Central Volume Of Distribution Research Articles

Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment.

Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Accelerated lymph flow from infusion of crystalloid fluid during general anesthesia

BackgroundKinetic analysis of crystalloid fluid yields a central distribution volume (Vc) of the same size as the expected plasma volume (approximately 3 L) except during general anesthesia during which Vc might be only half as large. The present study examined whether this difference is due to influence of the intravascular albumin balance.MethodsA population volume kinetic analysis according to a three-compartment model was performed based on retrospective data from 160 infusion experiments during which 1–2.5 L of crystalloid fluid had been infused intravenously over 20–30 min. The plasma dilution based on blood hemoglobin (Hb) and plasma albumin (Alb) was measured on 2,408 occasions and the urine output on 454 occasions. One-third of the infusions were performed on anesthetized patients while two-thirds were given to awake healthy volunteers.ResultsThe Hb-Alb dilution difference was four times greater during general anesthesia than in the awake state (+ 0.024 ± 0.060 versus − 0.008 ± 0.050; mean ± SD; P < 0.001) which shows that more albumin entered the plasma than was lost by capillary leakage. The Hb-Alb dilution difference correlated strongly and positively with the kinetic parameters governing the rate of fluid transfer through the fast-exchange interstitial fluid compartment (k12 and k21) and inversely with the size of Vc. Simulations suggest that approximately 200 mL of fluid might be translocated from the interstitial space to the plasma despite ongoing fluid administration.ConclusionsPronounced plasma volume expansion early during general anesthesia is associated with a positive intravascular albumin balance that is due to accelerated lymphatic flow. This phenomenon probably represents adjustment of the body fluid volumes to anesthesia-induced vasodilatation.

Abstract 7165: Clinical population pharmacokinetic (popPK) analysis of NBF-006, a novel siRNA inhibitor of glutathione-S-transferase P (GSTP) encapsulated in a lipid nano particle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC)

Abstract GSTP has an important role in detoxification and antioxidative damage response. Additionally, GSTP has a chaperone function that regulates multiple oncogenic pathways such as KRAS and JNK. Since alternative pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a drug product comprised of GSTP siRNA encapsulated within a novel LNP. It is designed to deliver siRNA to localized and metastatic lung tumors. Unlike other well-established drug modalities, there is a general need for increased understanding of the PK of RNA therapeutics. For NBF-006, we present popPK analysis of patients who have undergone treatment in a Phase I (a/b) clinical study. A primary goal of popPK modeling is to identify PK parameters and sources of variability in a population. Other goals include correlating drug exposures with administered doses through identification of predictive covariates in a target population and establishing whether fixed dosing as opposed to weight-based dosing can be utilized in future clinical studies. Ultimately this analysis will help to inform decision-making for dosing regimens in future clinical trial designs and to better predict PK variability across populations. A total of 48 advanced NSCLC (N=38), pancreatic (N=5), or colorectal cancer (N=5) patients received 4 doses (QW) of NBF-006 by infusion at 0.15, 0.3, 0.6, 1.2 or 1.6 mg/kg followed by a 2-week rest period. In all studies, serial blood samples were collected at weeks 1 and 4. Plasma concentrations of siRNA were determined by hybridization ELISA. PopPK analysis was performed to characterize NBF-006 PK and to explore intrinsic and extrinsic covariate effects that could affect NBF-006 exposure. The analysis included 695 quantifiable PK observations. A popPK model with two-compartment disposition and linear elimination adequately described the PK profile of NBF-006. Exploratory data analysis of dose-normalized PK profiles suggested that exposure increased proportionally with increasing dose from 0.15 to 1.6 mg/kg. Little to no apparent accumulation nor exposure reduction was observed between weeks 1 and 4. The impact of individual patient covariates, including body weight, baseline ALT, sex, KRAS mutation, cancer type and race, was assessed on PK parameters. None of the covariates evaluated had a significant effect on NBF-006 clearance or central distribution volume (Vc) in the model. Vc showed a slight positive trend with higher body weight, but was not statistically significant. A popPK model was successfully developed for NBF-006. No covariates were identified that impact NBF-006 exposure. The lack of a relationship of exposure with body weight suggests the potential to use fixed dosing in future clinical studies. Citation Format: Michael P. Hall, Zhihong O'Brien, Xi Chen, Angelean Hendrix, Stacy Brenes-Coto, Sonya Zabludoff. Clinical population pharmacokinetic (popPK) analysis of NBF-006, a novel siRNA inhibitor of glutathione-S-transferase P (GSTP) encapsulated in a lipid nano particle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7165.

The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model.

Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066L/h/46.4kg, 0.0055L/h/46.4kg, 0.0081L/h/46.4kg, 0.0029L/h/46.4kg, 0.6750L/46.4kg, and 1.19L/46.4kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

Nlmixr2 Versus NONMEM: An Evaluation of Maximum A Posteriori Bayesian Estimates Following External Evaluation of Gentamicin and Tobramycin Population Pharmacokinetic Models.

The objective of this project is to compare the results of the same study carried out on NONMEM and nlmixr2. This analysis consists of evaluating previously published population pharmacokinetic models of gentamicin and tobramycin in our population of interest with sparse concentrations. A literature review was performed to determine the gentamicin and tobramycin models in critically ill adult patients. In parallel, gentamicin and tobramycin dosing data, information on the treatment, the patient, and the bacteria were collected retrospectively in 2 Quebec establishments. The external evaluations were previously performed using NONMEM Version 7.5. Model equations were rewritten with R, and external evaluations were performed using nlmixr2. Predictive performance was assessed based on the estimation of bias and imprecision of the prediction error for maximum a posteriori (MAP) Bayesian PK parameter and observed concentrations. Comparison between nlmixr2 and NONMEM was performed on 4 gentamicin and 3 tobramycin population pharmacokinetic models. Compared to NONMEM, for gentamicin and tobramycin clearance and central volume of distribution, nlmixr2 produced individual pharmacokinetic parameters with bias values ranging from -32.5% to 5.67% and imprecision values ranging from 6.33% to 32.5%. Despite these differences, population bias and imprecision for sparse concentrations were low and ranged from 0% to 5.3% and 0.2% to 6.5%, respectively. The external evaluations performed with both software packages resulted in the same interpretation in terms of population predictive performance for all 7 models. Nlmxir2 showed comparable predictive performance with NONMEM with sparse concentrations that are, at most, sampled twice within a single dose administration (peak and trough).

Population pharmacokinetic modeling of oral brepocitinib in healthy volunteers and patients with immuno-inflammatory diseases.

The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration-time profile of brepocitinib plasma concentration after single- and multiple-oral administration in healthy volunteers (HVs) and patients with immuno-inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed-effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two-compartment model with first-order absorption and a lag time for tablet formulation, dose-dependent bioavailability, and Box-Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70-kg non-Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well-characterized by a two-compartment model with first-order absorption and dose-dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters.

Daily fluid intake as a novel covariate affecting the population pharmacokinetics of polymyxin B in patients with sepsis

BackgroundPolymyxin B dosing in patients with sepsis is difficult because pathophysiological changes and supportive therapies alter drug pharmacokinetics (PK). This study aimed to investigate the impact of fluid management and renal function on the PK of polymyxin B and to propose alternative dosing regimens. MethodsPatients (aged ≥ 18 y) with sepsis and receiving intravenous polymyxin B for ≥ 96 h were enrolled. Blood samples were collected at steady state. Plasma concentrations were measured by liquid chromatography-tandem mass spectrometry and subjected to population PK modelling. Monte Carlo simulations were used to optimise dosage regimens. ResultsEighty-three patients with a median (range) daily fluid intake of 4.2 (1.3–8.4) L and a creatinine clearance (CrCL) of 87.5 (17.3–309.7) mL/min were included. Polymyxin B PK was adequately characterised by a two-compartment model. The PK covariate analysis revealed daily fluid intake statistically significantly affected central volume of distribution and central compartment clearance (CL), and CrCL influenced CL. Simulation indicated that a decreased dosing would be suitable for patients with renal dysfunction (CrCL < 40 mL/min), and therapeutic drug monitoring is recommended to avoid exposure fluctuation when patients have fluid overload. ConclusionsFluid management as well as renal function are essential factors affecting polymyxin B PK for patients with sepsis, which can help optimise dosage regimens.

P1044 Mirikizumab Pharmacokinetics and Exposure-Response in a Phase 2 Study in Patients With Moderately to Severely Active Crohn’s Disease

Abstract Background Mirikizumab (miri) is a humanized anti–interleukin-23-p19 monoclonal antibody approved for the treatment of ulcerative colitis (UC) and under development for Crohn’s disease (CD). This analysis characterises miri pharmacokinetics (PK) and the relationship between miri exposure and efficacy response using data from a phase 2 trial in adults with moderately to severely active CD. Methods AMAG was a randomised, double-blind, placebo-controlled trial conducted in 14 countries. Patients received placebo, miri 200 mg, 600 mg, or 1000 mg as induction regimens administered intravenously (IV) every 4 weeks (Q4W) through Week 12, followed by 36 weeks of maintenance treatment with continuous treatment of miri 200 mg, 600 mg, or 1000 mg IV or miri 300 mg administered subcutaneously (SC) Q4W. PK parameters were analysed by non-linear mixed-effects modelling. Covariate effects on miri exposure were evaluated using simulation-based estimations. Exposure-response (ER) for patients achieving endoscopic response by Simple Endoscopic Score for Crohn’s Disease (SES-CD) at Weeks 12 and 52 were assessed using logistic regression models. Results 186 patients were included. The estimated systemic clearance (CL), central volume of distribution (V), and SC bioavailability (F) were 0.022 L/hr, 3.31 L, and 33.4%, respectively. Lower baseline values for SES-CD (indicative of a less severe CD) were associated with reduced CL. Lower body weight and higher albumin levels were also associated with reduced CL. Higher body weight was associated with higher V and lower baseline body mass index correlated with higher SC F. Impacts on PK parameters were small relative to random variability and not considered clinically relevant. The model-based ER analyses for endoscopic response probability at Week 12 detected a significant treatment effect relative to placebo (p&amp;lt;0.001) and a significant ER (p=0.001) in a dose range of 200-1000 mg. The ER analyses indicated near maximal efficacy for IV dose between 600 mg and 1000 mg during the Induction Period. There was no significant relationship between miri exposure and the probability of achieving endoscopic response by SES-CD at Week 52, indicating exposures produced by the maintenance doses provided similar efficacy. Conclusion Miri PK characteristics in adults with active CD were consistent with miri UC studies. Overall, none of the covariates identified as being significantly correlated with miri PK parameters were considered clinically relevant. No patient factors evaluated in this analysis justify dose adjustment. These findings support the miri induction dose 900 mg IV Q4W and maintenance dose 300 mg SC Q4W selected for phase 3 CD study.

Dabigatran pharmacokinetic-pharmacodynamic in sheep: Informing dose for anticoagulation during cardiopulmonary bypass.

The effect of the anticoagulant, dabigatran, and its antagonist, idarucizumab, on coagulation remains poorly quantified. There are few pharmacokinetic-pharmacodynamic data available to determine dabigatran dose in humans or animals undergoing cardiopulmonary bypass. Five sheep were given intravenous dabigatran 4mg/kg. Blood samples were collected for thromboelastometric reaction time (R-time) and drug assay at 5, 15, 30, 60, 120, 240, 480min, and 24h. Plasma dabigatran concentrations and R-times were analyzed using an integrated pharmacokinetic-pharmacodynamic model using non-linear mixed effects. The impact of idarucizumab 15mg/kg administered 120min after dabigatran 4mg/kg and its effect on R-time was observed. A 2-compartment model described dabigatran pharmacokinetics with a clearance (CL 0.0453L/min/70kg), intercompartment clearance (Q 0.268L/min/70kg), central volume of distribution (V1 2.94L/70kg), peripheral volume of distribution (V2 9.51L/70kg). The effect compartment model estimates for a sigmoid EMAX model using Reaction time had an effect site concentration (Ce50 64.2mg/L) eliciting half of the maximal effect (EMAX 180min). The plasma-effect compartment equilibration half time (T1/2keo) was 1.04min. Idarucizumab 15mg/kg reduced R-time by approximately 5min. Dabigatran reversibly binds to the active site on the thrombin molecule, preventing activation of coagulation factors. The pharmacologic target concentration strategy uses pharmacokinetic-pharmacodynamic information to inform dose. A loading dose of dabigatran 0.25mg/kg followed by a maintenance infusion of dabigatran 0.0175mg/kg/min for 30min and a subsequent infusion dabigatran 0.0075mg/kg/min achieves a steady state target concentration of 5mg/L in a sheep model.

Clofazimine pharmacokinetics in HIV-infected adults with diarrhea: Implications of diarrheal disease on absorption of orally administered therapeutics.

Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea-associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)-infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea-associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV-infected adults with/without Cryptosporidium infection using nonlinear mixed-effects modeling. Covariates describing cryptosporidiosis-associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two-compartment model with lag time and first-order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h-1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children.

Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups. We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters. Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM. Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.

A population pharmacokinetic model of methotrexate in Korean patients with haematologic malignancy.

This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with haematologic malignancy, identify factors affecting methotrexate PK, and propose an optimal dosage regimen for the Korean population. Data were retrospectively collected from 188 patients with acute leukaemia or non-Hodgkin's lymphoma who were admitted to Severance Hospital during the period from November 2005 to January 2016. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. A two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.09 L for central volume of distribution ( ), 17.65 L for peripheral volume of distribution ( ), 12.89 L/h for clearance (CL) and 0.655 L/h for inter-compartmental clearance in a 50 kg patient. Covariate analyses showed that, at the weight of 50 kg, CL decreased by 0.11 L/h for each 1-year increase in age above 14 years old and decreased 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (= + ) was 0.85 L/kg, which was similar to those in the Western or Chinese populations. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with haematologic malignancy.

Evaluation of body weight–based dosing, alternative dosing regimens, and treatment interruptions for α1-proteinase inhibitors and implications on biochemical efficacy in patients with α1-antitrypsin deficiency

IntroductionThe recommended standard dose for α1-proteinase inhibitor (A1PI) augmentation therapy is 60 mg/kg once-weekly (QW) intravenous (IV) infusions that aim to maintain systemic A1PI levels >11 μM, the biochemical efficacy threshold, in patients with α1-antitrypsin deficiency (AATD). However, this standard dose may not be optimal for all patients. Body weight–based dosing, alternative dosing regimens, and treatment interruption periods were evaluated using population pharmacokinetic (PopPK) modeling and simulations. MethodsA nonlinear mixed-effects PopPK model with covariate effects was developed using data from 3 clinical studies investigating 60 mg/kg QW IV A1PI infusions in patients with AATD (n = 65) to evaluate A1PI pharmacokinetic (PK) characteristics. Model-based simulations were conducted for predefined body weight categories, alternative dosing regimens (60–180 mg/kg QW or once every 2 weeks [Q2W]), and treatment interruption periods ranging from 3 to 14 days. ResultsA1PI PK characteristics were well described by a 2-compartment turnover model with zero-order input and linear elimination. Body weight was a statistically significant determinant of variability in central volume of distribution. Model-based simulations suggested that patients with a higher body weight may attain the 11 μM threshold quicker than patients with a lower body weight and that QW dosing was better at maintaining A1PI levels >11 μM, even when higher Q2W doses were administered. Missing a dose for as few as 3 days could result in A1PI levels <11 μM. DiscussionFindings suggest that doses higher than 60 mg/kg administered QW might be more clinically beneficial in some patients with AATD, and that body weight should be considered in dose optimization.

Population pharmacokinetics of mycophenolic acid and dose optimisation in adult Chinese kidney transplant recipients

1. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of MPA, and optimise the dosage for adult kidney transplant recipients. 2. One-hundred and four adult renal transplant patients were enrolled. The PPK model was established using the Phoenix® NMLE software and the stepwise methods were filtered for significant covariates. Monte Carlo simulations were performed to optimise the dosage regimen. 3. A two-compartment model with first-order absorption and elimination (including lag time) provided a more accurate description of MPA pharmacokinetics. Serum albumin (ALB) significantly affected the central apparent clearance (CL/F), whereas post-transplant time and creatinine clearance were associated with a central apparent volume of distribution (V/F). The estimated population values obtained by the final model were 17.5 L/h and 93.97 L for CL/F and V/F, respectively. Simulation results revealed that larger mycophenolate mofetil doses are required as the ALB concentration decreases. This study established a PPK model of MPA and validated it using various methods. ALB significantly affected CL/F and recommended optimal dose strategies were given based on the final model. These results provide a reference for the personalised therapy of MPA for kidney transplant patients.

Model-informed precision dosing in vancomycin treatment.

Introduction: While vancomycin remains a widely prescribed antibiotic, it can cause ototoxicity and nephrotoxicity, both of which are concentration-associated. Overtreatment can occur when the treatment lasts for an unnecessarily long time. Using a model-informed precision dosing scheme, this study aims to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for vancomycin to determine the optimal dosage regimen and treatment duration in order to avoid drug-induced toxicity. Methods: The data were obtained from electronic medical records of 542 patients, including 40 children, and were analyzed using NONMEM software. For PK, vancomycin concentrations were described with a two-compartment model incorporating allometry scaling. Results and discussion: This revealed that systemic clearance decreased with creatinine and blood urea nitrogen levels, history of diabetes and renal diseases, and further decreased in women. On the other hand, the central volume of distribution increased with age. For PD, C-reactive protein (CRP) plasma concentrations were described by transit compartments and were found to decrease with the presence of pneumonia. Simulations demonstrated that, given the model informed optimal doses, peak and trough concentrations as well as the area under the concentration-time curve remained within the therapeutic range, even at doses smaller than routine doses, for most patients. Additionally, CRP levels decreased more rapidly with the higher dose starting from 10days after treatment initiation. The developed R Shiny application efficiently visualized the time courses of vancomycin and CRP concentrations, indicating its applicability in designing optimal treatment schemes simply based on visual inspection.

Dosing recommendation of nirmatrelvir/ritonavir using an integrated population pharmacokinetic analysis.

Protease inhibitor nirmatrelvir coadministered with ritonavir as a pharmacokinetic enhancer (PAXLOVID™; Pfizer Inc) became the first orally bioavailable antiviral agent granted Emergency Use Authorization in the United States in patients ≥12 years old with mild to moderate coronavirus disease 2019 (COVID-19). This population pharmacokinetic analysis used pooled plasma nirmatrelvir concentrations from eight completed phase I and II/III studies to characterize nirmatrelvir pharmacokinetics when coadministered with ritonavir in adults with/without COVID-19. Influence of covariates (e.g., formulation, dose, COVID-19) was examined using a stepwise forward selection (α = 0.05) and backward elimination (α = 0.001) approach. Simulations with 5000 subjects for each age and weight group and renal function category were performed to support dosing recommendations of nirmatrelvir/ritonavir for adults with COVID-19 and guide dose adjustments for specific patient populations (e.g., renal insufficiency, pediatrics). The final model was a two-compartment model with first-order absorption, including allometric scaling of body weight and dose-dependent absorption (power function on relative bioavailability). Nirmatrelvir clearance (CL) increased proportionally to body surface area-normalized creatinine CL (nCLCR) up to 70 ml/min/1.73 m2 and was independent of nCLCR above the breakpoint. Significant covariates included carbamazepine or itraconazole coadministration as markers for drug interactions, COVID-19 on CL, formulation on relative bioavailability, and age on central volume of distribution. Simulation results support current dosing recommendations of nirmatrelvir/ritonavir 300/100 mg twice daily (b.i.d.) in adults with normal renal function or mild impairment and pediatrics (12 to <18 years) weighing ≥40 kg and nirmatrelvir/ritonavir 150/100 mg b.i.d. in adults with moderate renal impairment.

Pharmacokinetics of remimazolam after intravenous infusion in anaesthetised children

BackgroundThe pharmacokinetic properties of the new benzodiazepine remimazolam have been studied only in adults. We investigated the pharmacokinetics of remimazolam after i.v. infusion in anaesthetised paediatric patients. MethodsTwenty-four children (2–6 yr, ASA physical status 1–2, BMI 15–18 kg m−2) undergoing general anaesthesia with sevoflurane were enrolled. During surgery, remimazolam was administered as an i.v. infusion over 1 h at 5 mg kg−1 h−1 for 5 min, followed by 1.5 mg kg−1 h−1 for 55 min. Plasma concentrations of remimazolam and its metabolite CNS7054 were determined from arterial blood samples using ultra-high performance liquid chromatography–mass spectrometry. Pharmacokinetic modelling was performed by population analysis. ResultsPharmacokinetics were best described by a three-compartment model for remimazolam and a two-compartment model for CNS7054 linked by a transit compartment. Remimazolam showed a high clearance of 15.9 (12.9, 18.2) ml kg−1 min−1 (median, Q25, Q75), a small central volume of distribution of 0.11 (0.08, 0.14) L kg−1 and a short terminal half-life of 67 (49, 85) min. The context-sensitive half-time after an infusion of 4 h was 17 (12, 21) min. The metabolite CNS7054 showed a low clearance of 0.89 (0.33, 1.40) ml kg−1 min−1, a small central volume of distribution of 0.011 (0.005, 0.016) L kg−1, and a long terminal half-life of 321 (230, 770) min. ConclusionsRemimazolam in children was characterised by a high clearance and short context-sensitive half-time. When normalised to weight, pharmacokinetic properties were similar to those reported for adults. Clinical trial registrationChiCTR2200057629.

Model based assessment of food and acid reducing agent effects on oral absorption of mezigdomide (CC-92480), a novel cereblon E3 ligase modulator.

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell-killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high-fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model. The HSs received single oral doses of 0.4-3.2 mg mezigdomide with full PK profiles collected. A two-compartment linear PK model with first-order absorption and lag time best described mezigdomide PK profiles in HSs. The population PK parameters of absorption rate constant, lag time, central volume of distribution, clearance, peripheral volume of distribution, and intercompartmental clearance were estimated to be 1.18 h-1 (interoccasion variability [IOV]: 65%), 0.423 h (IOV: 31%), 440 L (interindividual variability [IIV]: 63%), 35.1 L/h (IIV: 40%), 243 L (IIV: 26%), and 36.8 L/h (IIV: 26%), respectively. High-fat meal increased oral bioavailability by ~30% and PPI co-administration decreased oral bioavailability by ~64%. Mezigdomide demonstrated a linear dose-exposure relationship in HSs. The PK model suggests a modest effect of high-fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.

Mirikizumab Pharmacokinetics in Patients with Moderately to Severely Active Ulcerative Colitis: Results from Phase III LUCENT Studies.

Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis. Serum pharmacokinetic data in patients receiving mirikizumab 50-1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations. Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18-64%). The subcutaneous bioavailability of mirikizumab was 48%. Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required. ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).