and resulted in dose-related anti-Xa activity across the dose range. The PK of CX3002 were predictable, and correlated with PD effects. Continued clinical investigation of CX3002 was supported. Chinadrugtrials.org.cn identifier: CTR20190153.

Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of Mirogabalin in Healthy Chinese Participants: A Randomized, Double-Blind, Placebo-Controlled Study.

Mirogabalin is a treatment option for patients with neuropathic pain; however, safety, tolerability, and pharmacokinetics (PK) data specifically for Chinese individuals are limited to a single-dose study. We aimed to assess these for both single- and multiple-dose mirogabalin in healthy Chinese participants. In this randomized, double-blind, placebo-controlled, phase I study, 54 healthy Chinese men and women aged 18-45years were randomly allocated to receive single- (5, 10, or 15mg, daily) or multiple-dose (5mg titrated to 15mg, twice-daily, over 22days) oral mirogabalin or placebo. In each of three single-dose groups, 10 participants received mirogabalin and 2 received placebo; in the multiple-dose group, 14 participants received mirogabalin and 4 received placebo. The primary endpoints were PK, safety, and tolerability variables, including treatment-emergent adverse events (TEAEs), laboratory tests, and vital signs. PK data were collected for both single- and multiple-dose cohorts and evaluated by non-compartmental analysis. Single- and multiple-dose mirogabalin was generally well tolerated with no deaths, serious TEAEs, or TEAEs leading to treatment discontinuation. Frequently reported TEAEs included dizziness, nystagmus, increased blood triglycerides, headache, and increased blood uric acid and creatine phosphokinase. Single-dose mirogabalin was rapidly absorbed (median time to maximum plasma concentration, 1.00h) and eliminated (mean terminal elimination half-life, 2.57-3.08h). The exposure was approximately dose-proportional. In the multiple-dose cohort, the trough plasma concentration increased dose-proportionally, and exposure and clearance were comparable to that following a single 15-mg dose. The mean cumulative amount excreted into urine up to 48h post-dose increased in a dose-proportional manner, the mean cumulative percentage excreted into urine was 61.9%-74.3%, and renal clearance remained relatively constant. Consistent with previous phase I studies in other populations, mirogabalin was safe and well tolerated in healthy Chinese participants at single and multiple doses of up to 15mg twice-daily.

Prenatal Lipopolysaccharide Exposure Alters Hepatic Drug-Metabolizing Enzyme Expression in Mouse Offspring via Histone Modifications

Inflammation is a major regulator of drug-metabolizing enzymes (DMEs), therefore contributing to the interindividual variability of drug effects. However, whether prenatal inflammation affects DMEs expression in offspring remains obscure. This study investigated the effects of prenatal lipopolysaccharide (LPS) exposure on hepatic expression of inflammatory-related genes, nuclear receptors, and DMEs in offspring mice. Prenatal LPS exposure on gestational day (GD) 10 led to higher expression of NF-κB, Pxr, and Cyp2b10, while lower expression of Car, Ahr, Cyp3a11, and Ugt1a1 in postnatal day (PD) 30 offspring. However, multiple doses of LPS exposure on GD10-14 resulted in higher levels of inflammatory-related genes, Cyp1a2, and Cyp2b10, and lower levels of Pxr and Cyp3a11 in PD30 offspring liver. For PD60 offspring, decreased hepatic expression of NF-κB and IL-6, and increased expression of Pxr and Cyp3a11 were seen in single-dose LPS groups, whereas opposite results were observed in the multiple-dose LPS groups. Notably, enhanced H3K4me3 levels in the PXR response elements of the Cyp3a11 promoter were observed in the liver of PD60 offspring mice from dams treated with multiple doses of LPS during pregnancy. Overall, this study suggests that parental LPS exposure could persistently alter the hepatic expression of DMEs, and histone modifications may contribute to the long-term effects.

Compound Shuganjieyu Capsule on CYP450 Enzyme Activity.

Objective To evaluate the potential drug-drug interactions of the Shuganjieyu capsule by establishing a Chronic Unpredictable Mild Stress (CUMS) depression model combined with the Cocktail probe substrate method. Methods The whole study was divided into the single-dose and multiple-dose groups. Animals were randomly divided into further subgroups in each group. Following chronic unpredictable mild stress model development, Shuganjieyu capsules were administered to the drug administration group. The single-dose subgroup received the drug for one day, and the multiple-dose subgroup received the drug for three months. Liver microsomes of each group were extracted, and the effects of the Shuganjieyu capsule on the CYP450 enzyme were investigated by liquid chromatography-mass spectrometry (LC-MS) (LC-MS) based on the Cocktail probe substrate method. The immunohistochemical method and RT-qPCR were used to detect the activity of CYP450 immunoprotein in rat liver. Results In the single-dose subgroup, there were no statistical differences between the administration and model groups. In the multiple-dose subgroup, the conversion and protein expression rates of CYP1A2 and CYP2C19 were significantly increased in the model group compared with the blank group. In the administration group, the conversion and protein expression rates of CYP1A2 and CYP2C19 were inhibited. Conclusion Long-term administration of the Shuganjieyu capsule could relieve depression-related behaviors in CUMS rats and downregulate the CYP1A2 and CYP2C19 enzyme activities in CUMS rats by inhibiting the expression of CYP1A2 and CYP2C19 protein. Long-term administration of the Shuganjieyu capsule may affect the bioavailability of other drugs metabolized by CYP1A2 and CYP2C19 enzymes, but the clinical guidance's specific significance needs to be clarified further.

Effectiveness of Single vs Multiple Doses of Prophylactic Intravenous Antibiotics in Implant-Based Breast Reconstruction

Multiple-dose antibiotic prophylaxis is widely used to prevent infection after implant-based breast reconstruction despite the lack of high-level evidence regarding its clinical benefit. To determine whether multiple-dose antibiotic prophylaxis is superior to single-dose antibiotic prophylaxis in preventing surgical site infection (SSI) after implant-based breast reconstruction. This prospective, multicenter, randomized clinical superiority trial was conducted at 7 hospitals (8 departments) in Sweden from April 25, 2013, to October 31, 2018. Eligible participants were women aged 18 years or older who were planned to undergo immediate or delayed implant-based breast reconstruction. Follow-up time was 12 months. Data analysis was performed from May to October 2021. Multiple-dose intravenous antibiotic prophylaxis extending over 24 hours following surgery, compared with single-dose intravenous antibiotic. The first-choice drug was cloxacillin (2 g per dose). Clindamycin was used (600 mg per dose) for patients with penicillin allergy. The primary outcome was SSI leading to surgical removal of the implant within 6 months after surgery. Secondary outcomes were the rate of SSIs necessitating readmission and administration of intravenous antibiotics, and clinically suspected SSIs not necessitating readmission but oral antibiotics. A total of 711 women were assessed for eligibility, and 698 were randomized (345 to single-dose and 353 to multiple-dose antibiotics). The median (range) age was 47 (19-78) years for those in the multiple-dose group and 46 (25-76) years for those in the single-dose group. The median (range) body mass index was 23 (18-38) for the single-dose group and 23 (17-37) for the multiple-dose group. Within 6 months of follow-up, 30 patients (4.3%) had their implant removed because of SSI. Readmission for intravenous antibiotics because of SSI occurred in 47 patients (7.0%), and 190 women (27.7%) received oral antibiotics because of clinically suspected SSI. There was no significant difference between the randomization groups for the primary outcome implant removal (odds ratio [OR], 1.26; 95% CI, 0.69-2.65; P = .53), or for the secondary outcomes readmission for intravenous antibiotics (OR, 1.18; 95% CI, 0.65-2.15; P = .58) and prescription of oral antibiotics (OR, 0.72; 95% CI, 0.51-1.02; P = .07). Adverse events associated with antibiotic treatment were more common in the multiple-dose group than in the single-dose group (16.4% [58 patients] vs 10.7% [37 patients]; OR, 1.64; 95% CI, 1.05-2.55; P = .03). The findings of this randomized clinical trial suggest that multiple-dose antibiotic prophylaxis is not superior to a single-dose regimen in preventing SSI and implant removal after implant-based breast reconstruction but comes with a higher risk of adverse events associated with antibiotic treatment. EudraCT 2012-004878-26.

Use of liquid chromatography-tandem mass spectrometry for determination of higenamine in urine following oral administration of traditional Chinese medicine.

Since higenamine (HG) was first included in the World Anti‐doping Agency (WADA) 2017 Prohibited List, an increasing number of plants have been found to contain this ingredient. As a result, doctors are hesitant to prescribe traditional Chinese medicine (TCM) to athletes. Thus, it is very important to assess the risks of doping violations due to HG following the oral administration of TCM. We determined the drug concentration‐time curves for HG in urine by liquid chromatography–tandem mass spectrometry (LC–MS/MS) after single or multiple administrations of lotus seed powder on volunteers, the single dose was equivalent to 750 μg of HG, and the multiple doses were equivalent to 90 μg of HG each, 3 times daily for 5 consecutive days. For the single‐dose group, the HG could be detected in urine 0.5 h after administration and reached a maximum concentration of 16.5 ng/mL 1 h after administration. For the multiple‐dose group, the HG concentrations in urine showed two peaks at 29 and 77 h post‐administration with 22.6 and 23.1 ng/mL, respectively. At the dosage used in this study, the maximum concentration of HG in some urine samples exceeded the WADA limit of 10.0 ng/mL; the risk was still very high, so athletes must avoid this amount of HG when using TCM. In addition, our study provided further data supporting the presence of sulfonated metabolites of HG in urine samples.

Pharmacokinetics and Tissue Residue Profiles of Enrofloxacin in Crucian Carp (Carassius auratus gibelio) Following Single and Multiple Oral Administration.

The pharmacokinetics, tissue distribution, and elimination of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated to the crucian carp (Carassius auratus gibelio) after single (20 mg/kg b. w.) and multiple oral administration (20 mg/kg b.w. one time daily for 5 days) at 28°C. The concentrations of ENR and CIP in the plasma and tested tissues (muscle/skin, liver, and kidney) were detected simultaneously by high-performance liquid chromatography (HPLC), and the pharmacokinetic data were analyzed with a non-compartmental model using WinNonLin 6.1 PK software (Pharsight Corporation, Mountain View, CA, USA). The pharmacokinetic characteristics of ENR in crucian carp exhibited slow absorption, wide tissue distribution, and long elimination half-life. In the single-dose group, the peak concentrations (Cmax) of ENR in the plasma, muscle/skin, liver, and kidney were 8.93 μg/mL, 13.9 μg/g, 31.2 μg/g, and 27.3 μg/g, respectively, observed at 3 h, 6 h, 1 h, and 3 h after dosing. The elimination half-lives (T1/2λz) of ENR in plasma, muscle/skin, liver, and kidney were calculated to be 67.4, 82.8, 94.4, and 114 h, respectively. In the multiple-dose group, the Cmax of ENR in the plasma, muscle/skin, liver, and kidney were 18.4 μg/mL, 26.8 μg/g, 82.8 μg/g, and 74.5 μg/g, respectively, achieved at 3 h, 6 h, 1 h, and 1 h after the last dose. The T1/2λz of ENR in the plasma, muscle/skin, liver, and kidney were calculated to be 76.4 h, 91.5 h, 114 h, and 148 h, respectively. During the multiple-dose administration, significant accumulations of ENR and CIP were observed in the plasma and tissues of crucian carp, possibly due to their long elimination half-lives. In both dose groups, the AUC0−∞ for both ENR and CIP followed the order of liver > kidney > muscle/skin > plasma. The finding suggested that the liver may play an important role in the metabolism of ENR. According to the calculated PK/PD indices of Cmax/minimum inhibitory concentrations (MIC) and AUC24h/MIC, the multiple-dose regimen would be highly effective against pathogenic bacteria with a MIC value of ≤ 1.84 μg/ml. Depletion studies indicated that a withdrawal period of at least 29 or 32 days was necessary to guarantee food security after single or multiple oral gavage administration at 28°C.