Population Pharmacokinetic Data Research Articles

Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1.

To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses. A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed. Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6mmol) by week 52. The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6years with relatively preserved kidney function.

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.

Population Pharmacokinetics of Bepirovirsen in Healthy Participants and Participants with Chronic Hepatitis B Virus Infection: Results from Phase 1, 2a, and 2b Studies.

Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis. Population PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration-time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations. Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure. This analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.

A population pharmacokinetic model using allometric scaling for baricitinib in patients with juvenile idiopathic arthritis.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight-based dosing regimens. The phase 3, randomized, double-blind, placebo-controlled withdrawal, efficacy and safety trial, JUVE-BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age-based dose cohorts were compared to concentrations from adult patients receiving 4-mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight-based posology in pediatric patients with JIA that matched the adult 4-mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2-compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2-mg QD for patients 10 to <30 kg and 4-mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight-based dosing in pediatric patients with JIA.

Population pharmacokinetic modeling of levodropropizine: extended application to comparative analysis between commercial formulations and exploration of pharmacokinetic effects of diet.

Levodropropizine, a nonopioid antitussive agent, is being increasingly used in clinical practice with the development of several formulations for symptomatic relief of acute and chronic bronchitis. However, scientific and quantitative population pharmacokinetic analyses of levodropropizine are lacking. Moreover, no integrated quantitative comparison has been performed between formulations. This study quantitatively evaluated and predicted pharmacokinetic properties of formulations through population pharmacokinetic model-based comparisons of commercially available formulations. Plasma concentration profile results from bioequivalence studies of 60-mg immediate release (IR) levodropropizine tablets in 40 healthy Korean males were used as population pharmacokinetic modeling data. For interindividual variability in levodropropizine pharmacokinetics, body surface area was identified as an effective covariate that was positively correlated with peripheral compartment distribution volume. Population pharmacokinetic model for IR tablets well-described the levodropropizine syrup and capsule datasets, suggesting no significant differences in pharmacokinetics among IR tablets, syrups, and capsules of levodropropizine. In contrast, pharmacokinetic profiles differed between 90-mg controlled release (CR) and IR levodropropizine tablets; however, separate parameter estimation was possible by applying the same model structure. In terms of pharmacokinetics, twice-daily regimen of 90-mg CR tablets was equivalent to thrice-daily regimen of 60-mg IR tablets. However, at steady-state, interindividual plasma concentration variability within population was reduced by approximately 36.71-83.18%. For levodropropizine CR tablets, a high-fat diet significantly delayed gastrointestinal absorption but maintained overall plasma exposure equivalent. This study provides useful quantitative judgment data for precision medicine of levodropropizine and can be helpful in predicting the pharmacokinetics of levodropropizine based on commercialized formulation switching.

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study.

Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited population pharmacokinetic (PPK) data are available for pediatric HSCT patients. This study aimed to develop a PPK model and recommend optimal oral MMF dosage in pediatric HSCT patients. This prospective study involved pediatric HSCT patients at a tertiary academic institution. Patients received oral MMF 15-20 mg/kg twice daily for aGVHD prophylaxis and treatment. The PPK analysis was conducted using a nonlinear mixed-effects modeling method. Simulation was performed considering different body surface areas (BSAs) (0.5 m2, 1.0 m2, 1.5 m2) and dosing (400 mg/m2, 600 mg/m2, 900 mg/m2 twice daily). Based on the simulation, an optimal dosage of oral MMF was suggested. A total of 20 patients and 80 samples were included in the PPK model development. A one-compartment model with first-order absorption adequately described the pharmacokinetics of mycophenolic acid (MPA). BSA was a statistically significant covariate on Vd/F. Simulation suggested the optimal dosage of oral MMF as 900 mg/m2 twice daily, respectively. A reliable PPK model was developed with good predictive performance. This model-informed optimal MMF dosage in pediatric HSCT patients can provide valuable dosing guidance in real-world clinical practice.

Clinical Factors Associated with Cytokine Release Syndrome and Dosing Recommendations for Restarting Elranatamab Following an Interruption

BACKGROUND In the MagnetisMM-3 (NCT04649359) study, elranatamab (ELRA) administered at a dose of 76 mg once-weekly (QW) with 2 step-up priming doses of 12 mg on day 1 and 32 mg on day 4 had a manageable safety profile, with 56.3% of patients developing cytokine release syndrome (CRS) and 98.8% of events occurring with the first 3 doses. Here, we report clinical factors associated with CRS and dosing recommendations for restarting treatment after dose interruptions in patients with relapsed or refractory multiple myeloma (RRMM) undergoing treatment with ELRA. METHODS Eligible patients received ELRA subcutaneously in step-up priming doses of 12 and 32 mg on days 1 and 4 of cycle 1, respectively, followed by 76 mg of ELRA QW. CRS events were graded according to the criteria of the American Society for Transplantation and Cellular Therapy and managed according to published guidelines. Multivariable analyses were performed to identify clinical factors associated with CRS. Baseline factors (extramedullary disease by BICR, prior antibody-drug conjugate, prior CAR-T, number of prior lines of therapy [≤5, &amp;gt;5], sex, and age [continuous variable]) were included in the model for CRS after the initial dose, and only post-baseline factors (time to previous CRS and time to initial tocilizumab use) were included in the model for CRS after the second dose. A previously described population pharmacokinetic (PK) model was used to simulate different interruption scenarios and determine how long it takes for ELRA exposure to drop below the threshold associated with CRS events (Hibma J, et al. Poster presented at PAGE 31 2023 [abstract 10648]). The data used to develop this model was collected from the following open-label elranatamab trials: MagnetisMM-1 (NCT03269136; phase 1), MagnetisMM-2 (NCT04798586; phase 1), MagnetisMM-3 (NCT04649359; phase 2), and MagnetisMM-9 (NCT05014412; phase 1/2). Of 183 patients who were treated in MagnetisMM-3 with the 2 step-up priming dosing, 106 patients (57.9%) experienced CRS, 43.7% grade 1, 13.7% grade 2, and 0.5% grade 3. Tocilizumab was used to manage CRS. Of the 130 CRS events, 37 (28.5%; 20 grade 1 and 17 grade ≥2) were treated with tocilizumab, and 93 (71.5%; 82 grade 1 and 11 grade ≥2) were not. After the initial elranatamab dose, 79/183 patients had CRS. The presence of extramedullary disease was predictive of a decreased risk of CRS after the initial dose. Of the 180 who received a second elranatamab dose, 35 had CRS afterwards. In a multivariable model also adjusting for CRS after the initial dose, prior tocilizumab use was predictive of a decreased risk of CRS after the second dose. After receiving doses of 76 mg of ELRA, 16 instances of dose delays lasting &amp;gt;6 to ≤12 weeks were observed. In most of these instances (11/16; 68.8%), patients did not repeat the 32-mg step-up dose. In 5 instances, patients restarted treatment with 32 mg of ELRA. No patients experienced CRS after retreatment. For the 4 instances of dose delays lasting &amp;gt;12 weeks after a 76-mg dose, patients repeated the 32-mg step-up dose in 2 instances, and patients received &amp;gt;32 mg ELRA after the interruption in the other 2 instances, with none experiencing CRS after retreatment. With dose delays of 6-12 weeks, ELRA exposure decreases below the C max after a 32-mg dose but not less than that for the 12-mg dose. With dose delays &amp;gt;12 weeks, ELRA exposure decreases below the C max after a 12-mg dose. To minimize the risk of CRS events after dose interruptions, clinical and PK data and modeling were used to develop recommendations for restarting therapy (Figure). CONCLUSIONS Extramedullary disease and use of tocilizumab were associated with a decreased risk of CRS. Based on clinical and PK data and modeling, it is recommended that patients receiving 76 mg ELRA who then experience dose delays lasting 6-12 or &amp;gt;12 weeks should restart treatment at doses of 32 or 12 mg, respectively.

Population Pharmacokinetics (PopPK) and Exposure-Response (E-R) Analyses for Belantamab Mafodotin Monotherapy in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Enrolled in DREAMM-2 and DREAMM-3

Background: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate (ADC) with a humanized afucosylated anti-BCMA monoclonal antibody (mAb) conjugated to a cytotoxic payload (microtubule-disrupting agent monomethyl auristatin F [MMAF]) by a protease-resistant maleimidocaproyl (mc) linker. This ADC binds to BCMA and induces cell death by direct cell killing and immune-mediated mechanisms. The DREAMM-2 trial (NCT03525678) showed rapid, deep, and durable responses to single-agent belamaf in patients with RRMM. The Phase 3 DREAMM-3 trial (NCT04162210) evaluated single-agent belamaf vs. pomalidomide plus low-dose dexamethasone in patients with RRMM at second relapse or later (Weisel et al., J Clin Oncol 41, 2023 [suppl 16; abstr 8007]); DREAMM-3 did not meet its primary endpoint on superiority for progression free survival (PFS). The present analysis evaluated the PopPK of the ADC and cytotoxin cysteine-mcMMAF (cys-mcMMAF) as well as the E-R relationships for key efficacy and safety endpoints to contribute to further understanding of belamaf. Methods: Patients with RRMM were administered intravenous (IV) doses of belamaf 2.5 or 3.4 mg/kg Q3W in DREAMM-2 (n=218) and 2.5 mg/kg Q3W in DREAMM-3 (n=217). Previously built PopPK models of ADC and cys-mcMMAF were updated and used to predict individual Cycle 1 exposure measures for the E-R analyses performed on the DREAMM-3 belamaf arm only. Exposure-efficacy analyses evaluated the probability of response (PoR), PFS, and time to response (TTR). Exposure-safety analyses evaluated the probability of occurrence of adverse events of special interest such as changes in best corrected visual acuity (BCVA), grade ≥2 or ≥3 corneal events, grade ≥3 thrombocytopenia and infusion-related reactions (IRR). Logistic regression models were used to assess event probabilities, while Cox proportional-hazard models were used to assess time to event endpoints. Stepwise covariate analyses were performed. Results: The PopPK data were described well by two-compartment models with linear elimination. The ADC model included time-varying clearance and the cys-mcMMAF model included decreasing MMAF:mAb ratio after each dose. ADC clearance was reduced on average by 30% over the first 5 months on treatment. The PopPK of ADC and cys-mcMMAF were both influenced by disease-related factors (baseline concentrations of soluble BCMA [sBCMA], immunoglobulin G, and albumin), as well as body weight and to a lower extent body mass index. Mild to severe renal impairment, mild hepatic impairment, age, race (Black or Asian), or prior therapies were not found to impact the PopPK of belamaf. Cycle 1 ADC average concentrations (C avg) were inversely correlated with disease burden factors and highly correlated (r=0.97) with ADC trough concentration (C tau). In DREAMM-3, PoR and PFS were higher and longer with higher ADC exposure when evaluated independently of other covariates. In the final model, PoR and PFS were respectively lower and shorter with higher baseline sBCMA or prior anti-CD38 mAb treatment; PoR was also related to presence of extra medullary disease. TTR was not related to ADC exposure or other factors. Safety endpoints were associated with exposure. Higher ADC C avg was associated with higher probability of developing grade ≥2 or ≥3 corneal events and inversely associated with time to their onset. ADC C avg was similarly associated with changes in BCVA but with a lower intercept for BCVA-related endpoints. Baseline sBCMA was inversely associated with probability of grade ≥2 corneal events. Lower baseline platelet count (but not ADC exposure) was associated with increased probability of grade ≥3 thrombocytopenia. ADC C avg was inversely associated with probability of IRR. In addition, the observed incidence of post-treatment anti-belamaf antibodies was low (&amp;lt;1%) with no observed impact on PK, efficacy, or safety. Conclusion: PopPK and E-R analyses for DREAMM-3 demonstrated the impact of disease factors and patient characteristics on PK, efficacy, and safety endpoints following single-agent belamaf, consistent with prior results for later-line populations.

Abstract 16208: Population Pharmacokinetics of Intravenously and Orally Administered Sotalol in Patients With Cardiac Arrhythmias

Introduction: Recently, an intravenous (IV) formulation of sotalol was approved to provide a loading dose before initiating oral sotalol therapy to reduce hospitalization days. However, the population pharmacokinetics (PK) of sotalol after administration of an IV loading dose regimen in patients with atrial fibrillation were not characterized. Understanding the PK of IV sotalol loading dose in patients with atrial fibrillation is required to ensure safety and optimal therapeutic outcomes. Hypothesis: The population PK model of IV and orally administered sotalol can be developed using data from two clinical PK studies with reasonable empirical Bayes estimates (EBEs) of PK parameters absorption rate constant (Ka), clearance (CL), and volume of distribution (Vd). Methods: The PK dataset of sotalol was from: 1) Relative bioavailability study with IV and oral sotalol PK data by sponsor AltaThera Inc., 2) Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) registry study. Population PK was evaluated using NONMEM® 7.5, Perl-speaks-NONMEM (PsN®) version 5.3.0. Results: 545 sotalol concentrations in 25 patients were analyzed. A one-compartment model with a first-order elimination rate best described the data (Figure 1). The data correlated QTc interval levels within the observed sotalol concentration range (1.2 to 1900 ng/mL) were below 500 ms. In the final model, the EBE’s of sotalol PK parameters were, Ka - 1.44 hr -1 , CL 0.46 - L/h/kg, and the Vd -5.6 L/kg. Further PK/PD studies are needed to establish the correlation between sotalol PK and safety in this population. Conclusions: The PK of sotalol after IV and oral doses were adequately described using a population PK modeling approach. The QTc levels correlated to the plasma concentrations in this study were within the safety limit of 500 ms. This population PK model could be used to correlate the PK with safety (QTc interval prolongation) further to optimize the sotalol IV and oral dosing regimen.

Non-compartmental and population pharmacokinetic analysis of dapsone in healthy NIGERIANS: A pilot study.

Dapsone is employed for both non-dermatological and dermatological indications but with non-existent population pharmacokinetics (popPK) data in Nigerians. This study was therefore designed to develop a popPK model in Nigerians. Non-compartmental analysis and nonlinear mixed effects modelling were utilized for data analysis. Eleven participants administered 50 mg dapsone tablet were included in the analysis. Derived pharmacokinetic parameters were: Cmax = 1.16 ± 0.32 μg/mL, Tmax = 3.77 ± 2.40 h, and t1/2z = 30.23 ± 11.76 h. PopPK model parameter estimates with inter-individual variability were Tlag = 0.40 h (10.0%, fixed); ka = 1.78 h-1 (75.9%); V/F = 89.25L (21.6%); and Cl/F = 1.32 Lh-1 (27.7%). Sex was significantly associated with Cl/F, and body weight with V/F. Best popPK model was one-compartment with lag time, and first-order absorption and elimination. Sex and body weight significantly influenced the clearance and distribution volume of dapsone respectively.

Population Pharmacokinetics of Ranibizumab Delivered via the Port Delivery System Implanted in the Eye in Patients with Neovascular Age-Related Macular Degeneration.

The port delivery system with ranibizumab (PDS) is designed to continuously deliver ranibizumab to maintain therapeutic drug concentrations in the vitreous of the eye for an extended duration. The PDS has been evaluated for the treatment of neovascular age-related macular degeneration in the Ladder (PDS 10, 40, and 100mg/mL, with refill exchanges as needed, versus monthly intravitreal ranibizumab 0.5mg), Archway (PDS 100mg/mL with 24-week refill exchanges, versus monthly intravitreal ranibizumab 0.5mg), and ongoing Portal (PDS 100mg/mL with 24-week refill exchanges) clinical trials. Data from Ladder, Archway, and Portal were used to develop a population pharmacokinetics (PK) model to estimate the ranibizumab release rate from the PDS implant, describe ranibizumab PK in serum and aqueous humor, and predict the concentration in vitreous humor. A model was developed to adequately describe the serum and aqueous humor PK data, as suggested by goodness-of-fit plots as well as visual predictive checks. In the final model, the first-order implant release rate was estimated to be 0.00654 (1/day), corresponding to a half-life of 106days, consistent with the implant release rate determined invitro. The model-predicted vitreous concentrations achieved with PDS 100mg/mL given every 24weeks were below the intravitreal peak concentration and above the intravitreal trough concentration of ranibizumab over the entire 24-week refill interval. The results demonstrate a durable release of ranibizumab from the PDS with a half-life of 106days, providing vitreous exposure to ranibizumab for at least 24weeks that is within the range of exposure for monthly intravitreal treatment.

Generating immunogenomic data-guided virtual patients using a QSP model to predict response of advanced NSCLC to PD-L1 inhibition

Generating realistic virtual patients from a limited amount of patient data is one of the major challenges for quantitative systems pharmacology modeling in immuno-oncology. Quantitative systems pharmacology (QSP) is a mathematical modeling methodology that integrates mechanistic knowledge of biological systems to investigate dynamics in a whole system during disease progression and drug treatment. In the present analysis, we parameterized our previously published QSP model of the cancer-immunity cycle to non-small cell lung cancer (NSCLC) and generated a virtual patient cohort to predict clinical response to PD-L1 inhibition in NSCLC. The virtual patient generation was guided by immunogenomic data from iAtlas portal and population pharmacokinetic data of durvalumab, a PD-L1 inhibitor. With virtual patients generated following the immunogenomic data distribution, our model predicted a response rate of 18.6% (95% bootstrap confidence interval: 13.3-24.2%) and identified CD8/Treg ratio as a potential predictive biomarker in addition to PD-L1 expression and tumor mutational burden. We demonstrated that omics data served as a reliable resource for virtual patient generation techniques in immuno-oncology using QSP models.

In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model.

Cefditoren, the active form of cefditoren pivoxil, is an oral cephalosporin antimicrobial drug. Although cefditoren exhibits high antimicrobial activity against Streptococcus pneumoniae, its pharmacokinetics/pharmacodynamics (PK/PD) characteristics remain unknown. This study aimed to determine its PK/PD parameter with target values for cefditoren against S. pneumoniae in S. pneumoniae lung-infected mice and to simulate MIC range of S. pneumoniae that can be expected to be treated at approved cefditoren doses in human using population pharmacokinetic (PPK) data from patients. Susceptibility testing and time-kill assays against S. pneumoniae ATCC® 49619 were performed for in vitro PD evaluation. Based on the results of a PK study in healthy mice and PD studies in S. pneumoniae lung-infected mice, optimal PK/PD parameters were determined using the correlation curve between the PK/PD parameters and lung bacterial count changes. The target value was calculated to achieve a 2 log10 reduction in the lung bacterial counts. In vitro PD evaluation showed that cefditoren had a potent antimicrobial effect against S. pneumoniae in a time-dependent manner at concentrations above the MIC. In PK/PD analyses, both fAUC24/MIC and fCmax/MIC were well correlated with bactericidal efficacy, achieving 2 log10-kill with fAUC24/MIC ≥ 63 and fCmax/MIC ≥ 16. Cefditoren pivoxil has good therapeutic efficacy against acute pneumonia caused by S. pneumoniae with a MIC ≤ 0.031-0.063mg/L at approved doses in adults and children.

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.

Relationship between decrement time and recovery time in pediatric total intravenous anesthesia with propofol and remifentanil.

Propofol target-controlled infusion is now used in many countries for the administration of total intravenous anesthesia (TIVA) and uses population pharmacokinetic data incorporated into the target-controlled infusion pump to administer a dose which will achieve a target concentration selected by the practitioner. Modern target-controlled infusion pumps can include an estimate of how long it will take for the plasma propofol concentration to fall to a value programmed into the pump, once the propofol infusion is stopped. This is known as decrement time. Many users consider decrement time to be equivalent to recovery time for the patient, despite the several assumptions that makes. To determine if the decrement time estimated by the target-controlled infusion pumps at the end of anesthesia could be reliably used to predict recovery time for individual patients. Target-controlled infusion pumps at Birmingham Children's Hospital are programmed with a propofol decrement concentration of 1.5 μg.mL-1 . Patients for a variety of surgical procedures were anesthetised with propofol-remifentanil TIVA. Eye opening was used as a surrogate of recovery time. Data were analyzed using median absolute deviation, Mann-Whitney U test, and linear regression to see if there was any correlation with decrement time and recovery time, total dose of propofol administered, duration of anesthesia and patient age. A total of 55 patients were audited. Median age was 7.2 years (range 0.9-15.9), and median weight was 26 kg (range 8.5-77). Median decrement time was 11.8 min (IQR 8.3-21), while median recovery time was 15 min (IQR 9-20). Recovery time was the same as decrement time in 2% of patients, less than in 40% of patients and more in 58% of patients. Two thirds of patients opened eyes at an estimated plasma propofol concentration between 1.2 and 1.8 μg.mL-1 . The median absolute deviation for the difference between decrement time and recovery time was 5.7 min, from a median of 1 min. Analysis demonstrated there was no statistical correlation between decrement time to 1.5 μg.mL-1 and recovery time, age, total propofol dose administered, or duration of anesthesia, for individual patients. There was variation between decrement time to 1.5 μg.mL-1 and recovery time of over 5 min in nearly half of patients. Decrement time to 1.5 μg.mL-1 must be used with caution when trying to predict recovery time for individual patients following TIVA.

Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant

Bezlotoxumab is approved for prevention of recurrent Clostridioides (Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI who are at high risk for recurrent CDI. Previous studies have shown that although serum albumin levels are an important predictor for bezlotoxumab exposure, this has no clinically meaningful impact on efficacy. This pharmacokinetic modeling study assessed whether hematopoietic stem cell transplant (HSCT) recipients, at increased risk of CDI and exhibiting decreased albumin levels within the first month posttransplant, are at risk of clinically relevant reductions in bezlotoxumab exposure. Observed bezlotoxumab concentration-time data pooled from participants in Phase III trials MODIFY I and II (ClinicalTrials.gov identifiers NCT01241552/NCT01513239) and three Phase I studies (PN004, PN005, and PN006) were used to predict bezlotoxumab exposures in two adult post-HSCT populations: A Phase Ib study of posaconazole including allogeneic HSCT recipients (ClinicalTrials.gov identifier NCT01777763; posaconazole-HSCT population); and a Phase III study of fidaxomicin for CDI prophylaxis (ClinicalTrials.gov identifier NCT01691248; fidaxomicin-HSCT population). The bezlotoxumab PK model used the minimum albumin level for each individual in post-HSCT populations to mimic a "worst-case scenario." Predicted worst-case bezlotoxumab exposures for the posaconazole-HSCT population (N=87) were decreased by 10.8% versus bezlotoxumab exposures observed in the pooled Phase III/Phase I data set (N=1587). No further decrease was predicted for the fidaxomicin-HSCT population (N=350). Based on published population pharmacokinetic data, the predicted decrease in bezlotoxumab exposure in the post-HSCT populations is not expected to have a clinically meaningful effect on bezlotoxumab efficacy at the recommended 10 mg/kg dose. Dose modification is therefore not required in the hypoalbuminemia setting expected post-HSCT.

Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady-state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2-compartment model including the effect of body weight (allometric scaling),first-order absorption and elimination, and absorption lag time. Steady-state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration-time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6-minute walking distance or incidence of ambrisentan-related adverse events in pediatric patients. The similar ambrisentan exposure and exposure-response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body-weight-based dosing in the pediatric population with PAH.

The association between UGT1A1 polymorphisms and treatment toxicities of liposomal irinotecan

Initial dose adjustment is recommended for patients with known UGT1A1∗28 homozygosity for both conventional irinotecan and liposomal irinotecan (nal-IRI). A recent population pharmacokinetic (PK) study showed that Asian patients had a lower prevalence of UGT1A1∗28 homozygosity but a significantly higher maximum blood concentration of SN-38 (SN-38 Cmax) and a higher incidence of grade ≥3 neutropenia after nal-IRI administration than Caucasian patients. The current study investigated the association of UGT1A1 polymorphisms, including the Asian prevalent UGT1A1∗6, PK and toxicities of nal-IRI-based therapy in the Asian population. A total of 162 patients with nal-IRI-based therapy and available UGT1A1∗6 and UGT1A1∗28 genotyping were included, with 82 Asian patients from six previous phase I or II studies of nal-IRI (cohort 1) and another 80 patients with nal-IRI+ 5-fluorouracil/leucovorin every 2 weeks as real-world practice in a single institute in Taiwan (cohort 2). The frequency of UGT1A1∗6 or UGT1A1∗28 homozygosity/compound heterozygosity was 9.3%, with UGT1A1∗6/∗6 in 2.5%, UGT1A1∗28/∗28 in 1.9% and UGT1A1∗6/∗28 in 4.9%. Among the 53 patients in cohort 1 with available PK data, all 7 patients with homozygosity/compound heterozygosity harbored UGT1A1∗6 and had a significantly higher level of median dose-normalized area under the concentration-time curve (AUC) and Cmax of SN-38 than those with single heterozygosity/wild type. Of the entire study population, the incidence of grade ≥3 neutropenia and diarrhea was significantly higher in patients with homozygosity/compound heterozygosity than in those with single heterozygosity/wild type, 73.3% versus 38.1% (P= 0.012, Fisher's exact test) and 33.3% versus 9.5% (P= 0.018, Fisher's exact test), respectively. The results suggest that the recommendation of a lower starting dose of nal-IRI for patients with UGT1A1∗28 homozygosity should be extended to include patients with UGT1A1∗6 homozygosity/compound heterozygosity.

593. Population Pharmacokinetic Model Development for Epetraborole and Mycobacterium avium Complex (MAC) Lung Disease Patients Using Data from Phase 1 and 2 Studies

593. Population Pharmacokinetic Model Development for Epetraborole and <i>Mycobacterium avium</i> Complex (MAC) Lung Disease Patients Using Data from Phase 1 and 2 Studies

Meropenem for children with severe pneumonia: Protocol for a randomized controlled trial.

Background: Pneumonia, caused by infection or other factors, seriously endangers the health of children. Meropenem is an effective broad-spectrum antibiotic using in the treatment of infectious diseases. In the therapy of pneumonia, meropenem is mostly employed for the treatment of moderate to severe pneumonia. Previously, we established a population pharmacokinetics (PPK) model for meropenem in pediatric severe infection and simulated the control rate of the time during which the free plasma concentration of meropenem exceeds the minimum inhibitory concentration (MIC) is 70% of the dosing interval (70% fT > MIC). Therefore, we plan to conduct a multicenter randomized controlled trial (RCT) to compare the efficacy and safety between conventional regimen and model regimen for meropenem in pediatric severe pneumonia. Methods: One hundred patients (aged 3months to 15years) will be recruited in this RCT. They will be assigned randomly (at a 1:1 ratio) to a conventional treatment group (20mg/kg, q8h, with 0.5-1h infusion) and a model treatment group (20mg/kg, q8h, with 4h infusion). The primary outcome will be 70% fT > MIC. Secondary outcomes will be the prevalence of meropenem therapy failure, duration of antibiotic therapy, changes in levels of inflammatory indicators, changes in imaging examination results, and prevalence of adverse events. Ethical approval of our clinical trial has been granted by the ethics committee of Beijing Children's Hospital ([2022]-E-133-Y). This trial has been registered in the Chinese Clinical Trial Registry (ChiCTR2200061207). Discussion: Based on our previous PPK data, we have designed this RCT. It is hoped that it will promote rational use of antibacterial drugs in children suffering from severe pneumonia. Clinical Trial Registration: http://www.chictr.org.cn identifier, ChiCTR2200061207.