Population Pharmacokinetic Model Research Articles

Population pharmacokinetics and exposure–response relationships of maribavir in transplant recipients with cytomegalovirus infection

Maribavir is approved for management of post-transplant cytomegalovirus (CMV) infections refractory and/or resistant to CMV therapies at a dose of 400 mg twice daily (BID). Population pharmacokinetic (PopPK) and exposure–response analyses were conducted to support the appropriateness of 400 mg BID dosing. A PopPK model was developed using non-linear mixed-effects modeling with pooled maribavir plasma concentration–time data from phase 1 and 2 studies (from 100 mg up to 1200 mg as single or repeated doses) and the phase 3 SOLSTICE study (400 mg BID). Exposure–response analyses were performed for efficacy, safety, and viral resistance based on data collected in the SOLSTICE study. Maribavir PK after oral administration was adequately described by a two-compartment model with first-order elimination, first-order absorption, and an absorption lag-time. There was no evidence that maribavir PK was affected by age, sex, race, diarrhea, vomiting, disease characteristics, or concomitant use of histamine H2 blockers, or proton pump inhibitors. In the SOLSTICE study, higher maribavir exposure was not associated with increased probability of achieving CMV DNA viremia clearance, nor with reduced probability of treatment-emergent maribavir-resistant CMV mutations. A statistically significant association with maribavir exposure was identified for taste disturbance, fatigue, and treatment-emergent serious adverse events, while transplant type, enrollment region, CMV DNA level at baseline, and/or CMV resistance at baseline were identified as additional risk factors for these safety outcomes. In conclusion, the findings of these PopPK and exposure–response analyses provide further support for the recommended maribavir dose of 400 mg BID.

Selecting the Best Pharmacokinetic Models for a Priori Model-Informed Precision Dosing with Model Ensembling.

When utilizing population pharmacokinetic (popPK) models for a priori dosage individualization, selecting the best model is crucial to obtain adequate doses. We developed and evaluated several model-selection and ensembling methods, using external evaluation on the basis of therapeutic drug monitoring (TDM) samples to identify the best (set of) models per patient for a priori dosage individualization. PK data and models describing both hospitalized patients (n = 134) receiving continuous vancomycin (26 models) and patients (n = 92) receiving imatinib in an outpatient setting (12 models) are included. Target attainment of four model-selection methods was compared with standard dosing: the best model based on external validation, uninformed model ensembling, model ensembling using a weighting scheme on the basis of covariate-stratified external evaluation, and model selection using covariates in decision trees that were subsequently ensembled. Overall, the use of PK models improved the proportion of patients exposed to concentrations within the therapeutic window for both cohorts. Relative improvement of proportion on target for best model, unweighted, weighted, and decision trees were - 7.0%, 2.3%, 11.4%, and 37.0% (vancomycin method-development); 23.2%, 7.9%, 15.6%, and, 77.2% (vancomycin validation); 40.7%, 50.0%, 59.5%, and 59.5% (imatinib method-development); and 19.0%, 28.5%, 38.0%, and 23.8% (imatinib validation), respectively. The best (set of) models per patient for a priori dosage individualization can be identified using a relatively small set of TDM samples as external evaluation. Adequately performing popPK models were identified while also excluding poor-performing models. Dose recommendations resulted in more patients within the therapeutic range for both vancomycin and imatinib. Prospective validation is necessary before clinical implementation.

Evaluation and application of population pharmacokinetic models for optimising linezolid treatment in non-adherence multidrug-resistant tuberculosis patients

BackgroundPopulation pharmacokinetic (popPK) models can optimise linezolid dosage regimens in patients with multidrug-resistant tuberculosis (MDR-TB); however, unknown cross-centre precision and poor adherence remain problematic. This study aimed to assess the predictive ability of published models and use the most suitable model to optimise dosage regimens and manage compliance. MethodsOne hundred fifty-eight linezolid plasma concentrations from 27 patients with MDR-TB were used to assess the predictive performance of published models. Prediction-based metrics and simulation-based visual predictive checks were conducted to evaluate predictive ability. Individualised remedial dosing regimens for various delayed scenarios were optimised using the most suitable model and Monte Carlo simulations. The influence of covariates, scheduled dosing intervals, and patient compliance were assessed. ResultsSeven popPK models were identified. Body weight and creatinine clearance were the most frequently identified covariates influencing linezolid clearance. The model with the best performance had a median prediction error (PE%) of -1.62 %, median absolute PE of 29.50 %, and percentages of PE within 20 % (F20, 36.97 %) and 30 % (F30, 51.26 %). Monte Carlo simulations indicated that a twice-daily 300 mg linezolid dose may be more efficient than 600 mg once daily. For the ‘typical’ patient treated with 300 mg twice daily, half the dosage should be taken after a delay of ≥ 3 h. ConclusionsMonte Carlo simulations based on popPK models can propose remedial regimens for delayed doses of linezolid in patients with MDR-TB. Model-based compliance management patterns are useful for balancing efficacy, adverse reactions, and resistance suppression.

Population pharmacokinetic and dose-response models of nepadutant, a selective antagonist of the NK2 receptors, in infants with colic.

The aim of the current analyses was to develop a population pharmacokinetic model for nepadutant in infants with colic, and a pharmacokinetic-pharmacodynamic model based on observations of duration of crying and fussing following oral nepadutant administration in infants (3-25 weeks) with colic. The models were developed based on data obtained at baseline and following treatment with placebo, nepadutant 0.1mg/kg or nepadutant 0.5mg/kg administered for 7days. A continuous response variable, duration of crying and fussing in minutes within 2h interval, was assembled based on records from "baby's day" diary. The pharmacokinetics of nepadutant was described by a one-compartment model with first-order absorption and elimination with body weight as a structural covariate incorporated allometrically. For an infant weighing 5.3kg, the estimated apparent clearance was 68.6L/h (12% relative standard error) and exhibited large variability (78% coefficient of variation). The pharmacokinetic-pharmacodynamic model described (i) a circadian rhythm in the response with lowest and highest observations at 4a.m. and 9p.m., respectively, (ii) a placebo effect increasing and flattening out with time in an exponential manner, and (iii) a statistically significant (P < .01) linearly increasing response with dose. The observed and model predicted relative change in response from baseline was -35% and -28% (95% prediction interval -36%; -19%) following placebo, and -44% and -36% (-46%; -27%) after 0.5mg/kg. Population pharmacokinetic and dose-response models were successfully developed characterizing the available nepadutant pharmacokinetics and duration of crying and fussing data in infants.

Population pharmacokinetic analysis and dosing optimization of colistin sulphate in lung transplant recipients with pneumonia: A prospective study

ObjectiveCurrently, there is a lack of information on the clinical pharmacokinetics (PK), effectiveness, and safety of colistin sulphate (CS) in lung transplant recipients. This study aims to improve CS dosing regimens and evaluate its population PK in lung transplant recipients. MethodsThis study evaluated the clinical efficacy, microbiological efficacy, and adverse events of CS in lung transplant recipients. The NONMEM program was employed to construct the population PK model, and Monte Carlo simulations were executed to establish dosing regimens according to the probability of target attainment (PTA). ResultsThe study included 146 CS concentrations, spanning from 0.05 to 4.18 mg/L from 39 lung transplant recipients with multidrug-resistant Gram-negative bacteria. 26 (66.67%) patients successfully eradicated bacteria, and 30 (76.92%) patients had clinical cure or improvement. Additionally, only 2 (5.13%) patients developed CS-related nephrotoxicity. The PK profile was effectively represented by a one-compartmental model with linear elimination. Creatinine clearance and concomitant furosemide use were recognized as covariates influencing the clearance of CS. Based on the PTA results, a daily dosage of 1.5 million IU, divided into 2–3 administrations, could attain a PTA exceeding 90% for MIC ≤ 1 µg/mL at creatinine clearance of about 110 mL/min. However, this regimen would lead to insufficient exposure for MIC ≥ 2 µg/mL. ConclusionsThe clearance of CS is significantly influenced by concomitant furosemide use and renal function. The currently recommended dosing regimens by label sheet may result in subtherapeutic exposure for MIC exceeding 1 mg/L in lung transplant recipients.

Application of Pharmacometrics in Advancing the Clinical Research of Antibody-Drug Conjugates: Principles and Modeling Strategies.

Antibody-drug conjugates (ADCs) have become a pivotal area in the research and development of antitumor drugs. They provide innovative possibilities for tumor therapy by integrating the tumor-targeting capabilities of monoclonal antibodies with the cytotoxic effect of small molecule drugs. Pharmacometrics, an important discipline, facilitates comprehensive understanding of the pharmacokinetic characteristics of ADCs by integrating clinical trial data through modeling and simulation. However, due to the complex structure of ADCs, their modeling approaches are still unclear. In this review, we analyzed published population pharmacokinetic models for ADCs and classified them into single-analyte, two-analyte, and three-analyte models. We also described the benefits, limitations, and recommendations for each model. Furthermore, we suggested that the development of population pharmacokinetic models for ADCs should be rigorously considered and established based on four key aspects: (1) research objectives; (2) available in vitro and animal data; (3) accessible clinical information; and (4) the capability of bioanalytical methods. This review offered insights to guide the application of pharmacometrics in the clinical research of ADCs, thereby contributing to more effective therapeutic development.

Pharmacokinetic and pharmacodynamic data from the NEOLEV1 and NEOLEV2 studies

ObjectivesTo confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.DesignPharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear...

Population pharmacokinetic study in children with vascular anomalies: body weight as a key variable in predicting the initial dose and dosing frequency of sirolimus.

The main challenges faced when using sirolimus in children with vascular anomalies (VAs) still include significant pharmacokinetic (PK) variability, uncertainty in the target concentration range, as well as inconsistencies in initial dosing and dosing frequency. The aim of this study is to establish a new population pharmacokinetic (PPK) model for children with VAs to guide the individualized use of sirolimus. A PPK study was performed using data from children with VAs who received sirolimus between July 2017 and April 2022. A nonlinear mixed-effect modeling with a one-compartment model structure was applied. Monte Carlo simulation was employed to propose specific dosing recommendations to achieve the target trough concentrations (C trough) of 5-15ng/mL. In total, 134 blood concentrations from 49 pediatric patients were used to characterize the sirolimus pharmacokinetics. Covariate analysis identified body weight (BW) as a significant factor affecting clearance (CL) in the final PPK model. The typical clearance rate and distribution volume, standardized to a BW of 16kg, were 4.06L/h (4% relative standard error, RSE) and 155L (26% RSE), respectively. Optimal dosing regimens were simulated for different BWs. For a twice-daily regimen, the recommended doses were 0.05, 0.06, 0.07, and 0.08mg/kg/day for BW of <10, 10-20, 20-40, and ≥40kg, respectively; for a once-daily regimen, the recommended doses were 0.06, 0.07, 0.08, and 0.09mg/kg/day for BW of <10, 10-30, 30-50, and ≥50kg, respectively. Notably, sirolimus C trough could be maintained between 5-15ng/mL across various dosing frequencies based on the recommended dosing regimen. We established a PPK model of sirolimus for children with VAs and proposed an initial dosing strategy. Integrating initial dose and medication frequency recommendations into sirolimus' guidelines will broaden its clinical options and simplify the clinical management for childhood VAs.

Rutin and Physalis peruviana Extract: Population Pharmacokinetics in New Zealand Rabbits

Background/Objectives: An extract of calyces from Physalis peruviana with hypoglycemic activity is being considered as a potential herbal medicine. Preclinical pharmacokinetics (PK) studies of the extract in rats, focusing on plasma concentrations of its main compound, rutin, and its metabolites, revealed PK interactions in the extract matrix that improved the absorption of rutin metabolites compared to the pure compound, among other PK effects. This research aimed to study the PK of rutin alone and in the extract and assess potential PK interactions in the extract matrix on the flavonoid and its metabolites in rabbits, a nonrodent species; Methods: Animals received pure rutin or extract orally and intravenously. The PK analysis used noncompartmental and population pharmacokinetics (popPK) methods, and simple allometry was applied to predict human PK parameters; Results: The rutin concentration–time profile fit a two-compartment model with first-order elimination, while its metabolites fit a double first-order absorption model. The extract matrix led to increased absorption, distribution, and elimination of rutin as well as increased bioavailability of its metabolites in rabbits; Conclusions: The popPK model defined the equations for PK parameters describing these findings, and the increased volume of distribution and clearance of rutin was maintained in human predictions. These results will support the development of a new herbal medicine.

Pharmacokinetic and Pharmacodynamic Interaction of Finerenone with Diltiazem, Fluconazole, and Ritonavir in Rats.

Finerenone, a novel selective non-steroidal mineralocorticoid receptor antagonist, has been indicated in chronic kidney disease associated with type 2 diabetes mellitus. Considering the potential complications of diabetes, finerenone can be co-administered with various drugs, including fluconazole, diltiazem, and ritonavir. Given that finerenone is a substrate of cytochrome P450 (CYP) 3A4, the concurrent administration of finerenone with CYP3A4 inhibitors (diltiazem or fluconazole or ritonavir) could potentially lead to drug interactions, which may cause adverse events such as hyperkalemia. No studies have investigated interactions between finerenone and diltiazem or fluconazole or ritonavir. Therefore, this study aims to investigate the pharmacokinetic interaction of finerenone with diltiazem or fluconazole or ritonavir and to evaluate the impact of fluconazole on the pharmacodynamics of finerenone. The pharmacokinetic study included four rat groups (n=8 rats/group), including a control group (finerenone alone) and test groups (finerenone pretreated with diltiazem or fluconazole or ritonavir) using both non-compartment analysis (NCA) and population pharmacokinetic (pop-PK) modeling. The pop-PK model was developed using non-linear mixed-effects modeling in NONMEM® (version 7.5.0). In the pharmacodynamic study, serum potassium (K+) levels were measured to assess the effects of fluconazole on finerenone-induced hyperkalemia. The NCA results indicated that the area under the plasma concentration-time curve (AUC) of finerenone increased by 1.86- and 1.95-fold when coadministered with fluconazole and ritonavir, respectively. In contrast, diltiazem did not affect the pharmacokinetics of finerenone. The pharmacokinetic profiles of finerenone were best described by a one-compartment disposition with first-order elimination and dual first-order absorption kinetics. The pop-PK modeling results demonstrated that the apparent clearance of finerenone decreased by 50.3% and 49.2% owing to the effects of fluconazole and ritonavir, respectively. Additionally, the slow absorption rate, which represents the absorption in the distal intestinal tract of finerenone, increased by 55.7% due to the effect of ritonavir. Simultaneously, a pharmacodynamic study revealed that finerenone in the presence of fluconazole caused a significant increase in K+ levels compared with finerenone alone. Coadministration of finerenone with fluconazole or ritonavir increased finerenone exposure in rats. Additionally, the administration of finerenone in the presence of fluconazole resulted in elevated K+ levels in rats. Further clinical studies are required to validate these findings.

Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults

Trichuris trichiura is a soil‐transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co‐administered with ivermectin. A fixed‐dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure–response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed‐effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure–response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two‐compartmental model with first‐order absorption and the pharmacokinetics of ivermectin was described using a two‐compartmental model with zero‐order followed by first‐order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure–response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.

Exposure–response relationships of mirvetuximab soravtansine in patients with folate receptor‐α‐positive ovarian cancer: Justification of therapeutic dose regimen

AimsThis study aimed to investigate exposure–response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first‐in‐class antibody–drug conjugate approved for the treatment of folate receptor‐α‐positive platinum‐resistant ovarian cancer.MethodsMIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV‐treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy‐controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757).ResultsIn the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression‐free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration–time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV.ConclusionThe trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

Model-Informed Precision Dosing of Tacrolimus: A Systematic Review of Population Pharmacokinetic Models and a Benchmark Study of Software Tools.

Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment. We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration. We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey. Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.

Guiding the starting dose of the once-daily formulation of tacrolimus in "de novo" adult renal transplant patients: a population approach.

The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period. A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5. A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60years and younger. The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60years or younger would be highest, while CYP3A5*/1 non-carriers older than 60years would require the lowest doses.

The impact of age and renal function on the pharmacokinetics and protein binding characteristics of fludarabine in paediatric and adult patients undergoing allogeneic haematopoietic stem cell transplantation conditioning

AimTo evaluate the population pharmacokinetics of unbound F-Ara-A (the circulating metabolite of fludarabine) in 211 patients (age range, 0.1–63.4 years) undergoing allogeneic haematopoietic stem cell transplantation conditioning.MethodsTotal (n = 2480) and unbound (n = 1403) F-Ara-A concentrations were measured in blood samples collected at timed intervals after fludarabine doses ranging from 10 to 50 mg/m2 and infused over 0.42–1.5 h. A three-compartment population pharmacokinetic model was developed based on unbound plasma concentrations and used to estimate F-Ara-A unbound pharmacokinetic parameters and fraction unbound (fu). A number of covariates, including glomerular filtration rate (GFR) and post-menstrual age (PMA), were evaluated for inclusion in the model.ResultsThe base population mean estimates ± relative standard error (%RSE) for unbound clearance from the central compartment (CLu) and inter-compartmental clearances (Q2u, Q3u) were 3.42 ± 3%, 6.54 ± 24% and 1.47 ± 16% L/h/70 kg, respectively. The population mean estimates (%RSE) for the unbound volume of distribution into the central (V1u) and peripheral compartments (V2u, V3u) were 9.65 ± 8%, 8.17 ± 9% and 16.4 ± 10% L/70 kg, respectively, and that for fu was 0.877 ± 1%. Covariate model development involved differentiating F-Ara-A CLu into non-renal (1.81 ± 9% L/h/70 kg) and renal components (1.02 ± 9%*GFR L/h/70 kg). A sigmoidal maturation factor was applied to renal CLu, with population mean estimates for the Hill exponent and PMA at 50% mature of 2.97 ± 4% and 69.1 ± 8% weeks, respectively.ConclusionPatient age and GFR are predictors of unbound F-Ara-A CLu. This has the potential to impact dose requirements. Dose individualisation by target concentration intervention will be facilitated by this model once it is externally validated.

Population pharmacokinetic-pharmacodynamic model of elinzanetant based on integrated clinical phase I and II data.

Elinzanetant is a potent and selective dual neurokin-1 (NK-1) and -3 (NK-3) receptor antagonist that is currently developed for the treatment of women with moderate-to-severe vasomotor symptoms (VMS) associated with menopause. Here, we report the development of a population pharmacokinetic (popPK) model for elinzanetant and its principal metabolites based on an integrated dataset from 366 subjects (including 197 women with VMS) collected in 10 phase I or II studies. The pharmacokinetics of elinzanetant and its metabolites could be well described by the popPK model. Within the investigated dose range of 40-160 mg, the oral bioavailability of elinzanetant was dose independent and estimated to be 36.7%. The clearance of elinzanetant was estimated to be 7.26 L/h and the central and peripheral distribution volume were 23.7 and 168 L. No intrinsic or extrinsic influencing factors have been identified in the investigated population other than the effect of a high-fat breakfast on the oral absorption of elinzanetant. The popPK model was then coupled to a pharmacodynamic model to predict occupancies of the NK-1 and NK-3 receptors. After repeated once-daily administration of the anticipated therapeutic dose of 120 mg elinzanetant, the model-predicted median receptor occupancies are >99% for NK-1 and >94.8% for NK-3 during day and night-time, indicating sustained and near-complete inhibition of both target receptors during the dosing interval.

Serum ganciclovir drug exposure in children receiving standard ganciclovir dosing.

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration-time curve (AUC24h) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4-17.0) and weight of 28.2 kg (5.6-73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th-95th percentiles) steady state AUC24h with standard dosing was 38.3 mg/L·h (24.8-329.2) with 13 children having an AUC24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%-78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation.

Population Pharmacokinetics of Casirivimab and Imdevimab in Pediatric and Adult Non-Infected Individuals, Pediatric and Adult Ambulatory or Hospitalized Patients or Household Contacts of Patients Infected with SARS-COV-2

IntroductionCasirivimab (CAS) and imdevimab (IMD) are two fully human monoclonal antibodies that bind different epitopes on the receptor binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and block host receptor interactions. CAS + IMD and was developed for the treatment and prevention of SARS-CoV-2 infections.MethodsA population pharmacokinetic (PopPK) analysis was conducted using pooled data from 7598 individuals from seven clinical studies to simultaneously fit concentration–time data of CAS and IMD and investigate selected covariates as sources of variability in PK parameters. The dataset comprised CAS + IMD-treated pediatric and adult non-infected individuals, ambulatory or hospitalized patients infected with SARS-CoV-2, or household contacts of patients infected with SARS-CoV-2.ResultsCAS and IMD concentration–time data were both appropriately described simultaneously by a two-compartment model with first-order absorption following subcutaneous dose administration and first-order elimination. Clearance estimates of CAS and IMD were 0.193 and 0.236 L/day, respectively. Central volume of distribution estimates were 3.92 and 3.82 L, respectively. Among the covariates identified as significant, body weight and serum albumin had the largest impact (20–34%, and ~ 7–31% change in exposures at extremes, respectively), while all other covariates resulted in small differences in exposures. Application of the PopPK model included simulations to support dose recommendations in pediatrics based on comparable exposures of CAS and IMD between different weight groups in pediatrics and adults following weight-based dosing regimens.ConclusionsThis analysis provided important insights to characterize CAS and IMD PK simultaneously in a diverse patient population and informed pediatric dose selection.

Vancomycin in Pediatric Patients with Cystic Fibrosis: Dose Optimization Using Population Pharmacokinetic Approach.

An increase in Staphylococcus aureus infections has been reported in pediatric patients with cystic fibrosis (CF) over the last few years. This pathogen is commonly treated with vancomycin, an antibiotic for which therapeutic drug monitoring (TDM) is recommended. Updated guidelines were recently published regarding new targets of exposure for the TDM of vancomycin through a Bayesian approach, using population pharmacokinetic (popPK) models. This study aims to assess the predictive performance of vancomycin popPK models in pediatric patients with CF and to recommend optimal initial dosing regimens based on simulations. Patient data were collected from two centers in Canada, and a literature review was conducted to identify all published vancomycin popPK models for pediatric CF patients. External evaluation and simulations were performed according to patient and occasion of treatment. A total of 53 vancomycin concentrations were collected from six pediatric CF patients. Only two popPK models of vancomycin for pediatric CF patients were identified through the literature review. The external evaluation results for both centers combined revealed a population bias of 28.1% and an imprecision of 33.7%. A re-estimation of parameters was performed to improve predictive performance. The optimal initial dosing regimen was 15 mg/kg/dose administered every 6 hours according to the per occasion remodel. The predictive performance and identified optimal initial dosing regimens associated with the model were different depending on the data used, showing external evaluation's importance before implementing a model in clinical practice.

Utilising paired measurements of phosphatidylethanol to monitor early success in alcohol abstinence.

Phosphatidylethanol (PEth) is a specific and persisting marker of ethanol (alcohol) consumption. Early success of medically necessary abstinence can be assessed by monitoring PEth disappearance at a biologically plausible rate. This requires an understanding of PEth elimination, its variability and its determinants. To achieve this, we characterised PEth elimination in drinkers who voluntarily abstained. We aimed to derive a nomogram from the data to assist practitioners in recognising abstinence. Twenty-nine usual drinkers who were prepared to abstain from alcohol consumption for 4 weeks were recruited. Erythrocyte PEth was measured weekly. A population pharmacokinetic model for PEth was developed, describing the time-course of PEth elimination. Estimates were derived for population average, inter-individual variability in PEth half-life and any covariate influences. These estimates informed a nomogram of PEth elimination that incorporated a boundary separating continued abstinence from resumed drinking. The nomogram was tested to identify drinking events among participants. The model estimated a population average elimination rate constant (k) of 0.088 day-1, corresponding to a half-life of 7.9 days with a residual coefficient of variation of 8.5%. Elimination was first order and no covariate influences were identified. The nomogram was internally assessed as predictively accurate for 21 successfully abstinent participants and in detecting alcohol consumption in 2 further participants, using a 99.9% prediction interval. The value of PEth in distinguishing alcohol abstinence from consumption is enhanced by using a nomogram to confirm abstinence within weeks of its medically necessary imposition. Further work will establish the value of this approach in clinical practice.