Population Pharmacokinetic Model Research Articles

Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV-Infected Patients with Moderate-to-Severe Renal Impairment.

Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration-time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM.

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.

Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA.

The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described. Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored. A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target. Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

Population Pharmacokinetic and Pharmacodynamic of Atorvastatin in Chinese Lung Transplant Recipients.

Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase to reduce lipid levels. This study aimed to establish a population pharmacokinetic and pharmacodynamic model for atorvastatin in Chinese lung transplant recipients (LTRs), particularly those using voriconazole (VOR) and with different genotypes. It evaluated precise dosing regimens and analyzed the correlation between atorvastatin exposure and clinical outcomes. A nonlinear mixed-effects model was used for the population pharmacokinetic/pharmacodynamic (PK/PD) analysis. A one-compartment population PK model was developed, incorporating VOR, SLCO2A1 rs76906503, and SLC22A8 rs2187383 to assess apparent clearance and volume of distribution. LDL-C was modeled as a biomarker to evaluate atorvastatin efficacy. A Monte Carlo simulation was conducted to assess various dosing schemes and the effects of different covariates on achieving the target LDL concentration. The correlation between atorvastatin exposure and clinical outcomes was also evaluated. Results indicated that the average probability of target attainment for optimal dosing regimens across various covariate results exceeded 45.8%. Dosages of 10, 20, and 40 mg were deemed suitable for LTRs. A lower dose was recommended for LTRs taking VOR or with mutant-type genotypes to avoid overexposure and adverse reactions. The population PK/PD model offers valuable guidance for evaluating atorvastatin dosing regimens in clinical settings, particularly for LTRs using VOR and those with different genotypes.

Are We Dosing Correctly? Population Pharmacokinetics of Cefepime in Critically Ill Pediatric Patients

Abstract Background Dosing guidelines of cefepime are well defined in healthy pediatric and adult populations but have not been extensively studied in critically ill pediatric patients. Patients who are critically ill may have significant alterations in antibiotic pharmacokinetics (PK) and pharmacodynamics (PD) due to many factors. Receipt of ECMO or CRRT may further alter PK/PD due to changes in clearance and volume of distribution and the depletion of plasma proteins. Since critically ill pediatric patients are likely to receive multiple courses of antimicrobials, optimization of drug dosing and delivery is critically important for individual patient outcomes. This study will test the hypothesis that the PK of cefepime is substantially altered in critically ill pediatric patients. Methods We prospectively enrolled patients in VUMC pediatric ICUs receiving cefepime, including those receiving ECMO or CRRT. Plasma samples were collected at opportune timepoints enriched for specific PK/PD metrics. Cefepime plasma concentrations were measured by LC-MS/MS. Weight, dose, interval, and administration time were extracted from the medical record. Monolix was used to fit population PK models using one and two-compartment models with a proportional error model. Covariate modeling was performed with a priori selected covariates: ECMO, CRRT, sex, race, ethnicity, gestational age, and creatinine clearance (CrCl). The final covariate model was used to perform probability of target attainment (PTA) analysis using Monte Carlo simulation. 6,000 subjects were simulated for each dosing regimen, with 3 weight categories (≤9 kg, 9-25 kg, and >25 kg) and 2 CrCl categories (≤90 mL/min and >90 mL/min). PTA was calculated over a grid of possible MIC values based on three targets, 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC. Results Preliminary data from 84 pediatric participants receiving cefepime were analyzed. Of these, 9 received CRRT and 10 received ECMO. An average of 3 samples were collected per participant. A two compartment with proportional error model was selected as the base model. Population PK parameter estimates for the base model, base model with weight, and final covariate model were calculated. Inclusion of weight and CrCl significantly improved model fit. CRRT, ethnicity, and gestational age did significantly improve model fit, but their inclusion in the model did not provide evidence of being significantly better than the model with only weight and CrCl. The results from the PTA analysis are seen in Figure 1. We observed an overall ordering of PTA by dosing regimen across all three targets, with q8h 3-hour infusion having the highest PTA and q12h 30-minute infusion having the lowest PTA. Increased CrCl led to reduced PTA and as weight increased, PTA also increased. Conclusion This study will be among the first and largest to characterize cefepime PK in the critically ill pediatric population. Clinicians should incorporate local antibiograms with these population PK models to determine optimal dosing in critically ill pediatric patients. The use of extended infusions may be beneficial for PK/PD target achievement, particularly for resistant pathogens. Since clinical covariates affect PK parameters, this population may also benefit from therapeutic drug monitoring. Figure 1. Comparison of PTA among four dosing regimens of cefepime at targets of 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC.

Comprehensive population pharmacokinetic modelling of sugemalimab, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody, in patients with solid tumours or lymphomas across multiple Phase I-III studies.

The aim of this study was to develop a population pharmacokinetics model for sugemalimab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1), using data from Phase I-III trials and to assess clinical factors affecting sugemalimab exposure. A nonlinear mixed-effect modelling approach was employed to analyse pooled data from nine studies involving 1628 subjects to characterize the PopPK of sugemalimab. This investigation examined the influence of various covariates on sugemalimab pharmacokinetics (PK), encompassing demographics, baseline hepatic and renal function-related covariates, and others (including anti-drug antibody [ADA], combination treatment, Eastern Cooperative Oncology Group [ECOG] performance score, tumour burden and tumour type). Estimation accuracy and predictive ability of the final model were evaluated using various methods. The influence of covariates on sugemalimab exposure was assessed by simulation from the final model. A two-compartment model with first-order elimination and time-varying clearance effectively described the PK of sugemalimab. Covariate analyses revealed significant relationships between sugemalimab clearance and body weight, albumin, gender, ADA, tumour burden and tumour type. The statistically significant covariates on central volume were body weight, albumin, gender and tumour type. No significant relationships were found in the final model for age, race, alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, alkaline phosphatase, combination treatment, creatinine clearance, ECOG, renal function or hepatic function. All significant covariates demonstrated less than a 20% effect on sugemalimab exposure. The PopPK model adequately described the pharmacokinetic profile of sugemalimab with no clinically meaningful impact observed on its exposure across all covariates. Dose adjustment does not appear to be necessary.

Population pharmacokinetics of tacrolimus whole blood and peripheral blood mononuclear cell concentrations in stable kidney-transplanted patients.

Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model. We prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM. Tacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (RC:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher RC:PBMC ratios of 42.4% and 60.7%, respectively. Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies.

Therapeutic drug monitoring of linezolid in Chinese premature neonates: a population pharmacokinetic analysis and dosage optimization.

This study aimed to develop a pharmacokinetic model of linezolid in premature neonates and evaluate and optimize the administration regimen. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect the blood concentration data of 54 premature neonates after intravenous administration of linezolid, and the relevant clinical data were collected. The population pharmacokinetic (PPK) model was established by nonlinear mixed effects modeling. Based on the final model parameters, the optimal administration regimen of linezolid in premature neonates with different body surface areas (BSA) was simulated and evaluated. The pharmacokinetic properties of linezolid in premature neonates are best described by a single-compartment model with primary elimination. The population typical values for apparent volume of distribution and clearance were 0.783 L and 0.154 L/h, respectively. BSA was a statistically significant covariate with clearance (CL) and volume of distribution (Vd). Monte Carlo simulations showed that the optimal administration regimen for linezolid in premature neonates was 6 mg/kg q8h for BSA 0.11 m2, 7 mg/kg q8h for BSA 0.13 m2, and 9 mg/kg q8h for BSA 0.15 m2 with minimum inhibitory concentration (MIC) ≤1 mg/L, 7 mg/kg q8h for BSA 0.11 m2, 8 mg/kg q8h for BSA 0.13 m2, and 10 mg/kg q8h for BSA 0.15 m2 with MIC = 2 mg/L. A pharmacokinetic model was developed to predict the blood concentration on linezolid in premature neonates. Based on this model, the optimal administration regimen of linezolid in premature neonates needs to be individualized according to different BSA levels.

A loading dose of clofazimine to rapidly achieve steady-state-like concentrations in patients with nontuberculous mycobacterial disease.

Clofazimine is a promising drug for the treatment of nontuberculous mycobacterial (NTM) diseases. Accumulation of clofazimine to reach steady-state plasma concentrations takes months. A loading dose may reduce the time to steady-state-like concentrations. We evaluated the pharmacokinetics (PK), safety and tolerability of a loading dose regimen in patients with NTM disease. Adult participants received a 4-week loading dose regimen of 300 mg clofazimine once daily, followed by a maintenance dose of 100 mg once daily (combined with other antimycobacterial drugs). Blood samples for PK analysis were collected on three occasions. A population PK model for clofazimine was developed and simulations were performed to assess the time to reach steady-state-like (target) concentrations for different dosing regimens. Twelve participants were included. The geometric mean peak and trough clofazimine concentrations after the 4-week loading phase were 0.87 and 0.50 mg/L, respectively. Adverse events were common, but mostly mild and none led to discontinuation of clofazimine. Our loading dose regimen reduced the predicted median time to target concentrations by 1.5 months compared to no loading dose (3.8 versus 5.3 months). Further time benefit was predicted with a 6-week loading dose regimen (1.4 versus 5.3 months). A 4-week loading dose regimen of 300 mg once daily reduced the time to target clofazimine concentrations and was safe and well-tolerated. Extending the loading phase to 6 weeks could further decrease the time to target concentrations. Using a loading dose of clofazimine is a feasible strategy to optimize treatment of NTM disease. NCT05294146.

Immunogenicity dynamics and covariate effects after satralizumab administration predicted with a hidden Markov model.

Immunogenicity is the propensity of a therapeutic protein to generate an immune response to itself. While reporting of antidrug antibodies (ADAs) is increasing, model-based analysis of such data is seldom performed. Model-based characterization of factors affecting the emergence and dissipation of ADAs may inform drug development and/or improve understanding in clinical practice. This analysis aimed to predict ADA dynamics, including the potential influence of individual covariates, following subcutaneous satralizumab administration. Satralizumab is a humanized IgG2 monoclonal recycling IL-6 receptor antagonist antibody approved for treating neuromyelitis optica spectrum disorder (NMOSD). Longitudinal pharmacokinetic (PK) and ADA data from 154 NMOSD patients in two pivotal Phase 3 studies (NCT02028884, NCT02073279) and PK data from one Phase 1 study (SA-001JP) in 72 healthy volunteers were available for this analysis. An existing population PK model was adapted to derive steady-state concentration without ADA for each patient. A mixed hidden Markov model (mHMM) was developed whereby three different states were identified: one absorbing Markov state for non-ADA developer, and two dynamic and inter-connected Markov states-transient ADA negative and positive. Satralizumab exposure and body mass index impacted transition probabilities and, therefore, the likelihood of developing ADAs. In conclusion, the mHMM model was able to describe the time course of ADA development and identify patterns of ADA development in NMOSD patients following treatment with satralizumab, which may allow for the formulation of strategies to reduce the emergence or limit the impact of ADA in the clinical setting.

Application of machine-learning models to predict the ganciclovir and valganciclovir exposure in children using a limited sampling strategy.

Intravenous ganciclovir and oral valganciclovir display significant variability in ganciclovir pharmacokinetics, particularly in children. Therapeutic drug monitoring currently relies on the area under the concentration-time (AUC). Machine-learning (ML) algorithms represent an interesting alternative to Maximum-a-Posteriori Bayesian-estimators for AUC estimation. The goal of our study was to develop and validate an ML-based limited sampling strategy (LSS) approach to determine ganciclovir AUC0-24 after administration of either intravenous ganciclovir or oral valganciclovir in children. Pharmacokinetic parameters from four published population pharmacokinetic models, in addition to the World Health Organization growth curve for children, were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles of children. Different ML algorithms were trained to predict AUC0-24 based on different combinations of two or three samples. Performances were evaluated in a simulated test set and in an external data set of real patients. The best estimation performances in the test set were obtained with the Xgboost algorithm using a 2 and 6 hours post dose LSS for oral valganciclovir (relative mean prediction error [rMPE] = 0.4% and relative root mean square error [rRMSE] = 5.7%) and 0 and 2 hours post dose LSS for intravenous ganciclovir (rMPE = 0.9% and rRMSE = 12.4%). In the external data set, the performance based on these two sample LSS was acceptable: rMPE = 0.2% and rRMSE = 16.5% for valganciclovir and rMPE = -9.7% and rRMSE = 17.2% for intravenous ganciclovir. The Xgboost algorithm developed resulted in a clinically relevant individual estimation using only two blood samples. This will improve the implementation of AUC-targeted ganciclovir therapeutic drug monitoring in children.

Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis?

Guidelines for bacterial meningitis in children recommend intravenous ceftriaxone 50 mg/kg (max 2 g) twice daily (BD) or 100 mg/kg (max 4 g) once daily (OD), leaving the decision regarding the dose frequency to the prescriber. We investigated the cerebrospinal fluid (CSF) penetration of ceftriaxone to evaluate whether one dosing regimen is superior. Unbound ceftriaxone concentrations were measured in serum and CSF samples from children aged 0-18 years treated with ceftriaxone if there was a sample remaining after clinical tests were performed. A serum-CSF population pharmacokinetic model was developed using non-linear mixed-effects modeling. The once- and twice-daily dosing regimens were simulated, and the probability of target attainment (PTA) was determined for maintaining a CSF concentration above a minimum inhibitory concentration (MIC) of 1 mg/L for common meningitis pathogens and 4 mg/L for Staphylococcus aureus for 100% of the dosing interval. Sixteen serum and 87 CSF samples were collected from 98 children (age range 0.1-18.5 years). The final two-compartment serum-CSF model included a renal maturation function with weight scaling on clearance and volume of distribution. The estimated serum:CSF uptake was 20.1%. For MIC 1 mg/L, the 24 h PTA was higher for OD (88%) compared with BD (53%) dosing, although both achieved a 100% PTA at steady state. For S. aureus (MIC 4 mg/L), neither dosing regimen was sufficient. Our findings support the use of a 100 mg/kg once daily regimen for empirical treatment of bacterial meningitis due to earlier achievement of the pharmacodynamic target. Neither dosing regimen was adequate for S. aureus meningitis.

Dried Blood Spots Sampling and Population Pharmacokinetic Modeling for Dosing Optimization of Piperacillin in Chinese Neonates.

Piperacillin is commonly used off-label in neonates for the treatment of bacterial infections. This study aimed to assess a dried blood spots (DBS)-based microsampling strategy for supporting population pharmacokinetics and treatment optimization of piperacillin in Chinese neonates. DBS samples from neonatal patients were collected at predefined intervals. Drug blood concentrations were quantified using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling approach. The pharmacokinetic/pharmacodynamics (PK/PD) target was 75% of the time with the unbound drug plasma concentration above the minimum inhibitory concentration (fT>MIC), with a toxicity threshold of unbound drug plasma trough concentration above 64 mg/L. A total of 45 piperacillin samples from 24 neonates were collected. The pharmacokinetics of piperacillin was described using a one-compartment model with postmenstrual age (PMA) as the most significant covariate on clearance. Simulations showed that dosing regimens achieving >90% PK/PD target attainment with <10% risk of possible toxicity were: PMA 33-35 weeks (50 mg/kg q12h), 35-37 weeks (50 mg/kg q8h), and 37-41 weeks (50 mg/kg q6h). In conclusion, Using DBS sampling, we developed a population pharmacokinetic model of piperacillin in Chinese neonates, incorporating PMA to determine optimal dosing regimens.

Population pharmacokinetic model of ABL001/CTX-009 (anti-VEGF/DLL4) in adult cancer patients with solid tumor.

ABL001/CTX-009 is a bispecific antibody targeting delta-like ligand-4 and vascular endothelial growth factor A. In this study, we developed a population pharmacokinetic (PK) model of ABL001/CTX-009 in patients with solid tumors. A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study (NCT03292783). A population PK model was developed using a nonlinear mixed-effect method and was evaluated by graphical and numerical methods. Using the model, the steady-state concentrations were simulated to compare weight-based and fixed-dose regimens and to find optimal dosing intervals. The PK of ABL001/CTX-009 was well described by a two-compartment model with a parallel first-order and Michaelis-Menten elimination kinetics. Body weight was selected as a significant covariate on V1. Model evaluation results suggested that the model was adequate and robust with good precision. Simulations after administrations of fixed or weight-based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three-week administration showed comparable plasma concentrations. In conclusion, the model well described the plasma concentrations of ABL001/CTX-009 in patients with solid tumors. The simulation suggested that weight-based dose and fixed dose can provide equivalent systemic exposure.

Target-site cefiderocol pharmacokinetics in soft tissues of healthy volunteers.

Cefiderocol may potentially be used to treat skin and soft tissue infections (SSTIs). However, the pharmacokinetics of cefiderocol in human soft tissues have not yet been determined. The objective of the present PK study was to investigate whether target-site concentrations of cefiderocol are sufficiently high for the treatment of SSTIs. In this pharmacokinetic study, a single intravenous dose of 2 g cefiderocol was administered to eight healthy male volunteers. Drug concentrations were determined in plasma, muscle and subcutis over 8 h. Free plasma concentrations were calculated using the plasma protein binding determined with ultrafiltration. Free tissue concentrations were obtained using microdialysis. Penetration ratios were calculated as AUC0-8h_free_tissue/AUC0-8h_free_plasma. A population pharmacokinetic model was developed, and the probability of target attainment (PTA) was determined using Monte Carlo simulations. Cefiderocol showed good tissue penetration, with mean penetration ratios ± standard deviation of 0.99 ± 0.33 and 0.92 ± 0.30 for subcutis and muscle, respectively. Cefiderocol pharmacokinetics in plasma were best described with a two-compartment model, and tissue concentrations were described by scaling the tissue concentrations to concentrations in the peripheral compartment of the plasma model. For a thrice-daily regimen with 2 g doses intravenously infused over 3 h, PTA was ≥90% for MIC values up to 4 mg/L, both based on free plasma and soft tissue pharmacokinetics. This study indicates that a dose of 2 g cefiderocol achieves concentrations in plasma considered sufficient for treating relevant bacterial species. Assuming a comparable PK/PD target for soft tissues, sufficiently high concentrations would also be achieved in soft tissues.

Modeling the Impact of Ensitrelvir on SARS-CoV-2 Dynamics and Its Application for Assessment of Transmission Mitigation of Patients with COVID-19.

Mathematical modeling can provide quantitative understanding of the viral dynamics and viral reduction effects of drugs and enable simulations of the dynamics in various scenarios. In this study, a drug effect model of ensitrelvir was developed to describe the viral reduction effect. Using the model, we also estimated the impact of treatment with ensitrelvir on the reduction in the number of infected patients at the population level in Japan. The drug effect model of ensitrelvir was developed based on a viral dynamic model for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a population pharmacokinetic model of ensitrelvir using 10,477 samples of viral load from 1447 patients with coronavirus disease 2019 (COVID-19) in a phase 2/3 study. It was assumed that the drug effect on SARS-CoV-2 promoted the viral clearance depending on the free plasma concentrations. We estimated the impact of ensitrelvir treatment on the reduction in the number of infected patients at the population level in Japan using the susceptible-infectious-recovered-susceptible (SIRS) model including transmission mitigation. The viral reduction effect of ensitrelvir was characterized as a promotion of viral clearance depending on the plasma ensitrelvir concentrations using the Emax model. The maximum reduction effect was considered to depend on the time from symptom onset to treatment. The maximum transmission mitigation effect was observed when treatment was initiated within 12-24h of symptom onset, and secondary infections could be reduced by administering ensitrelvir as soon as possible after symptom onset. The viral reduction by ensitrelvir could be characterized based on the viral dynamics, and the dynamics could be estimated using the drug effect model. Furthermore, the drug effect on population level transmission based on the dynamics could be estimated. Thus, the simulation could be conducted for various conditions.

Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer.

Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers. A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks. A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics. The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model. NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

6461 VRDN-003, A Full Antagonist Antibody To The IGF-1 Receptor For Thyroid Eye Disease (TED): Safety And Pharmacokinetic Results Of Subcutaneous Administration In Healthy Volunteers

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. B. Dickinson: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. A. Matthew: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. J. Vijayaraghavan: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. C. Michalsky: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. V. Bedian: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. Introduction: While VRDN-001 is a full antagonist antibody to the IGF-1 receptor (IGF-1R) with phase 2 proof-of-concept data showing clinically meaningful improvements in thyroid eye disease (TED) symptoms after 2 intravenous (IV) infusions, VRDN-003 is a next-generation half-life extended version of VRDN-001. VRDN-003’s half-life extension has the potential to provide sustained pharmacokinetics (PK) and pharmacodynamics (PD) with less frequent administration. We present results from an ongoing study to assess the safety, PK, PD, and bioavailability of VRDN-003 for subcutaneous (SC) administration. Methods: Healthy volunteers (HVs) were randomized to receive a single dose of VRDN-003 or placebo in the following 4 IV or SC dose cohorts: IV 5.0 mg/kg, IV 15.0 mg/kg, SC 300 mg, or SC 600 mg. Preliminary treatment-emergent adverse events (AEs) were assessed through December 12, 2023, and will continue to be assessed through study exit (120 days). Preliminary PK parameters including bioavailability were assessed by noncompartmental analysis, and a 2-compartment Population PK model was employed to simulate exposures following repeat SC dosing. Results: Twenty-eight HVs received either VRDN-003 IV (n=8), VRDN-003 SC (n=12), placebo IV (n=4), or placebo SC (n=4). AEs were reported by 25% (2/8) of participants who received VRDN-003 IV, 25% (3/12) who received VRDN-003 SC, and 13% (1/8) who received placebo. Of the AEs, 3 were deemed treatment related, all occurring in VRDN-003 SC-treated patients and all grade 1/mild as follows: injection site reaction, insomnia, and hepatic enzyme increased. No serious AEs were reported. VRDN-003 half-life was estimated at 40-50 days, 4-5 times longer than VRDN-001; bioavailability is currently estimated to be approximately 60% after SC administration. Simulated dosing regimens show the potential for VRDN-003 to be administered SC Q4W or Q8W and reach exposure levels observed with the VRDN-001 parent molecule in its prior phase 2 study. Conclusions: A single dose of VRDN-003 administered IV or SC to HVs was well tolerated and showed favorable PK for SC administration including a half-life of 40-50 days, 4-5 times longer than its parent molecule, VRDN-001. These results show the potential for VRDN-003 SC dosing regimens with the goal of reducing the treatment burden associated with achieving IGF-1R blockade in TED. Safety and efficacy of VRDN-003 SC will be further assessed in planned clinical studies enrolling patients with TED. Presentation: 6/1/2024

Population Pharmacokinetics Modeling and Simulation of Deutenzalutamide, A Novel Androgen Receptor Antagonist, in Patients With Metastatic Castration-Resistant Prostate Cancer.

Deutenzalutamide is a new molecular entity androgen receptor antagonist. The primary aim of this study was to develop a population pharmacokinetic model of deutenzalutamide and evaluate effects of intrinsic and extrinsic factors on pharmacokinetics. A nonlinear mixed-effects modeling approach was performed to develop the population pharmacokinetic of deutenzalutamide using data from 1 Phase I trial of deutenzalutamide. Goodness-of-fit plots, prediction-corrected visual predictive check, and bootstrap analysis were carried out to evaluate the final model. Simulation for the developed model was used to evaluate the covariate effects on the pharmacokinetics of deutenzalutamide. A 2-compartment model with first-order absorption and elimination from the central compartment was established for deutenzalutamide. The final covariate included body weight on peripheral compartment volume. This is the first research developing the population pharmacokinetic model of deutenzalutamide in patients with metastatic castration-resistant prostate cancer, and it is expected to support the future clinical administration of deutenzalutamide.

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients.

Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.