Concentration-time Profiles Research Articles

Rat PermQ: A permeability- and perfusion-based physiologically based pharmacokinetic model for improved prediction of drug concentration-time profiles in rat

Rat PermQ: A permeability- and perfusion-based physiologically based pharmacokinetic model for improved prediction of drug concentration-time profiles in rat

In vitro and in vivo characterization of Invega Sustenna® (paliperidone palmitate long-acting injectable suspension).

The aim of this study was to comprehensively characterize paliperidone palmitate (PP) long-acting suspension (Invega Sustenna®) through reverse engineering. We developed a series of analytical methods to assess critical quality attributes of four batches of Invega Sustenna®. The size distributions of the four batches of suspensions were measured using laser diffraction, and variations in the D50 and D90 parameters were observed. The morphology of suspension was determined through scanning electron microscope (SEM), which exhibited irregular granular shape across all batches. The size distributions determined by SEM images were similar to the laser diffraction results. Thermal characteristics were detected using differential scanning calorimetry (DSC) and crystalline properties were assessed by powder X-ray diffraction (PXRD), displaying consistency among the four batches in these two aspects. In vitro dissolution methods (sample separation and dialysis bag methods) were developed to evaluate the release behaviors of Invega Sustenna® and four lots showed a similar dissolution pattern. Furthermore, following a single-dose intramuscular administration to rats, two batches of Invega Sustenna® with the largest size differences demonstrated comparable plasma concentration-time profiles and pharmacokinetics parameters, indicative of one month long-acting release. In summary, we established a systematic quality characteristics assessment for Invega Sustenna®, including particle size distribution, particle morphology, thermal characteristics, crystalline properties, in vitro dissolution kinetics and in vivo pharmacokinetics. Our work will assist pharmaceutical companies and regulatory agencies in the development and regulatory assessment of novel or generic products of long-acting injectable suspension.

The Kinetics of Cystatin C and Serum Creatinine in Acute Kidney Injury.

Acute kidney injury (AKI) is a common condition affecting a significant portion of hospitalized and critically ill patients. Current AKI diagnosis relies on serum creatinine (sCr), which has several recognized limitations that impact the timely detection and response to AKI management. Serum cystatin C (sCys) has characteristics that can overcome the limitations of sCr, but head-to-head comparisons of these biomarkers is difficult to study prospectively. A quantitative assessment of the kinetics of sCys and sCr during AKI is necessary to support clinical workflow implementation for AKI diagnosis and management. A quantitative systems pharmacology (QSP) model was developed using MATLAB and Simbiology (The MathWorks, Natick, MA), to simulate the concentration-time profiles of sCr and sCys under varying degrees of AKI across a spectrum of baseline kidney function. The model incorporated parameters from existing literature and used a contemporary sCr and sCys GFR equation to assess the time to reach AKI diagnostic criteria for both biomarkers. The model demonstrated that sCys achieves steady-state concentration and meets AKI diagnostic thresholds significantly faster than sCr, with an advantage of six to 48 hours, depending on CKD stage. sCys exhibited greater sensitivity in detecting GFR reductions, with the ability to detect AKI within 12-24 hours post-AKI, compared to 12-72 hours for sCr. The study also identified that for sCys, absolute value diagnostic cutoffs are more effective than percentage-based thresholds and can provide consistent detection across different CKD stages. sCys has superior kinetics for early AKI detection compared to sCr, making it a valuable addition to AKI diagnostic protocols, particularly in high-risk populations. Daily monitoring of sCys in patients at risk for AKI would facilitate more timely detection and potentially improve clinical outcomes. Future research should focus on validating sCys diagnostic criteria and integrating it with other biomarkers to enhance AKI management.

P-1220. Humanizing Plasma and Pulmonary Epithelial Lining Fluid (ELF) Exposures of Cefiderocol in Standardized Murine Lung Infection Model

Abstract Background The clinical translation of preclinical in vivo murine infection models can be enhanced by humanizing exposures. However, humanizing plasma exposures does not ensure equivalent exposures at other target sites, such as the ELF, due to interspecies differences in penetration. We developed both plasma and ELF human simulated regimens (HSRs) of cefiderocol in a standardized murine lung infection model.Table 1.Cefiderocol %free time>MIC plasma profiles of mouse and man Methods In accordance with the collaboration for prevention and treatment of MDR bacterial infections (COMBINE) murine lung infection model, specific pathogen-free, 6-8 week old female CD-1 mice were rendered neutropenic and received a single 5 mg/kg IP injection of uranyl nitrate 3 days prior to inoculation. Under isoflurane anesthesia, mice were inoculated with 0.05 mL of a ∼108 CFU/mL bacterial suspension of Klebsiella pneumoniae via intranasal route. A historic cefiderocol plasma HSR from a murine thigh model was used as a baseline regimen. Two hours after inoculation, cefiderocol HSRs were administered. Groups of 6 mice were euthanized at predefined timepoints throughout the dosing interval for plasma and bronchoalveolar fluid collection. Samples were assayed by LC-MS/MS and urea correction was used to determine ELF concentrations. Murine plasma protein binding (32%) was determined previously and used to calculate free drug. Pharmacokinetic models for both plasma and ELF were fitted to the data in Phoenix WinNonlin and HSRs were mathematically altered and subsequently confirmed in the model.Figure 1.Free cefiderocol plasma concentration-time profiles in humans receiving 2g q8h as 3h infusion and mice receiving a human-simulated regimen. Results Cefiderocol 2g q8h 3h infusion plasma exposures were recapitulated in the murine model with 5, 7.5, 10, 3.5, and 1 mg/kg at 0, 1, 2, 4, and 6h, administered every 8h, as presented in Table/Figure 1. ELF penetration for cefiderocol was greater in infected mice relative to man, necessitating a dosage reduction to 3.75, 5, 6.25, 1.75, and 1 mg/kg at 0, 1, 2, 4, and 6h, administered every 8h, to humanize ELF exposures (Figure 2).Figure 2.Cefiderocol pulmonary epithelial lining fluid concentration-time profiles in humans receiving 2g q8h as 3h infusion and mice receiving a human-simulated regimen. Conclusion Plasma and ELF HSRs for cefiderocol were developed and validated in the COMBINE murine neutropenic lung infection model. Cefiderocol ELF penetration was greater in mice than man, underscoring the importance of understanding interspecies differences in target site penetration for bench-to-bedside translation. Disclosures Andrew J. Fratoni, PharmD, InsightRX: Grant/Research Support Erin Duffy, PhD, CARB-X: Employee David P. Nicolau, PharmD, CARB-X: Grant/Research Support|Innoviva: Grant/Research Support|Innoviva: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Shionogi: Honoraria|Venatorx: Grant/Research Support

P-1116. Distribution of Rifaquizinone in Bone, Synovial Fluid and Plasma: A Phase 1 Trial in Patients Undergoing Total Hip or Knee Arthroplasty

Abstract Background Rifaquizinone (RFQ, TNP-2092) is a novel multitargeting drug conjugate in development for the treatment of prosthetic joint infections (PJIs). RFQ exerts its antibacterial activity by inhibiting RNA polymerase, DNA gyrase, and topoisomerase IV. This study was to evaluate RFQ concentrations in joint synovial fluids and bone tissues, plasma pharmacokinetics (PK), safety, and tolerability of RFQ for injection in adult patients undergoing total hip or knee arthroplasty (THA/TKA). Methods This was a single-center, phase 1, open-label study (NCT04294862) conducted in the USA. Eligible patients received a single IV infusion of RFQ 300 mg 2 hours before anesthesia. Bone and synovial samples were collected during the arthroplasty surgery and analyzed for RFQ concentrations. Results Between 1 Mar 2021 and 16 Dec 2021, 13 (9 THA and 4 TKA) patients were enrolled in the study. One subject did not receive a full dose of RFQ and was excluded from PK analysis. The mean bone RFQ concentrations were 2650, 1180, 362 and 410 ng/g in acetabulum, femoral head (THA patients), distal femur and tibia (TKA patients), respectively. The mean synovial fluid concentrations of RFQ were 6840 and 1090 ng/mL in THA and TKA patients, respectively. The mean plasma concentration-time profiles were comparable between THA and TKA patients and consistent with the PK profiles in previous studies. Four (30.8%) patients experienced at least one drug-related treatment-emergent adverse event (TEAE). There were no severe TEAEs or TEAEs leading to discontinuation of study drug. Conclusion RFQ was safe and well tolerated in THA and TKA patients. The mean bone and synovial fluid concentrations of RFQ at about 2 hours after a single 300 mg infusion were all reached above the MBBC90 (250 ng/mL) level for S. epidermidis. The acetabulum and synovial fluid concentrations in THA patients also exceeded the MBBC90 (2000 ng/mL) level for S. aureus. The local concentrations of RFQ are expected to rise further and exceed the MBBC90 when patients are treated with multiple doses of RFQ. Disclosures Javad Parvizi, MD, FRCS, TenNor Therapeutics (Suzhou) Ltd: Investigator Chad A Krueger, MD, TenNor Therapeutics (Suzhou) Ltd: Investigator Jing Chen, Master of Science, TenNor Therapeutics (Suzhou) Ltd: Employee Huan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Changlin Ai, Master of Medicine, TenNor Therapeutics (Suzhou) Ltd: Employee Guozhu Geng, MD, TenNor Therapeutics (Suzhou) Ltd: Employee Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee

P-2029. Results from a Phase 1 First in Human Study of Pemivibart: An Extended Half-Life Monoclonal Antibody (mAb)

Abstract Background Pemivibart (PEM) is a half-life extended recombinant human monoclonal IgG1 antibody that targets the SARS-CoV-2 spike protein receptor binding domain. PEM has been granted emergency use authorization (EUA) for the pre-exposure prophylaxis of COVID-19 in certain adults and adolescents with moderate-to-severe immune compromise.Table 1.Preliminary Pharmacokinetic Parameter Estimates of Pemivibart [Mean ± SD] Methods This is an ongoing Phase 1, first in human, randomized, blinded, placebo (PBO) controlled, single ascending dose study conducted in healthy participants (ppts) aged 18-65 years to evaluate PEM administered by slow IV push. Ppts were randomized 8:2 in one of 3 cohorts (n=8 PEM, n=2 placebo): PEM 1500 mg, 2500 mg, and 4500 mg. The primary objective was to assess the safety and tolerability of PEM. Secondary endpoints included serum pharmacokinetic (PK) parameters (estimated using non-compartmental analysis methodology) and immunogenicity. The trial will continue through 12 months; here we summarize the data through the 6-month timepoint.Figure 1:Mean ± Standard Deviation Serum Pemivibart Dose-Normalized Concentration-Time Profile Results Thirty ppts were randomized (24 PEM, 6 PBO); 28 ppts received the full dose as planned; two ppts received approximately 93% of the full dose of study drug due to an administration error. In the PEM arm, the median age was 32.5 years, 13.3% of ppts were 55 years or older, most ppts were white (83.3%) and not Hispanic or Latinx (93.3%). Mean body mass index was 25.78 kg/m2 across all ppts and similar between cohorts and study arms. There were no deaths, serious adverse events (SAEs), or AEs leading to permanent study drug discontinuation. Infusion-related adverse events occurred in 4 ppts (2 each in Cohort 2 and 3, respectively); these events were self-limited and resolved within 5 minutes without treatment. No unexpected safety signals were observed. PEM demonstrated linear PK with apparent dose-proportional exposure and extended serum half-life (mean 46, 44, and 50 days in Cohort 1, 2, and 3, respectively [Table 1]). No substantial anti-drug antibodies (ADAs) have been observed. Conclusion In this Phase 1 study of PEM administered by slow IV push at doses up to 4500 mg, no AEs leading to study drug discontinuation, or SAEs were reported to date in healthy adults. PEM demonstrated linear and dose-proportional PK. Complete trial data to be presented. Disclosures Anna Holmes, PhD, Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Private Company) Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Ed Campanaro, MS, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Lida Mehr, B.S., Invivyd, Inc.: Advisor/Consultant Anuja Raut, M.S., Invivyd, Inc.: Advisor/Consultant Amanda Copans, Pharm.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kristin Narayan, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company)

Pharmacokinetics of Depemokimab Delivered by Safety Syringe Device or Autoinjector in Healthy Adults: A Phase I, Single-Dose Study.

This Phase I, randomized, multicenter, open-label, parallel-group, single-dose study assessed the relative bioavailability of the anti-interleukin-5 antibody depemokimab (100mg) when administered subcutaneously via either a safety syringe device (SSD) or an autoinjector (AI). Healthy adult participants were randomized I:I to SSD or AI treatment arms and I:I:I to the injection site (upper arm, abdomen, or thigh). Participants were followed up for 30 weeks; blood samples were collected for pharmacokinetic (PK) assessment before dosing on Day 1 and up to Week 26. Depemokimab concentration profile as measured by plasma maximum concentration (Cmax), the area under the concentration-time curve from time zero extrapolated to infinity (AUC0-inf), PK parameters, immunogenicity, and safety were assessed. Overall, 140 participants were enrolled (n=70 per arm). Mean plasma concentration-time profiles of depemokimab were similar in both treatment arms, regardless of the injection site, adjusted geometric mean AI:SSD ratios for Cmax and AUC0-inf were 1.03 and 1.03, respectively, with all 90% confidence intervals within the bioequivalence bounds of 0.80-1.25. PK parameters were comparable across treatment arms. Treatment-related adverse events were reported in 19% of SSD and 20% of AI participants, with headache being the most common across both arms; no adverse events led to study withdrawal. These results support the use of either SSD or AI for subcutaneous administration of depemokimab.

Derivation of human toxicokinetic parameters and internal threshold of toxicological concern for tenuazonic acid through a human intervention trial and hierarchical Bayesian population modeling.

Tenuazonic acid (TeA), a mycotoxin produced by Alternaria alternata, contaminates various food commodities and is known to cause acute and chronic health effects. However, the lack of human toxicokinetic (TK) data and the reliance on external exposure estimates have stalled a comprehensive risk assessment for TeA. To bridge this gap, a human TK trial and population-based TK (PopTK) modeling were applied to determine human TK parameters of TeA, and the results were applied for risk screening using population biomonitoring data and threshold of toxicological concern (TTC)-based approaches. Ten healthy volunteers participated in the TK trial during which the volunteers ingested a bolus dose of TeA at the (external) TTC (1500 ng/kg bw). Blood, urine, and fecal samples were collected over 48 h and analyzed using UPLC-MS/MS. Concentration-time profiles were fit with a multi-compartmental PopTK model using a hierarchical Bayesian population structure. Utilizing a probabilistic framework, fitted TK parameters were used to derive internal TTC (iTTC) values for comparison to blood and urine biomonitoring data. Risk screening with data from five diverse biomonitoring cohorts was performed using Hazard Quotient (HQ) and probabilistic individual margin of exposure (IMOE) approaches. TeA was estimated to have a population median half-life of 1.9 [90% CI: 1.4-2.7] hours and volume of distribution of 4.4 [3.1-6.1] L/kg, with inter-individual variability geometric standard deviations of 2.4- and 1.7-fold, respectively. Probabilistic lower confidence bound iTTCs were derived of 0.5 nmol/L in blood and 2.53 nmol/kg-d urinary excretion. Risk screening HQs were mostly >1 for the three blood biomonitoring cohorts and < 1 for the two urinary biomonitoring cohorts; results from probabilistic IMOE calculations were qualitatively consistent. A comprehensive human TK study was performed for TeA for the first time, demonstrating the importance of integrating TK and population variability for a more comprehensive risk evaluation, particularly for interpreting biomonitoring data. The results for TeA point to the critical need for toxicity data to move beyond TTC-based risk screening. A critical gap in food safety research was addressed studying the toxicokinetics of tenuazonic acid (TeA) in humans and using these data to derive an internal threshold of toxicological concern (iTTC) for comparison to human biomonitoring data. The innovative approach-combining a human intervention trial with population-based toxicokinetic modeling-accounts for inter-individual variability and provides a more comprehensive understanding of population exposure to TeA. The resulting probabilistic iTTC and risk screening methodologies offer improved tools for interpretation of biomonitoring data. These findings have significant implications for food safety regulations and public health protection, potentially influencing future mycotoxin risk assessment strategies.

Clinical Pharmacokinetics of Psilocin After Psilocybin Administration: A Systematic Review and Post-Hoc Analysis.

Psilocybin is currently being extensively studied as a potential therapeutic agent for multiple psychiatric disorders. Here, a systematic literature review of all published pharmacokinetic data on the pharmacologically active metabolite of psilocybin, psilocin, is presented. The review includes clinical studies that reported pharmacokinetic data and/or parameters after psilocybin administration in humans. In addition, raw pharmacokinetic data from these studies was requested and/or extracted to further compare results across studies. In total, 309 publications were identified, of which 19 publications were ultimately included, which covered 12 unique clinical datasets. Except for one study that investigated intravenous psilocybin, all included studies administered psilocybin orally. Psilocybin acts as a pro-drug and is rapidly absorbed and transformed to psilocin after oral administration. In the majority of studies, unconjugated psilocin was measured while some also measured conjugated and total concentrations. Psilocin's biphasic concentration-time profiles demonstrates fast and extensive disposition with an apparent distribution volume of 505-1267 L and a terminal half-life of 1.23-4.72 h. Only 1.5-3.4% of the dose is excreted as psilocin in urine. Psilocin is mainly transformed to 4-hydroxyindole-3-acetic acid and in less amounts to conjugated psilocin, where 4-hydroxyindole-3-acetic acid formation may occur prior to systemic psilocin absorption. Information on the absolute bioavailability of psilocin was limited, and estimated at 55% in one study. No covariates nor food effects have been reported, based on four studies with known fasting status. Overall, we found the pharmacokinetic parameters of psilocin to be consistent between studies. This review may guide the further clinical development of psilocybin-based therapies.

Population Pharmacokinetics of Telmisartan in Healthy Subjects and Hypertensive Patients.

Telmisartan exhibits significant pharmacokinetic (PK) variability, but it remains unclear whether its PK profile is altered in hypertensive patients. This study aimed to characterize telmisartan PKs by conducting a meta-analysis and developing a pooled population PK model based on data from healthy subjects and hypertensive patients. Relevant literature was identified by a systematic approach. Eighteen studies were selected for analysis, which included 394 healthy subjects receiving single doses of telmisartan, 190 healthy subjects receiving repeated doses, along with 295 hypertensive patients receiving repeated doses. Pooled population PK analysis incorporated 20 mean concentration-time profiles from 14 studies. Meta-analyses were performed using OpenMeta-Analyst, and population PK modeling was performed using NONMEM®. Repeated telmisartan doses increased peak plasma concentrations. However, other noncompartmental PK parameters remained consistent across healthy and hypertensive populations. Telmisartan PKs were best described using a two-compartment model with first-order absorption and elimination in pooled analysis. Typical PK parameter values for apparent clearance (CL/F), apparent central and peripheral volumes of distribution (V1/F and V2/F), absorption rate constant (ka), and absorption lag time were 18.3 L/h, 20.7 L, 360 L, 0.183 h-1 and 0.228 h, respectively. Interindividual variabilities in CL/F, V1/F, and ka were 84%, 122%, and 106%, respectively. Covariate analysis revealed significantly lower CL/F (63.7%) and V1/F (90.3%) values in hypertensive patients than healthy subjects. These findings quantified the variability of telmisartan PK profile and highlighted the differences between healthy individuals and hypertensive patients, suggesting the need for optimized dosage strategies to improve therapeutic outcomes.

Population Pharmacokinetics of Enrofloxacin in Ctenopharyngodon idella Based on the Sparse Sampling Method and a Nonlinear Mixed Effect Model Following Intravenous and Oral Administration.

The objective of this study was to implement population pharmacokinetic (PPK) of enrofloxacin (EF) in grass carp (Ctenopharyngodon idella) after a single oral administration and a single intravenous administration based on a nonlinear mixed effect model. The plasma samples collected by the sparse sampling method were detected by high-performance liquid chromatography with a fluorescent detector. The initial pharmacokinetic (PK) parameters were evaluated by reference search and the calculation of a naïve pooled method. After oral administration, the concentration-time profile was best described by a one-compartment open model. The absorption rate constant (Ka), apparent distribution volume (V), and systemic clearance (CL) were estimated to be 3.11/h, 4.36 L/kg, and 0.079 L/h/kg, respectively. After intravenous administration, the concentration-time curve was best simulated by a two-compartment open model. The apparent distribution volume of the central compartment (V1), apparent distribution volume of the peripheral compartment (V2), CL, and clearance from the central compartment to the peripheral compartment (CL2) were estimated to be 0.42, 2.05 L/kg, 0.067, and 2.94 L/h/kg, respectively. Finally, the bioavailability was calculated to be 84.81%. The parameter of AUC/minimum inhibitory concentration value was estimated to be more than 506.32 for Aeromonas hydrophila, Aeromonas sobria, and Flavobacterium columnare indicating that EF at 20 mg/kg has high effectiveness for these pathogens. This study supported a concise method for conducting PK study in aquatic animals that facilitated the development of PK methodology in aquaculture.

Population Pharmacokinetic Modeling of Certepetide in Human Subjects With Metastatic Pancreatic Ductal Adenocarcinoma.

Certepetide (aka LSTA1 and CEND-1) is a novel cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide being developed to treat solid tumors. Certepetide is designed to overcome existing challenges in treating solid tumors by delivering co-administered anticancer drugs into the tumor while selectively depleting immunosuppressive T cells, enhancing cytotoxic T cells in the tumor microenvironment, and inhibiting the metastatic cascade. A population pharmacokinetic (PK) analysis was conducted to characterize the concentration-time profile of patients with metastatic exocrine pancreatic cancer receiving certepetide in combination with nab-paclitaxel and gemcitabine, and to investigate the effects of clinically relevant covariates on PK parameters. The PK of certepetide was characterized by a 2-compartment model with linear elimination and a proportional residual error structure. Body weight and baseline creatinine clearance (CrCL) were found to have statistically significant effects on central and peripheral volume (Vc and Vp) and clearance (CL) parameters, respectively, during model development and were included as covariate effects in the final PK model. Forest plots demonstrated a potentially clinically meaningful impact of high body weight (100kg) on certepetide exposure (steady-state maximum concentration [Cmax,ss] and area under the concentration-time curve [AUCss]), as well as low and high CrCL (50 and 150mL/min) on AUCss. Exposure predictions illustrated a relationship between certepetide exposure (AUCss) and renal function, with increasing exposure and decreasing CL of certepetide observed with worsening renal function. Modeling will strengthen the understanding of certepetide's PKs and will inform dose optimization in ongoing drug development activities.

Comprehensive Parent-Metabolite PBPK/PD Modeling Insights Into Methotrexate Personalized Dosing Strategies in Patients With Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a major public health concern, which can cause serious outcomes. Low-dose methotrexate (MTX) is a cornerstone in RA treatment, but there is significant heterogeneity in clinical response. To evaluate underlying sources of pharmacokinetic variability and clinical response of MTX, a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed using PK-sim and Mobi (version 11.1). The PBPK model included metabolism and transportation by AXO1, FPGS, GGH, RFC, and MRP2, with renal and biliary excretion. We also developed various degrees of renal insufficiency populations with subsequent dosing optimizations. A total of 23 MTX plasma concentration-time profiles were used, with 97% of predicted plasma concentrations within a two-fold range compared to observed data. The PBPK/PD modeling and simulation demonstrated that variability in renal clearance and enzymes related to MTX are likely important drivers of PK variability and there is a quantitative relationship between MTX-PG3 and RA treatment response. The PBPK/PD model could be used to guide improvement in MTX dose regimens for RA patients.

A Pharmacokinetic/Pharmacodynamic Study of Esomeprazole Comparing a Dual Delayed-Release Formulation (YYD601) to a Conventional Formulation Following Multiple Administrations in Healthy Adult Subjects.

YYD601 is a new dual delayed-release formulation of esomeprazole, developed to enhance plasma exposure and prolong the duration of acid suppression. This study aimed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of YYD601 20 mg following single and multiple oral administrations in healthy, fasting adult Koreans, and to compare these outcomes to those of the conventional esomeprazole 20 mg capsule. A randomized, open-label, two-period crossover study was conducted in 28 participants, who were divided into two treatment groups: one group received YYD601 20 mg, and the other received conventional esomeprazole 20 mg, once daily for five consecutive days. Blood samples for PK analysis were collected pre-dose and up to 24hours post-dose. The primary PK parameters (AUClast and AUCτ) were evaluated. PD endpoints included integrated gastric acidity, percentage of time with intragastric pH > 4 over 24-hour and nighttime intervals, and percent change in serum gastrin levels after multiple dosing. A total of 22 participants completed the study. YYD601 displayed more prolonged plasma concentration-time profiles than the conventional formulation, although the extent of the systemic exposure (AUC values) showed no statistically significant difference between the two formulations. With regard to the 24-hour gastric acid inhibition, YYD601 was comparable to the conventional formulation. The YYD601 showed a greater tendency for acid inhibition at night, as indicated by the percentage change of time with nocturnal acid breakthrough and other PD parameters. Both treatments were well tolerated, with no serious adverse events reported. Through extended systemic exposure of esomeprazole, YYD601 produces gastric acid suppression that is comparable to that of the conventional esomeprazole formulation, with a greater tendency to suppress acid at night. YYD601 20 mg was safe and well tolerated following single and multiple oral administrations, supporting its use as an effective alternative to conventional esomeprazole therapy. http://clinicaltrials.gov, NCT03985319 (Date of registration: May 29, 2019; Study period: between July 2019 and March 2020).

Improving Individualized Salbutamol Treatment: A Population Pharmacokinetic Model for Oral Salbutamol in Virtual Patients.

Salbutamol, a short-acting β2-agonist used in asthma treatment, is available in multiple formulations, including inhalers, nebulizers, oral tablets, and intravenous, intramuscular, and subcutaneous routes. Each formulation exhibits distinct pharmacokinetic (PK) and pharmacodynamic (PD) profiles, influencing therapeutic outcomes and adverse effects. Although asthma management predominantly relies on inhaled salbutamol, understanding how these formulations interact with patient-specific characteristics could improve personalized medicine approaches, potentially uncovering the therapeutic benefits of alternative formulations for an individual patient. Herein, this study aims to analyze how covariates-such as age, weight, gender, body surface area (BSA), cytochrome P450 (CYP) expression, race, and health status-affect the therapeutic regime of orally administered salbutamol using population PK (popPK) modeling. The final model is intended as a tool to support the selection of optimal formulation and dosage regimen based on individual patient profiles. A dataset of 40 virtual patients derived from a physiologically based PK (PBPK) model of oral salbutamol was included in the popPK model. A two-compartment model with first-order elimination and absorption, with a transit compartment, best described the plasma concentration-time profile following a 4 mg dose. Relationships were identified between gender and mean transit time (Mtt) and clearance (Cl), as well as the effects of weight and BSA on the volume of distribution of the central compartment (V1) and Cl, and a significant impact of health status on Cl. Despite current contraindications for oral salbutamol, our findings suggest that certain individuals, particularly children, may benefit from oral treatment over inhalation. We also identified individual characteristics associated with increased salbutamol toxicity risk, indicating the need for dose adjustment or alternative administration. This study further highlights the potential of popPK modeling in personalized therapy through a fully in silico approach.

Review and External Evaluation of Population Pharmacokinetic Models for Vedolizumab in Patients with Inflammatory Bowel Disease: Assessing Predictive Performance and Clinical Applicability.

Several population pharmacokinetic models of vedolizumab (VDZ) are available for inflammatory bowel disease (IBD) patients. However, their predictive performance in real-world clinical settings remains unknown. This study aims to externally evaluate the published VDZ pharmacokinetic models, focusing on their predictive performance and simulation-based clinical applicability. A literature search was conducted through PubMed to identify VDZ population pharmacokinetic models. A total of 114 VDZ concentrations from 106 IBD patients treated at the University Medical Center "Zvezdara", Republic of Serbia, served as the external evaluation cohort. The predictive performance of the models was assessed using prediction- and simulation-based diagnostics. Furthermore, the models were utilized for Monte Carlo simulations to generate concentration-time profiles based on 24 covariate combinations specified within the models. Four published pharmacokinetic models of VDZ were included in the evaluation. Using the external dataset, the median prediction error (MDPE) ranged from 13.82% to 25.57%, while the median absolute prediction error (MAPE) varied between 41.64% and 47.56%. None of the models fully met the combined criteria in the prediction-based diagnostics. However, in simulation-based diagnostics, pvcVPC showed satisfactory results, despite wide prediction intervals. Analysis of NPDE revealed that only the models by Rosario et al. and Okamoto et al. fulfilled the evaluation criteria. Simulation analysis further demonstrated that the median VDZ concentration remains above 12 μg/mL at week 22 during maintenance treatment for approximately 45-60% of patients with the best-case covariate combinations and an 8-week dosing frequency. None of the published models satisfied the combined criteria (MDPE, MAPE, percentages of prediction error within ±20% and ±30%), rendering them unsuitable for a priori predictions. However, two models demonstrated better suitability for simulation-based applications.

Population Pharmacokinetics of Trofinetide in a Pediatric Population Aged 2-4Years with Rett Syndrome.

Weight-banded trofinetide dosing improved physician- and caregiver-rated efficacy measures and had acceptable tolerability in patients aged 2‒4years (DAFFODIL study) and 5‒20years (LAVENDER study) with Rett syndrome (RTT). Selection of weight-banded dosing regimens for these studies was based on population pharmacokinetic (popPK) modeling and exposure simulations. This study applied an updated popPK model to confirm steady-state trofinetide exposures achieved in DAFFODIL patients were within target range. A popPK model was developed using data from 14 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER and DAFFODIL studies. Individual exposure measures (area under concentration-time curve over 0-12h [AUC0-12] were generated via integration of the predicted concentration-time profile for each DAFFODIL study participant based on the popPK model and individual empiric Bayesian pharmacokinetic parameter estimates. Distributions of steady-state AUC0-12 values for each body-weight group were compared against target exposure (AUC0-12 = 800‒1200µg·h/mL). Distribution and box plots of simulated steady-state AUC0-12 values achieved with the weight-banded DAFFODIL dosing regimen used in younger individuals aged 2-4years with RTT (twice daily trofinetide 5g[≥ 9 to < 12kg] or 6g [≥ 12 to < 20kg]) indicated good overlap with the target exposure range. Median steady-state AUC0-12 values for both body-weight bands fell within the target exposure range. PopPK model-based simulations confirm that the weight-banded dosing regimen used in DAFFODIL is adequate to achieve target trofinetide exposure in 2- to 4-year-olds with RTT.

Bioequivalence of cefdinir dispersible tablets in healthy Chinese subjects under fasting and fed conditions: a single-centred, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial.

Cefdinir is a broad-spectrum antibiotic with good antibacterial activity against gram-positive and gram-negative bacteria and can be used for the treatment of various sensitive bacterial infections, such as community-acquired pneumonia, urinary tract infection and gonorrhoea. Herein, a single-centred, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial with a 7-day washout was conducted to investigate the pharmacokinetics, bioequivalence and safety of cefdinir dispersible tablets and the reference formulation of cefdinir capsules in healthy Chinese volunteers. Fifty-six healthy subjects were recruited and randomly assigned to the fasting and fed groups. After a single oral dose of the test or reference formulation (0.1 g), the cefdinir concentrations in the plasma were determined via HPLC-MS/MS, and pharmacokinetic parameters were obtained from the concentration‒time profiles. Overall, 24 and 31 individuals completed the evaluation under fasting and fed conditions respectively. The mean concentration‒time profiles for both formulations were similar, and the Cmax, AUC0-t and AUC0-∞ values were entirely within the bioequivalence range of 80.00% to 125.00%. Three subjects reported 5 AEs, and 8 subjects experienced 13 AEs in the fasting and fed groups respectively, but no participants withdrew from the trial because of AEs. All adverse reactions were grade I in severity, and no serious AEs or deaths occurred. The results demonstrated that these formulations were bioequivalent in healthy Chinese subjects under fasting and fed conditions, supporting the further clinical development of cefdinir dispersible tablets. This trial was registered in the China Drug Trials Registry (registration number: CTR20210441; registration date: March 11, 2021).

Machine learning-based prediction of pharmacokinetic parameters for individualized drug dosage optimization

AbstractThis study presents a data-driven approach to predict pharmacokinetic parameters and generate concentration–time curves for a two-compartment model. The method employs inverse modelling using optimization algorithms to estimate patient-specific parameters from observed data. Machine learning techniques are then applied to solve the forward problem, enabling the prediction of concentration–time profiles for various dose levels. The study incorporates patient background characteristics to improve predictive performance, aiming to enable individualized drug dosing. Results demonstrate accurate parameter prediction and close matching of generated curves to observed data across six dose levels. This approach offers a novel framework for personalizing pharmacokinetic profiles and improving drug dosing strategies and therapeutic outcomes in clinical practice.

Dynamic In Vitro PK/PD Infection Models for the Development and Optimisation of Antimicrobial Regimens: A Narrative Review.

The antimicrobial concentration-time profile in humans affects antimicrobial activity, and as such, it is critical for preclinical infection models to simulate human-like dynamic concentration-time profiles for maximal translatability. This review discusses the setup, principle, and application of various dynamic in vitro PK/PD infection models commonly used in the development and optimisation of antimicrobial treatment regimens. It covers the commonly used dynamic in vitro infection models, including the one-compartment model, hollow fibre infection model, biofilm model, bladder infection model, and aspergillus infection model. It summarises the mathematical methods for the simulation of the pharmacokinetic profile of single or multiple antimicrobials when using the serial or parallel configurations of in vitro systems. Dynamic in vitro models offer reliable pharmacokinetic/pharmacodynamic data to help define the initial dosing regimens of new antimicrobials that can be developed further in clinical trials. They can also help in the optimisation of dosing regimens for existing antimicrobials, especially in the presence of emerging antimicrobial resistance. In conclusion, dynamic in vitro infection models replicate the interactions that occur between microorganisms and dynamic antimicrobial exposures in the human body to generate data highly predictive of the clinical efficacy. They are particularly useful for the development new treatment strategies against antimicrobial-resistant pathogens.