Pharmacokinetic-pharmacodynamic Analysis Research Articles

P-1090. Rifaquizinone for the Treatment of Acute Bacterial Skin and Skin Structure Infections: A Multicenter, Double-Blind, Randomized, Active-Controlled, Phase 2 Trial

Abstract Background Rifaquizinone (RFQ, TNP-2092) is under development for the treatment of serious or life-threatening bacterial infections including those caused by gram-positive pathogens that have developed resistance to commonly used antibiotics. This study compared the safety, tolerability and efficacy of RFQ and vancomycin in patients with acute bacterial skin and skin structure infections (ABSSSIs). Methods A multi-center, randomized, double blind, positive controlled phase 2 clinical trial (NCT03964493) was conducted in adults with ABSSSIs in the USA. Eligible patients were randomized 2:1 to receive RFQ (300 mg) or vancomycin (1 g) IV q12h for 3 to 14 days. Patients who met the switching criteria may switch to commercially available oral antibiotics judged by the investigators. The total duration of the treatment was 7 to 14 days. The primary endpoint was safety and tolerability. The key secondary endpoint was the clinical response at early assessment (EA) visit. Results A total of 117 patients received at least 1 dose of study drugs. The incidences of adverse events (AEs) in RFQ and vancomycin groups were 46.2% (36/78) and 48.7% (19/39), respectively. The most of AEs were mild in severity. No drug-related serious AE was reported. The clinical response rate of RFQ at EA visit was higher than vancomycin in the ITT, modified ITT and Micro-ITT populations (Table 1). In patients infected with MRSA and fluoroquinolone-resistance (RF-Q) S. aureus, the clinical response rate of RFQ and vancomycin group were 78.1% (25/51) vs 57.9% (11/29), and 75.9% (22/51) vs 55.6% (10/29), respectively. Pharmacokinetic-pharmacodynamic (PK-PD) analysis indicated that more than 95% of patients achieved the systemic exposures required (AUC0-24h > 50 µg·h/mL) for the treatment of medical device associated biofilm infections. Conclusion RFQ was safe and well tolerated in patients with ABSSSIs. The early clinical response rates of RFQ in ITT, mITT and micro-ITT populations were all higher than that of vancomycin. More importantly, RFQ demonstrated higher early clinical response rates than vancomycin in patients infected with MRSA and FQ-R S. aureus. The PK-PD analysis indicated that sufficient drug exposures were achieved for medical device associated biofilm infections. Disclosures Huan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Guozhu Geng, MD, TenNor Therapeutics (Suzhou) Ltd: Employee Changlin Ai, Master of Medicine, TenNor Therapeutics (Suzhou) Ltd: Employee Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Jing Chen, Master of Science, TenNor Therapeutics (Suzhou) Ltd: Employee

Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: A population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite

Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining their association with dexamethasone-induced toxicity. Peak and trough concentrations were collected during the maintenance phase from pediatric ALL patients who received oral dexamethasone (6mg/m2/day). NONMEM was used to study the population pharmacokinetics including covariates. Pharmacokinetic (PK) and pharmacodynamic (PD) correlations between drug and its active metabolite exposure and adverse effects were examined. 382 samples (dexamethasone: n = 191; 6β-hydroxydexamethasone: n = 191) from 104 children (age range 3.0 -18.8 years) were collected. A one-compartment model described the data best. The estimated apparent dexamethasone total clearance was 26 L/h/70 kg with 18 % inter-individual variability, and an apparent volume of distribution of 123 L/70 kg, yielding a half-life of 3.3 h. Covariate analysis demonstrated that when asparaginase was co-administered, there was a 50 % reduction in both the clearance of dexamethasone and the extent to which dexamethasone was metabolized to 6β-hydroxydexamethasone. A statistically significant but weak positive correlation was observed between dexamethasone drug exposure and fasting hunger scores. Dexamethasone exposure significantly increased with asparaginase co-administration by inhibition of the CYP3A4 pathway. Our study found a statistically significant but weak positive correlation between dexamethasone exposure and increased hunger. These results support the need for more studies on how to personalize dexamethasone dosing in pediatric ALL treatment and adjust doses to limit side effects, especially in case of co-medication.

Safety, pharmacokinetics, and pharmacodynamics of sofnobrutinib, a novel non-covalent BTK inhibitor, in healthy subjects: First-in-human phase I study.

Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in exvivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC50) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC50 for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases.

Human serum albumin: prediction model and reference values for preterm and term neonates.

Human serum albumin (HSA) concentrations may alter HSA-bound drug distribution. This study aims to describe longitudinal real-world HSA trends, and to develop a prediction model for HSA concentrations using a large neonatal cohort. Patients admitted to the neonatal intensive care unit of the University Hospitals Leuven (postnatal age (PNA) ≤28days) were retrospectively included. Using linear mixed models, covariate effects on HSA were explored. A multivariable prediction model was developed (backward model selection procedure, 1% significance level). In total, 848 neonates were included [median(interquartile range) gestational age (GA) 35(32-38)weeks, birth weight (BW) 2400(1640-3130)grams]. Median HSA concentration was 32.3(28.7-35.6)g/L. Longitudinal analyses demonstrated increasing HSA concentrations with PNA and GA for most GA groups. Univariable analyses revealed significant associations of HSA with PNA, GA, BW, current weight, total and direct bilirubin, total plasma proteins, respiratory support, mechanical ventilation, sepsis, ibuprofen use, and C-reactive protein (p-values < 0.05). A high-performance (R2 = 76.3%) multivariable HSA prediction model was developed, and PNA- and GA-dependent HSA centiles were provided. Population-specific HSA centiles and an accurate neonatal HSA prediction model were developed, incorporating both maturational and non-maturational covariates. These results can enhance future clinical care and pharmacokinetic analyses to improve pharmacotherapy of HSA-bound drugs in neonates, respectively. To improve future pharmacokinetic modeling initiatives, a high-performance human serum albumin (HSA) prediction model was developed for (pre)term neonates, using a large, single-center cohort of real-world data. This prediction model integrates both maturational and non-maturational covariates, resulting in accurate HSA predictions in neonates. Additionally, HSA centiles based on postnatal and gestational age were developed, which can be easily applied in clinical practice when interpreting HSA concentrations of neonates. In general, unbound drug fractions are higher in neonates compared to older populations. To improve pharmacotherapy of HSA-bound drugs in neonates, the obtained results can be integrated in future pharmacokinetic-pharmacodynamic analyses.

Population Pharmacokinetic-Pharmacodynamic Analysis of a Reserpine-Induced Myalgia Model in Rats.

(1) Background: Fibromyalgia syndrome (FMS) is a chronic pain condition with widespread pain and multiple comorbidities, for which conventional therapies offer limited benefits. The reserpine-induced myalgia (RIM) model is an efficient animal model of FMS in rodents. This study aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of reserpine in rats, linking to its impact on monoamines (MAs). (2) Methods: Reserpine was administered daily for three consecutive days at dose levels of 0.1, 0.5, and 1 mg/kg. A total of 120 rats were included, and 120 PK and 828 PD observations were collected from 48 to 96 h after the first dose of reserpine. Non-linear mixed-effect data analysis was applied for structural PK-PD model definition, variability characterization, and covariate analysis. (3) Results: A one-compartment model best described reserpine in rats (V = 1.3 mL/kg and CL = 4.5 × 10-1 mL/h/kg). A precursor-pool PK-PD model (kin = 6.1 × 10-3 mg/h, kp = 8.6 × 10-4 h-1 and kout = 2.7 × 10-2 h-1) with a parallel transit chain (k0 = 1.9 × 10-1 h-1) characterized the longitudinal levels of MA in the prefrontal cortex, spinal cord, and amygdala in rats. Reserpine stimulates the degradation of MA from the pool compartment (Slope1 = 1.1 × 10-1 h) and the elimination of MA (Slope2 = 1.25 h) through the transit chain. Regarding the reference dose (1 mg/kg) of the RIM model, the administration of 4 mg/kg would lead to a mean reduction of 65% (Cmax), 80% (Cmin), and 70% (AUC) of MA across the brain regions tested. (4) Conclusions: Regional brain variations in neurotransmitter depletion were identified, particularly in the amygdala, offering insights for therapeutic strategies and biomarker identification in FMS research.

Exploring the multiple effects of nifedipine and captopril administration in spontaneously hypertensive rats through pharmacokinetic-pharmacodynamic analyses.

This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.

A pharmacokinetic-pharmacodynamic analysis of l-glutamine for the treatment of sickle cell disease: Implications for understanding the mechanism of action and evaluating response to therapy.

The mechanisms of action of l-glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three-week, dose-ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK-PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK-PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit-to-viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK-PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK-optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use.

NFS-18. LOWER BODY SURFACE AREA IS ASSOCIATED WITH INCREASED LIKELIHOOD OF PLEXIFORM NEUROFIBROMA RESPONSE TO MEK INHIBITION

Abstract BACKGROUND MEK inhibitors (MEKi) are altering the management approach for plexiform neurofibroma (PN), with high rates of treatment response to multiple MEKi. Despite these successes, a subset of PN fail to respond and little is known about the clinical features associated with treatment response. METHODS We performed a retrospective cohort study integrating clinical trial data (NCT01362803, NCT02407405, NCT02096471, NCT03231306, NCT03363217) to identify baseline clinical features associated with response of PN to MEKi. Partial response (PR) was defined as ≥20 percent reduction in tumor volume from baseline. RESULTS Of 232 eligible participants, adequate clinical trial and imaging data was available for 223 participants. In the primary analysis of 184 participants with central response evaluation, the median age was 15.2 years with a median tumor volume of 488 milliliters at clinical trial enrollment. One hundred and eighteen (64%) participants achieved a PR with median time to PR of 8 cycles. Thirty-five participants (19%) required a dose reduction prior to 6 cycles of therapy due to toxicity. Younger age and lower body surface area (BSA) were significantly associated with PR in univariate analysis while female sex and typical PN appearance (versus nodular) on imaging approached significance. In multivariable analysis, only lower BSA was significantly associated with response while typical PN appearance approached significance. In the multivariable analysis of pediatric participants treated per BSA-based dosing, lower BSA was the only feature significantly associated with PR. In the expanded analysis of all 223 participants, lower BSA and typical PN appearance were significantly associated with PR. CONCLUSION Lower BSA and typical appearance of PN were associated with PR to MEK inhibitors. Future studies of MEK inhibitor for PN should integrate tumor pharmacokinetic-pharmacodynamic analyses to prospectively explore the impact of BSA on treatment response.

Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis of Second-Line Anti-Tubercular Drugs in Indian Children with Multi-Drug Resistance.

To conduct a thorough pharmacokinetic (PK)- pharmacodynamic (PD) analysis of second-line anti-tubercular therapy (ATT) in children diagnosed with multi-drug resistant tuberculosis (MDR-TB). Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software. A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population. The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.

Pharmacokinetic-Pharmacodynamic Analysis of pH-Responsive Doxorubicin-Releasing Micelles with Anticancer Activity.

This study aimed to investigate the effect of in vivo pH-responsive doxorubicin (DOX) release and the targetability of pilot molecules in folic acid (FA)-modified micelles using a pharmacokinetic-pharmacodynamic (PK-PD) model. The time profiles of intratumoral DOX concentrations in Walker256 tumor-bearing rats were monitored using a microdialysis probe, followed by compartmental analysis, to evaluate intratumoral tissue pharmacokinetics. Maximal DOX was released from micelles 350 min after the administration of pH-responsive DOX-releasing micelles. However, FA modification of the micelles shortened the time to peak drug concentration to 150 min. Additionally, FA modification resulted in a 27-fold increase in the tumor inflow rate constant. Walker256 tumor-bearing rats were subsequently treated with DOX, pH-responsive DOX-releasing micelles, and pH-responsive DOX-releasing FA-modified micelles to monitor the tumor growth-time profiles. An intratumoral threshold concentration of DOX (55-64 ng/g tumor) was introduced into the drug efficacy compartment to construct a PD model, followed by PK-PD analysis of the tumor growth-time profiles. Similar results of threshold concentration and drug potency of DOX were obtained across all three formulations. Cell proliferation was delayed as the drug delivery ability of DOX was improved. The PK model, which was developed using the microdialysis method, revealed the intratumoral pH-responsive DOX distribution profiles. This facilitated the estimation of intratumoral PK parameters. The PD model with threshold concentrations contributed to the estimation of PD parameters in the three formulations, with consistent mechanisms observed. We believe that our PK-PD model can objectively assess the contributions of pH-responsive release ability and pilot molecule targetability to pharmacological effects.

Enhanced efficacy of brucine dissolving-microneedles as a targeted delivery system in rheumatoid arthritis treatment: a comprehensive pharmacokinetic-pharmacodynamic analysis.

Our previous studies have shown the therapeutic efficacy of brucine dissolving-microneedles (Bru-DMNs) in treating rheumatoid arthritis (RA). Bru delivered via the DMNs can bypass some of the issues related to oral and systemic delivery, including extensive enzymatic activity, liver metabolism and in the case of systemic delivery via hypodermic needles, pain resulting from injections and needle stick injury. However, the underlying mechanism of Bru-DMNs against RA has not been investigated in depth at the pharmacokinetic-pharmacodynamic (PK-PD) level. In this study, a microdialysis-based method combined with ultra-performance liquid chromatography-tandem mass spectrometry was developed for the simultaneous and continuous sampling and quantitative analysis of blood and joint cavities in fully awake RA rats. The acquired data were analyzed by the PK-PD analysis method. Bru delivered via microneedles showed enhanced distribution and prolonged retention in the joint cavity compared to its administration in blood. The correlation between the effect of Bru and its concentration at the action site was indirect. In this study, we explored the mechanism of Bru-DMNs against RA and established a visualization method to express the PK-PD relationship of Bru-DMNs against RA. This study provides insights into the mechanism of action of drugs with potential side effects administered transdermally for RA treatment.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-‍linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Non-invasive single cell aptasensing in live cells and animals.

We report a genetically encoded aptamer biosensor platform for non-invasive measurement of drug distribution in cells and animals. We combined the high specificity of aptamer molecular recognition with the easy-to-detect properties of fluorescent proteins. We generated six encoded aptasensors, showcasing the platform versatility. The biosensors display high sensitivity and specificity for detecting their specific drug target over related analogs. We show dose dependent response of biosensor performance reaching saturating drug uptake levels in individual live cells. We designed our platform for integration into animal genomes; thus, we incorporated aptamer biosensors into zebrafish, an important model vertebrate. The biosensors enabled non-invasive drug biodistribution imaging in whole animals across different timepoints. To our knowledge, this is the first example of an aptamer biosensor-expressing transgenic vertebrate that is carried through generations. As such, our encoded platform addresses the need for non-invasive whole animal biosensing ideal for pharmacokinetic-pharmacodynamic analyses that can be expanded to other organisms and to detect diverse molecules of interest.

Effects of L-Glutamine on Biomarkers of Response in Sickle Cell Disease: A Pharmacokinetics-Pharmacodynamics Analysis

OralL-glutamine (Endari®) has been approved by the US-FDA to reduce the acute complications of sickle cell disease (SCD) in patients at least 5 years of age. L-glutamine has several roles in the body including de novo synthesis of intracellular glutathione which acts as an antioxidant. However, the mechanisms of action by which L-glutamine could reduce complications in SCD require further investigation. Additionally, there are no known biomarkers to assess response to L-glutamine therapy. We conducted an open-label, dose-ascending trial (NCT04684381) of L-glutamine in pediatric (n=4) and adult (n=4) participants with SCD as well as in adult healthy volunteers (n=4) (Table 1). Over a three-week trial period with 4 study visits, serial blood samples were collected to define the pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD interactions of L-glutamine using a broad panel of laboratory investigations including amino acid concentrations, blood counts, percentage of dense red blood cells (%DRBC), whole blood viscosity, osmotic and oxygen gradient ektacytometry, and reactive oxygen species (ROS) of reticulocytes (ROS retic) and mature red blood cells (ROS RBC). In PK-PD analysis of amino acids, we focused analysis on arginine (Arg), citrulline (Cit), and ornithine (Orn) based on the hypothesis that L-glutamine improves endothelial function by increasing arginine bioavailability and augmenting nitric oxide (NO) production. Peak arginine concentration was directly correlated with both the maximum L-glutamine concentration (C max p=0.001) and area-under-the curve (AUC) (p=0.047) indicating improvement in arginine bioavailability, but there was no significant linear correlation with either the Arg:Orn or Arg:(Orn+Cit) ratios. In PK-PD analysis of osmotic gradient ektacytometry, L-glutamine C max was directly correlated with the elongation maximum (EI max), noted in all participants at visit 4 (p=0.033). In SCD participants, L-glutamine C max was inversely correlated with O hyper (osmolality at EI max/2) at visits 3 (p=0.044) and 4 (p=0.004). In PK-PD analysis of oxygen gradient ektacytometry in SCD participants, L-glutamine C max was inversely correlated with the point of sickling (POS) at visit 3 (p=0.005) but not at visit 4 (p=0.054). Together, these findings suggest that although L-glutamine may decrease cellular hydration (decreased O hyper) it may increase RBC deformability (increased EI max) and delay the onset of sickling after hypoxia (decreased POS). In PK-PD analysis of viscometry, higher L-glutamine C max was associated with higher whole blood viscosity measurements at all shear rates (p&amp;lt;0.05). However, L-glutamine C max was also directly correlated with hematocrit-to-viscosity ratio (HVR) at the highest shear rates in the overall population at visit 4 (p&amp;lt;0.05). In addition, L-glutamine C max for SCD participants was associated with increased hemoglobin concentration, an effect that was observed at visit 4 (p=0.025), and increased %DRBC, an effect detected at visits 3 (p=0.008) and 4 (p=0.007). In PK-PD analysis of ROS, L-glutamine AUC was inversely correlated with ROS Retic (p=0.024), but not ROS RBC, in all participants at visit 3. When considered as total ROS Retic (calculated as ROS retic × absolute reticulocyte count), there was a similar inverse correlation with glutamine AUC in SCD participants, although not statistically significant. In contrast to all other biomarkers, L-glutamine C max was not correlated with any ROS measurement. This PK-PD analysis of L-glutamine reveals biological effects that alter RBC characteristics and could modify SCD-related complications, with a complex interplay summarized in Figure 1. Prospective studies can validate these biomarkers and be used to monitor the effects of L-glutamine therapy in SCD patients.

Current Insights into Diagnosing and Treating Neurotuberculosis in Adults.

Neurotuberculosis has the highest morbidity and mortality risk of all forms of extrapulmonary tuberculosis (TB). Early treatment is paramount, but establishing diagnosis are challenging in all three forms of neurotuberculosis: tuberculous meningitis (TBM), spinal TB and tuberculomas. Despite advancements in diagnostic tools and ongoing research aimed at improving TB treatment regimens, the mortality rate for neurotuberculosis remains high. While antituberculosis drugs were discovered in the 1940s, TB treatment regimens were designed for and studied in pulmonary TB and remained largely unchanged for decades. However, new antibiotic regimens and host-directed therapies are now being studied to combat drug resistance and contribute to ending the TB epidemic. Clinical trials are necessary to assess the effectiveness and safety of these treatments, addressing paradoxical responses in neurotuberculosis cases and ultimately improving patient outcomes. Pharmacokinetic-pharmacodynamic analyses can inform evidence-based dose selection and exposure optimization. This review provides an update on the diagnosis and treatment of neurotuberculosis, encompassing both sensitive and resistant antituberculosis drug approaches, drawing on evidence from the literature published over the past decade.

Neurocognitive effect of biased µ-opioid receptor agonist oliceridine, a utility function analysis and comparison with morphine.

Oliceridine (Olinvyk®) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. We determined the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. The study had a randomized, double-blind, placebo-controlled, partial block 3-way crossover design. Experiments were performed in 20 male and female volunteers. Subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose) or placebo on three separate occasions. Prior to and following dosing, neurocognitive tests, cold pressor test and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as measure of benefit, slowing of saccadic peak velocity and increased body sway as measures of neurocognitive harm. The oliceridine and morphine C50's, i.e. the effect-site concentrations causing 50% effect, were: antinociception 13±2 and 23±7 ng/mL, saccadic peak velocity 90±14 and 54±15 ng/mL, and body sway 10±2 and 5.6±0.8 ng/mL, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI 0.17-0.7; p<0.01) for saccadic peak velocity and 0.33 (0.16-0.50; p<0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5-77 ng/mL, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from zero from 0-100 ng/mL. Over the concentration range 15-50 ng/mL the oliceridine utility was superior to that of morphine (p < 0.01). Similar observations were made for body sway. These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

Safety, Pharmacokinetics, and Exposure-Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease.

Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30mL/min/1.73m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10participants with normal kidney function (estimated glomerular filtration rate ≥90mL/min/1.73m2 ; Group 3) received a single dose of subcutaneous nedosiran sodium 170mg. Group 1a received nedosiran 8hours before beginning hemodialysis, Group 1b received nedosiran 2hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.

Screening of superior anti-osteoporotic flavonoids from Epimedii Folium with dual effects of reversing iron overload and promoting osteogenesis.

Iron overload is a risk factor for postmenopausal osteoporosis (PMOP) and lowering iron levels to regulate the labile plasma iron is the preferred therapy. Icariin (ICA), baohuoside I (BHS) and icaritin (ICT) are three flavonoids obtained from Epimedii Folium that are efficient in facilitating osteogenesis. In this study, an active flavonoid with dual effects of reversing iron overload and promoting osteogenesis was screened based on pharmacokinetics, iron complexation properties and the potential to downregulate iron overload, reversing PMOP. As a result, the in vivo absorption of three compounds was ICA > ICT > BHS, while the exposure in muscle and bone was BHS > ICT > ICA. In vitro complexation showed that only ICT complexed with Fe (III) at a 1:1 ratio on 3-OH and the ICT-Fe (III) complex (m/z 424.3750) was identified by UPLC-Q-TOF-MS. In vivo dynamic detection also showed that the concentration of ICT-Fe (III) complexes varied with the concentration of ICT in plasma. The behavioral blunting and bone loss in zebrafish induced by Fe (III) were significantly reversed by ICT in a dose-dependent manner. Pharmacokinetic-pharmacodynamic analysis showed that ICT was negatively correlated with serum ferritin and positively correlated with osteogenic markers including alkaline phosphatase, osteocalcin and osteoprotegerin. Bone loss in ovariectomized rats was significantly altered after ICT intervention, with reduced serum ferritin levels and improved osteogenic marker levels. These results demonstrated that ICT had favorable musculoskeletal penetration and iron complexation capability to shrink labile plasma iron, showing superior performance in anti-PMOP through the dual effects of reversing iron overload and promoting osteogenesis.

Influence of Intramuscular Injection Sites on Pharmacokinetics of Amoxicillin in Olive Flounder (Paralichthys olivaceus) and Its Implication for Antibacterial Efficacy.

This study aimed to investigate the effects of different injection sites, including dorsal, cheek, and pectoral fin muscles, on the pharmacological properties of amoxicillin (AMOX) in olive flounder (Paralichthys olivaceus) after a single intramuscular (IM) injection of 40 mg/kg. The AMOX concentration was measured using high-performance liquid chromatography-tandem mass spectrometry, followed by a non-compartmental model analysis. The peak serum concentrations (Cmax) achieved 3 h after dorsal, cheek, and pectoral fin IM injections were 202.79, 203.96, and 229.59 μg/mL, respectively. The area under the concentration-time curve (AUC) was 1697.23, 2006.71, and 1846.61 µg/mL·h, respectively. The terminal half-life (t1/2λZ) was prolonged for cheek and pectoral fin IM injections (10.12 and 10.33 h, respectively) compared to dorsal IM injection (8.89 h). In the pharmacokinetic-pharmacodynamic analysis, a higher T > minimum inhibitory concentration (MIC) and AUC/MIC values were observed after AMOX was injected into the cheek and pectoral fin muscles compared to the dorsal muscle. Muscle residue depletion was below the maximum residue level from day 7 after IM injection at all three sites. These findings suggest that the cheek and pectoral fin sites provide advantages regarding systemic drug exposure and prolonged action compared with the dorsal site.