Pharmacokinetic-pharmacodynamic Relationships Research Articles

P-1241. Cefepime Pharmacodynamics Against Pseudomonas aeruginosa Evaluated in a Chemostat Infection Model: Do Generalized Cephalosporin Targets Translate?

Abstract Background Cefepime (FEP) is used widely to treat infections caused by susceptible strains of Pseudomonas aeruginosa. However, nonclinical pharmacokinetic-pharmacodynamic (PK/PD) relationships for this drug-bug combination are not fully characterized. An in vitro chemostat (CS) model was used to assess the translatability of broadly established cephalosporin PK/PD targets to support development of FEP combined with taniborbactam (TAN), a novel serine- and metallo-β-lactamase inhibitor.Table.Antimicrobial susceptibility testing results and summary of cefepime pharmacodynamics against strains evaluated in the chemostat (CS) modelAR, denotes strains sourced from the CDC & FDA Antimicrobial Resistance Isolate Bank; FTB, cefepime-taniborbactam Methods Cefepime-taniborbactam (FTB) and FEP minimum inhibitory concentrations (MIC) were determined by reference broth microdilution (BMD) against P. aeruginosa isolates with no known acquired β-lactamases (N=6). Cefepime MICs were also assessed in 125 mL of TAN-supplemented media (4 µg/mL) to simulate CS conditions (CS MIC, Figure). In FEP dose-ranging studies in the dynamic CS model, bioreactors were inoculated with ≥ 5 log10 CFU/mL. FEP was dosed every 8 h for 24 h while media was infused to achieve a 2-h half-life. FEP concentrations were determined by a qualified bioanalytical method and used to calculate the percentage of time concentrations exceeded MIC values (T > MIC). Viable bacteria were quantified by serial dilution and plating at time points from 0 to 24 h. CS qualification was performed with Enterobacterales to confirm that the model recapitulated in vivo PD profiles reported previously by others.Figure.Schematic of the chemostat MIC (CS MIC) assay for an example strain with a CS MIC of 4 µg/mL. Results P. aeruginosa strains were FEP-susceptible (n=5) and -nonsusceptible (n=1) and BMD MICs ranged from 2 to 16 µg/mL. CS MICs were equal to (n=2), 2x (n=3), or 8x (n=1) the FTB BMD MIC (Table). All strains grew in the CS model to an average (standard deviation) bacterial burden of 7.3 (0.6) log10 CFU/mL. In composite PD models fit to dose-ranging data, change in bacterial burden from 0 to 24 h was best described by T > CS MIC versus T > BMD MIC. Reductions in bioburden were observed at T > CS MICs of 41-49% (Table). Conclusion In a dynamic in vitro model of P. aeruginosa infection, efficacious FEP exposures were similar to those established for Enterobacterales when indexed to CS MIC values. The results also indicate that differences between BMD and CS MIC should be considered when performing in vitro PK/PD profiling of discovery-phase antibacterials to prevent underestimation of therapeutic potential. Disclosures All Authors: No reported disclosures

Whole-Body Physiologically Based Pharmacokinetic Modeling of GalNAc-Conjugated siRNAs.

Background/Objectives: N-acetyl-galactosamine small interfering RNAs (GalNAc-siRNA) are an emerging class of drugs due to their durable knockdown of disease-related proteins. Direct conjugation of GalNAc onto the siRNA enables targeted uptake into hepatocytes via GalNAc recognition of the Asialoglycoprotein Receptor (ASGPR). With a transient plasma exposure combined with a prolonged liver half-life, GalNAc-siRNA exhibits distinct disposition characteristics. We aimed to develop a generic GalNAc-siRNAs whole-body physiologically based pharmacokinetic-pharmacodynamic (WB-PBPK-PD) model for describing the pharmacokinetic-pharmacodynamic (PK-PD) relationship and overall tissue distribution in the open-source platform Open Systems Pharmacology Suite. Methods: Model development was performed using published studies in mice leveraging the PK-Sim® standard implementation for large molecules with added implementations of ASGPR-mediated liver disposition and downstream target effects. Adequate model performance was achieved across study measurements and included studies adopting a combination of global and compound-specific parameters. Results: The analysis identified significant compound dependencies, e.g., endosomal stability, with direct consequences for the pharmacological effect. Additionally, knowledge gaps in mechanistic understanding related to extravasation and overall tissue distribution were identified during model development. The presented study provides a generic WB-PBPK-PD model for the investigation of GalNAc-siRNAs implemented in a standardized open-source platform.

Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study.

Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative diseases (NDD). The cyclized peptide NX210c is a thrombospondin type 1 repeat analogue derived from subcommissural organ-spondin. It exerts beneficial effects in animal models of NDD owing to its effects on neurons and endothelial cells. NX210c demonstrated a good safety profile in a single ascending dose phase 1a clinical study. The present multiple ascending dose phase 1b study was performed to evaluate the tolerability and pharmacological effects of repeated doses of NX210c in healthy elderly (age: > 55years) volunteers. This was a randomized, placebo-controlled, double-blind study (EudraCT No. 2022-002868-76), investigating safety/tolerability, pharmacokinetics, and pharmacodynamics (including blood and cerebrospinal fluid biomarkers). Participants received 5 or 10 mg/kg NX210c or placebo (10-min infusion) thrice weekly for 4 weeks in an ascending dose fashion. Follow-up was conducted 2 weeks after last dosing. The investigation included 29 participants. No serious adverse events were recorded and all adverse events were mild. Dedicated central nervous system testing did not reveal neurotoxicity. Biomarker evaluation showed a statistically significant reduction in blood claudin-5 and a trend toward reduction of blood homocysteine. In silico data modelling revealed salient pharmacokinetic-pharmacodynamic relationships, including reduction of claudin-5, neurofilament light chain, and SPARC-like protein 1 release, and degradation of homocysteine. Multiple doses of NX210c exhibited a good safety profile, showed non-cumulative pharmacokinetics, and exerted pharmacodynamic effects on biomarkers linked to BBB integrity. The effects of NX210c on claudin-5 and biomarkers influencing BBB integrity-and the overarching brain protection it offers-provide a novel therapeutic strategy targeting an underlying driver of neurodegenerative conditions for which disease-modifying treatments are limited or not available.

Alternate Sampling Matrices for Therapeutic Drug Monitoring of Immunosuppressants.

Immunosuppressant (IS) therapeutic drug monitoring (TDM) relies on measuring mostly pharmacologically inactive erythrocyte-bound and/or plasma protein-bound drug levels. Variations in hematocrit and plasma protein levels complicate interpretation of blood calcineurin inhibitor (CNI) and inhibitors of themolecular target of rapamycin (mTORi) concentrations. Variable binding of mycophenolic acid (MPA) to albumin similarly complicates its TDM in plasma. A different matrix may improve IS concentration-response relationships and better reflect exposures at sites of action. This review explores the evidence for IS TDM using peripheral blood mononuclear cell (PBMC), graft tissue, and total or unbound plasma concentrations. Tandem mass spectrometry provides the sensitivity for assessing these matrices. But several challenges must be addressed, including minimizing hemolysis during blood collection, preventing IS efflux during PBMC preparation, and determining the need for further purification of the PBMC fraction. Assessing and reducing nonspecific binding during separation of unbound IS are also necessary, especially for lipophilic CNIs/mTORi. Although TDM using PBMC or unbound plasma concentrations may not be feasible due to increased costs, plasma CNI/mTORi levels may be more easily integrated into routine TDM. However, no validated TDM targets currently exist, and published models to adjust blood CNI/mTORi concentrations for hematocrit or to predict PBMC, and total and unbound plasma IS concentrations have yet to be validated in terms of measured concentrations or prediction of clinical outcomes. Even if CNI/mTORi measurements in novel matrices do not become routine, they may help refine pharmacokinetic-pharmacodynamic relationships and improve mathematical models for TDM using whole blood. Notably, there is evidence to support measuring unbound MPA in patients with severe renal dysfunction, hypoalbuminemia, and hyperbilirubinemia, with some proposed TDM targets.

Population pharmacokinetic analyses for sulbactam-durlobactam using Phase 1, 2, and 3 data.

Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination approved in the United States for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus in adults. A population pharmacokinetic (PK) model of sulbactam-durlobactam in plasma was developed using data from eight Phase 1-3 studies. A total of 432 subjects and 8,100 plasma concentrations were available for the population PK data set. The combined model was a four-compartment (two compartments per drug) model with linear kinetics. Both renal clearance and nonrenal clearance were estimated, and total clearance was calculated as the sum of renal and nonrenal clearance. Individual renal clearances were scaled by baseline creatinine clearance. The sampling-importance-resampling analysis indicated that the parameters were estimated reliably with adequate precision. Hemodialysis (HD) and epithelial lining fluid (ELF) sub-models were developed for each analyte separately. Intermittent HD resulted in an approximately 30% decrease in the daily area under the concentration-time curve (AUC0-24) when HD was started 1 hour after the end of the infusion. Assuming protein binding estimates of 10% and 38% for durlobactam and sulbactam, respectively, ELF penetration ratios were found to be 41.3% for durlobactam and 86.0% for sulbactam. Of the statistically significant covariates of PK identified, which included body weight, body mass index, infection type, and region of origin, renal function was the only clinically relevant covariate. Overall, a robust description of the plasma PK of sulbactam and durlobactam was achieved. The resultant population PK model was expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships.

Optimizing β-lactam-containing antibiotic combination therapy for the treatment of Buruli ulcer.

The current treatment for Buruli ulcer is based on empirical evidence of efficacy. However, there is an opportunity for shortening its duration and improving response rates. Evolving understanding of the pharmacokinetic-pharmacodynamic relationships provides the basis for a stronger dose rationale for antibiotics. In conjunction with modelling and simulation, it is possible to identify dosing regimens with the highest probability of target attainment (PTA). This investigation aims to: (i) assess the dose rationale for a new combination therapy including amoxicillin/clavulanic acid (AMX/CLV) currently in clinical trials; and (ii) compare its performance with alternative dosing regimens including rifampicin, clarithromycin and AMX/CLV. In vitro estimates of the minimum inhibitory (MIC) concentration were selected as a measure of the antibacterial activity of different drug combinations. Clinical trial simulations were used to characterize the concentration vs. time profiles of rifampicin, clarithromycin and amoxicillin in a virtual cohort of adult and paediatric patients, considering the effect of baseline covariates on disposition parameters and interindividual variability in exposure. The PTA of each regimen was then assessed using different thresholds of the time above MIC. A weight-banded dosing regimen including 150-600 mg rifampicin once daily, 250-1000 mg clarithromycin and AMX/CLV 22.5mg/kg /1000 mg twice daily ensures higher PTA than the standard of care with AMX/CLV 45 mg/kg/2000 mg once daily. The higher PTA values support the proposed 4-drug combination (rifampicin, clarithromycin, AMX/CLV) currently under clinical investigation. Our findings also suggest that higher rifampicin doses might contribute to enhanced treatment efficacy.

Discovery of 6,7-Dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives as mGluR2 Negative Allosteric Modulators with In Vivo Activity in a Rodent's Model of Cognition.

Allosteric modulators of the metabotropic group II receptors, mGluR2 and mGluR3, have been widely explored due to their ability to modulate cognitive and neurological functions in mood disorders, although none have been approved yet. In our search for new and selective mGluR2 negative allosteric modulators (NAMs), series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives were identified from our published series of 1,3,5-trisubstituted pyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement in the mGluR2 NAM potency and subsequent selection of compound 11 based on its overall profile, including selectivity and ADMET properties. Further pharmacokinetic-pharmacodynamic (PK-PD) relationship built showed that compound 11 occupied the mGluR2 receptor in a dose-dependent manner. Additionally, the compound revealed in vivo activity in V-maze as a model of cognition from a dose of 0.32 mg/kg. Compound 11 was selected to be evaluated further.

Assessment of pharmacokinetics-pharmacodynamics to support omadacycline dosing regimens for the treatment of patients with acute bacterial skin and skin structure infections.

Pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy were evaluated using data from omadacycline-treated patients with acute bacterial skin and skin structure infections (ABSSSI) enrolled in two phase 3 studies. Patients received omadacycline 100 mg intravenously (IV) every 12 hours for two doses, followed by 100 mg IV every 24 hours (q24h), with the option to switch to 300 mg oral (PO) q24h after 3 days or 450 mg PO q24h for two doses, followed by 300 mg PO q24h for a total duration of 7-14 days. Clinical response was evaluated at 48-72 hours [early clinical response (ECR)], end of treatment (EOT), and 7-14 days after EOT. Using a population pharmacokinetic (PK) model and PK data from patients with Staphylococcus aureus at baseline, omadacycline free-drug plasma area under the concentration-time curve (AUC) values were determined, and the relationships between free-drug plasma AUC:MIC ratio and dichotomous efficacy endpoints were evaluated. Using these relationships, the population PK model, simulation, and an omadacycline MIC distribution for S. aureus, mean percent probabilities of response were evaluated. Statistically significant PK--PD relationships were identified for ECR (P = 0.016 and 0.013 for optimized two- and three-group free-drug plasma AUC:MIC ratios, respectively). At an MIC value of 0.5 µg/mL, percent probabilities of model-predicted success for ECR based on the univariable PK-PD relationships using continuous and two-group free-drug plasma AUC:MIC ratio variables were 91.9 and 95.6%, respectively, for the IV-to-PO dosing regimen and 89.3 and 88.4%, respectively, for the PO-only dosing regimen. These data support for omadacycline IV-to-PO and PO-only dosing regimens for ABSSSI and an omadacycline susceptibility breakpoint of 0.5 µg/mL for S. aureus.

Phase 2 pilot trial to optimise pharmacometric evaluations in Chagas disease (CHARM: CHAgas disease PharMacometrics)

Chagas disease is a neglected disease caused by Trypanosoma cruzi that currently affects about 7 million people in the Americas and the American diaspora. Only two drugs are available to treat Chagas disease, both are associated with a high incidence of adverse events, particularly in adults, and they are also complex to administer. New treatments are needed urgently, but there is no established method of evaluating new drugs. We describe the study protocol for a pilot phase 2 descriptive observational study of parasite dynamics within the host, followed by a randomised evaluation of the pharmacokinetic-pharmacodynamic properties of subcurative doses of anti-chagasic drugs in patients with chronic Chagas disease. This study is divided into three stages. The general objective of the study is to characterise the dynamics of the parasite within the host at steady state and the pharmacokinetic-pharmacodynamic relationships for each of the three drugs studied. This is based on characterising the structure and parameters of a pharmacodynamic model of parasite turnover within the host. Each stage of the study targets specific key parameters in the pharmacodynamic model of parasite dynamics (both the blood stage and the tissue stage) for individual research participants. The primary outcome measure for all three stages is blood-stage parasite density, measured by quantitative PCR. Upon completion, research participants will receive definitive treatment for Chagas disease in accordance with national guidelines. Registration ISRCTN (ISRCTN26467068; 01/07/2021).

Abstract 3338: Development of a CK2α inhibitor for treatment of wnt-driven colorectal cancer

Abstract A novel, potent and highly selective orally bioavailable small molecule inhibitor of Casein Kinase 2α (CK2α) has been developed and validated in pre-clinical models of wnt-driven colorectal carcinoma; and is poised to enter clinical development.CK2α is considered as a positive regulator of wnt signaling and tumorigenesis. The wnt pathway is known to be sensitive to and amplified by CK2α activity at multiple nodes and can be inhibited by loss of CK2α function. The human genetics of colorectal cancer (CRC) have been well characterized and approximately 80% tumors are identified as being wnt pathway mutation driven. CRC tumors can be further stratified into consensus molecular subtypes (CMS), with iCMS2 representing 37% of CRC patients, being characterized by ongoing wnt pathway upregulation. Development of CK2α inhibitors as a targeted therapy for CRC is therefore mechanistically well aligned to the wnt signaling drive and may serve as a promising therapeutic strategy for this cancer. A novel small molecule binding site on CK2α has been exploited to design and develop an inhibitor with Ki of 95 pM and exquisite selectivity over the kinome. This inhibitor has been comprehensively characterized using in vitro, ex vivo and in vivo pharmacology studies. Cellular mechanism of action studies in CRC cell lines have quantified the potency of target engagement, inhibition of known CK2α phospho-sites, inhibition of tumorigenic wnt pathway activity, and induction of apoptosis. This CK2α inhibitor was also profiled in a high content screen of CRC patient-derived organoids established from various driver mutation backgrounds. Use of these ex vivo models has validated the potent cytotoxic activity of CK2α inhibition in tumor samples with wnt-driven characteristics and highlights the potential therapeutic efficacy of CK2α inhibition in this setting. In vivo CRC xenograft studies have confirmed anti-tumor efficacy and developed the understanding of pharmacokinetic pharmacodynamic relationship between free plasma concentration of drug and inhibition of CK2α-specific biomarker in the tumor. The preclinical data presented establishes the strong rationale for clinical development of a novel CK2α inhibitor for the treatment of locally advanced or metastatic solid tumors, with an emphasis on wnt-driven CRC. Citation Format: Darren Cawkill. Development of a CK2α inhibitor for treatment of wnt-driven colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3338.

Physiologically based modeling of LNP-mediated delivery of mRNA in the vascular system

RNA therapeutics are an emerging, powerful class of drugs with potential applications in a wide range of disorders. A central challenge in their development is the lack of clear pharmacokinetic-pharmacodynamic relationship, in part due to the significant delay between the kinetics of RNA delivery and the onset of pharmacologic response. To bridge this gap, we have developed a physiologically-based pharmacokinetic/pharmacodynamic model for systemically administered mRNA-containing lipid nanoparticles in mice. This model accounts for the physiologic determinants of mRNA delivery, active targeting in the vasculature, and differential transgene expression based on nanoparticle coating. The model was able to well-characterize the blood and tissue pharmacokinetics of lipid nanoparticles, as well as the kinetics of tissue luciferase expression measured by ex vivo activity in organ homogenates and bioluminescence imaging in intact organs. The predictive capabilities of the model were validated using a formulation targeted to intercellular adhesion molecule-1 and the model predicted nanoparticle delivery and luciferase expression within 2-fold error for all organs. This modeling platform represents an initial strategy that can be expanded upon and utilized to predict the in vivo behavior of RNA-containing lipid nanoparticles developed for an array of conditions and across species.

Pharmacokinetic enhancement of oncolytic virus M1 by inhibiting JAK‒STAT pathway

Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and Cmax, and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

2532. Pharmacokinetic-Pharmacodynamic Analyses for Ceftobiprole Efficacy Based on Phase 3 Data from Patients with Staphylococcus aureus Bacteremia

2532. Pharmacokinetic-Pharmacodynamic Analyses for Ceftobiprole Efficacy Based on Phase 3 Data from Patients with <i>Staphylococcus aureus</i> Bacteremia

Pharmacokinetic-Pharmacodynamic Modeling of Midazolam in Pediatric Surgery.

Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic-pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2-17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5-120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects.

Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide administration in healthy participants.

Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing. The present study characterized the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 μg administered orally in 28 healthy participants. The plasma concentrations and subjective effects of LSD were continuously evaluated over a period of 24 h. Urine was collected during 3 time intervals (0-8, 8-16 and 16-24 h after LSD administration). Pharmacokinetic parameters were determined using compartmental modelling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modelling. Mean (95% confidence interval) maximal LSD concentrations were 1.8ng/mL (1.6-2.0) and 3.4ng/mL (3.0-3.8) after the administration of 85 and 170 μg LSD, respectively. Maximal concentrations were achieved on average after 1.7h. Elimination half-lives were 3.7h (3.4-4.1) and 4.0h (3.6-4.4), for 85 and 170 μg LSD, respectively. Only 1% of the administered dose was recovered from urine unchanged within the first 24 h, 16% was eliminated as 2-oxo-3-hydroxy-LSD. Urinary recovery was dose proportional. Mean (±standard deviation) durations of subjective effects were 9.3±3.2 and 11 ±3.7h, and maximal effects (any drug effects) were 77 ± 18% and 87 ± 13% after 85 and 170 μg of LSD, respectively. The present novel study validates previous findings. LSD exhibited dose-proportional pharmacokinetics and first-order elimination kinetics and dose-dependent duration and intensity of subjective effects. LSD is extensively metabolized and shows dose-proportional urinary recovery.

Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

Phytochemicals in Gastrointestinal Nematode Control: Pharmacokinetic-Pharmacodynamic Evaluation of the Ivermectin plus Carvone Combination.

A wide variety of plant-derived phytochemicals with anthelmintic effects have been described. Most of them have shown activity against parasites in vitro but have not been extensively explored in vivo. The aim of the current work was to study the pharmacokinetic-pharmacodynamic relationship of the combined administration of carvone (R-CNE) and ivermectin (IVM) to lambs. Three trials were conducted to evaluate the pharmacological interaction between R-CNE and IVM in lambs infected with resistant nematodes. Drug concentrations were measured in plasma, target tissues, and H. contortus by HPLC with fluorescent (IVM) and ultraviolet (R-CNE) detection. The effect of both compounds on parasites was estimated by the fecal egg count reduction. Coadministration with R-CNE significantly increased the plasma bioavailability of IVM. R-CNE showed a moderate anthelmintic effect, which was greater on the susceptible isolate of H. contortus. After the combination of R-CNE and IVM as an oral emulsion, both compounds were quantified in H. contortus recovered from infected lambs. However, R-CNE concentrations were much lower than those reported to achieve anthelmintic effects in the in vitro assays. Optimization of the pharmaceutical formulation, dose rate, and administration schedule is needed to take advantage of the intrinsic anthelmintic activity of phytochemicals.

Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics

Fexofenadine is useful in various allergic disease treatment. However, the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking. This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability. Polymorphisms of the organic-anion-transporting-polypeptide (OATP) 1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity. Therefore, modeling was performed using fexofenadine oral exposure data according to the OATP1B1- and 2B1-polymorphisms. OATP1B1 and 2B1 were identified as effective covariates of clearance (CL/F) and distribution volume (V/F)-CL/F, respectively, in fexofenadine pharmacokinetic variability. CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17- and 2.20-folds, respectively, depending on the OATP1B1 polymorphism. Among the individuals with different OATP2B1 polymorphisms, the CL/F and V/F differed by up to 1.73- and 2.00-folds, respectively. Ratio of the areas under the curves following single- and multiple-administrations, and the cumulative ratio were significantly different between OATP1B1- and 2B1-polymorphism groups. Based on quantitative prediction comparison through a model-based approach, OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability. Based on the established pharmacokinetic-pharmacodynamic relationship, the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25- and 0.87-times, respectively, and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well. This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine.

Blood, cellular, and tissular calcineurin inhibitors pharmacokinetic-pharmacodynamic relationship in heart transplant recipients: the INTRACAR study.

After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (Cblood)-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI Cblood within the therapeutic range. Other pharmacokinetic parameters, such as the intra-graft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intra-graft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intra-graft concentrations of CNI (CEMB). Cblood, and the concentration inside peripheral blood mononuclear cells (CPBMC), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the three matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. Cblood, CEMB and CPBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6 %) from 26 patients (76.5 %), all except one of low-grade. None of the PK parameters (Cblood, CEMB, CPBMC, CEMB/blood and CPBMC/blood) was associated with BPAR. In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters including Cblood, with the occurrence of BPAR. However, a trend was noticed for the CEMB and CEMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of CEMB and CPBMC for CNI TDM in HTR.

5613464 INTEGRATION OF PHARMACOKINETIC AND PHARMACODYNAMIC MODELS TO MULTI-CRITERIA DECISION ANALYSIS (MCDA) FOR PROSPECTIVE ASSESSMENT OF THE RISK-BENEFIT RATIO OF ORAL IRON CHELATORS IN PAEDIATRIC PATIENTS WITH TRANSFUSION-DEPENDENT HAEMOGLOBINOPATHIES

Background: Current therapies for the treatment of thalassaemia and other hereditary rare haemoglobinopathies are symptomatic and aim at controlling or reducing iron overload by chelation of iron from a very early age. Iron chelation ultimately prevents complications or comorbidities that can significantly reduce patient survival. Given the processes underlying iron homeostasis and current understanding of the chelation mechanism of available chelating agents, it may be possible to implement alternative, more efficient approaches for evidence generation in support of the dose rationale and their use across different populations affected by transfusion-dependent haemoglobinopathies. Aim: This study aimed to characterise the benefit-risk balance (BRB) of deferiprone in different populations, including children < 2 years old and paediatric sickle cell patients, using a nonlinear mixed effects modelling approach in conjunction extrapolation concepts and multicriteria decision analysis (MCDA). Methods: Based on the underlying pharmacokinetic-pharmacodynamic relationships as well as on the incidence of adverse events, extrapolation concepts were applied to predict the BRB of treatment in young adults, paediatric patients younger than 2 years, and paediatric sickle cell disease patients receiving deferiprone. Using individual patient-level data from a randomised controlled clinical trial (DEEP-2, EudraCT 2012-000353-31), preference elicitation methods were applied to select and prioritise endpoints or outcomes to be used in the evaluation of the BRB across the populations of interest. Subsequently, model parameter estimates obtained from each model/endpoint were used in a set of clinical simulation scenarios in which the effect of chelation therapy was evaluated during 12 months in a virtual cohort of patients. Results: Five endpoints were selected and ranked by the experts involved in the preference elicitation process (Fig.1). ‘Absence or prevention of complications (diabetes/hypothiroidism)’ and ‘occurrence of agranulocytosis’ were the most important criteria, while ‘incidence of arthralgia’ and ‘occurrence of neutropenia’ were considered less important. Clinical trial simulations revealed that the overall benefit score of deferiprone was higher for the treatment of paediatric SCD patient compared with the reference population (i.e. DEEP-2 study). Small but statistically significant differences were observed for the use of DFP in children younger than 2 years old and adolescents or young adults. Table 1 summarises the clinical and demographic baseline characteristics of the DEEP-2 study and virtual cohort of patients included in the different simulation scenarios. Conclusion: This study has shown that MCDA can be utilised in combination with modelling and simulation principles to prospectively assess the effect of interventions in subgroups of patients for which clinical data generation is challenging or not feasible. It also offers an opportunity to evaluate the implications of dose adjustment as well as changes in the clinical management of these patients, providing a less empirical basis for dose selection and treatment choices in rare paediatric conditions such as transfusion-dependent haemoglobinopathies. Table 1 - Demographics of the populations in the MCDA analysis. Reference population reflects the actual patients in the DEEP-2 study, whilst scenarios reflect the baseline characteristics from the virtual patient population. Population Age (years) Weight (kg) Blood consumption (mL/kg/year) Baseline ferritin (ng/mL) Reference population (DEEP-2 study) 8.9 (2.7-17.2) 26.5 (12.1-53.5) 155.4 (17.6-404.3) 1991 (586.2-6488.7) Scenario 1: Adolescents and young adults 17.6 (11.3-33.8) 58 (29-83.6) 139.7 (28.5-347.6) 1933 (432-10106) Scenario 2: Children < 2 years old 1.3 (0.6-1.9) 6.3 (1.1-9.3) 162.2 (21-382.9) 726.3 (253.3-1757) Scenario 3: Paediatric sickle cell patients 14.5 (12.4-17.8) 39 (30-62.4) 139.5 (23.8-338.2) 1598.4 (476.3-8993.9)