Developed Population Pharmacokinetic Model Research Articles

Proof of concept of physiologically based pharmacokinetic modelling in paediatric acute lymphoblastic leukaemia.

Physiologically based pharmacokinetic (PBPK) modelling is an alternative modelling technique that is increasingly used in pharmacokinetics. Due to its nature, it can be complementarily employed to population pharmacokinetics, especially when it comes to small population size. Here, we report the proof of concept of its application to accurately describe the pharmacokinetics of a recombinant L-asparaginase in paediatric patients with acute lymphoblastic leukaemia. Data from two randomized, double-blind, phase II/III clinical studies (MC-ASP.4/ALL; MC-ASP.5/ALL) were included to setup and evaluate the final model, respectively. Final population values for basic pharmacokinetic parameters were calculated (clearance: 0.0569 L/h/19.5 kg, volume of distribution: 1.251 L, half-life: 18.5 h, trough concentration: 140.9 IU/L). Pharmacokinetic parameter prediction as well as predictive performance of the model proofed to be comparable to a separately developed population pharmacokinetic model with 13% deviation in predicted median L-asparaginase trough levels. To the best of our knowledge, this is the first whole-body PBPK model of a non-antibody therapeutic protein.

Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii.

Colistimethate sodium (CMS) nebulization is associated with reduced systemic toxicity compared to intravenous injection, with potentially enhanced clinical efficacy. This study aimed to assess the pharmacokinetic (PK) properties of colistin during low-dose CMS nebulization in patients with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii. A nonlinear mixed-effects modeling approach was applied to develop population PK models for colistin in both epithelial lining fluid (ELF) and plasma. Twenty patients participated, and 80 ELF and 100 plasma samples were used for model development. Median colistin concentrations measured in ELF were 614-fold, 408-fold, and 250-fold higher than in plasma at 1, 3, and 5 h, respectively. Time courses in both ELF and plasma were best described by a one-compartment model with a Weibull absorption process. When the final model was simulated, the maximum free concentration and area under the free colistin concentration-time curve at steady state over 24 h in the plasma were approximately 1/90 and 1/50 of the corresponding values in ELF at steady state, respectively. For an A. baumannii MIC of 1 mg/L, inhaling 75 mg of CMS at 6 h intervals was deemed appropriate, with dose adjustments needed for MICs exceeding 2 mg/L. Using a nebulizer for CMS resulted in a notably higher exposure of colistin in the ELF than plasma, indicating the potential of nebulization to reduce systemic toxicity while effectively treating VAP.

Optimal Once-Daily Busulfan Administration in Pediatric Patients: A Simulation-Based Investigation of Intravenous Infusion Times.

Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity. Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens. Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion. While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.

Understanding hemoglobin contribution to high-dose methotrexate disposition-population pharmacokinetics in pediatric patients with hematological malignancies.

The aim of the present study was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) and to describe the influence of variability factors. The study included 50 patients of both sexes (aged 1-18years) who received 3 or 5g/m2 of HDMTX. A nonlinear mixed effect modeling approach was applied for data analysis. Parameter estimation was performed by first-order conditional estimation method with interaction (FOCEI), whereas stepwise covariate modeling was used to assess variability factors. The final model is a two-compartment model that incorporates the effect of body surface area and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical subject were estimated at 5.75 L/h/m2 for clearance (CL), 21.3 L/m2 for volume of the central compartment (V1), 8.2 L/m2 for volume of the peripheral compartment (V2), and 0.087 L/h/m2 for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 32% in MTX CL was observed among patients' hemoglobin values reported in the study. The developed population pharmacokinetic model can contribute to the therapy optimization during HDMTX in pediatric patients with ALL and NHL. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to the disposition of HDMTX.

P1018 Population pharmacokinetic and exposure-response analyses for efficacy and safety of risankizumab in subjects with moderately to severely active Ulcerative Colitis

Abstract Background Risankizumab (RZB) has been evaluated in subjects with moderately to severely active ulcerative colitis (UC) in the INSPIRE and COMMAND trials. Population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted at the end of Phase 2b and following Phase 3 to characterize RZB PK and its relationship with clinical efficacy and safety to support Phase 3 induction dose selection, and the final dose recommendations for induction and maintenance treatment. Methods PPK analyses in UC used a previously developed PPK model for Crohn’s disease with additional evaluation of covariates relevant to UC. ER relationships between RZB exposures and efficacy endpoints at the end of induction (Week 12), re-induction (Week 24; exploratory only) and maintenance (Week 52) periods were established using exploratory graphical analyses and logistic regression modeling. ER analyses for safety were performed for key variables through Weeks 12, 24 and 52 using graphical analyses. Results A two-compartment model with first-order absorption for SC administration and first-order elimination adequately described RZB PK. Among the various covariates assessed, body weight, baseline (BL) serum albumin, BL high-sensitivity C-reactive protein, BL fecal calprotectin, sex, advanced therapy IR status, BL pancolitis and corticosteroid use were statistically correlated with RZB clearance but their impact on exposure was not clinically relevant for efficacy. ER analyses for efficacy using Phase 2b induction data showed that while incremental improvement in efficacy was predicted with doses increasing from 1200 to 1800 mg, the magnitude of difference in efficacy was modest especially for endoscopy-driven endpoints. Phase 3 ER analyses for efficacy showed statistically significant trends of exposure-dependent increase in efficacy following induction treatment with 1200 mg IV at Week 0, 4 and 8, with greater response rates observed with higher exposures across all evaluated endpoints at Week 12, in line with the results from Phase 2b. ER analyses for maintenance demonstrated an exposure-dependent increase in efficacy for Week 52 endpoints, with modest improvement in efficacy when increasing the dose from 180 mg to 360 mg, and largely overlapping confidence intervals. ER analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment. Conclusion The PPK and ER analyses of RZB in subjects with UC characterized the disposition of RZB and its relationship to efficacy and safety, as well as the lack of impact by intrinsic and extrinsic factors on PK and efficacy. Results supported the final dosing regimen recommendations for the treatment of moderately to severely active UC.

Meltdose Tacrolimus Population Pharmacokinetics and Limited Sampling Strategy Evaluation in Elderly Kidney Transplant Recipients.

Meltdose tacrolimus (Envarsus®) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose individualization is essential. Relaxation of the upper age limits for kidney transplantations has resulted in larger numbers of elderly patients receiving tacrolimus. However, due to the physiological changes caused by aging, the tacrolimus pharmacokinetics (PK) might be altered. The primary aim was to develop a population PK model in elderly kidney transplant recipients. Secondary aims were the development and evaluation of a limited sampling strategy (LSS) for AUC estimation. A total of 34 kidney transplant recipients aged ≥65 years, starting on meltdose tacrolimus directly after transplantation, were included. An eight-point whole blood AUC0-24h and an abbreviated dried blood spot (DBS) AUC0-24h were obtained. The PK data were analyzed using nonlinear mixed effect modeling methods. The PK data were best described using a two-compartment model, including three transit compartments and a mixture model for oral absorption. The best three-sample LSS was T = 0, 2, 6 h. The best four-sample LSSs were T = 0, 2, 6, 8 h and T = 0, 1, 6, 8 h. The developed population PK model adequately described the tacrolimus PK data in a population of elderly kidney transplant recipients. In addition, the developed population PK model and LSS showed an adequate estimation of tacrolimus exposure, and may therefore be used to aid in tacrolimus dose individualization.

Optimizing the design of a pharmacokinetic trial to evaluate the dosing scheme of a novel tuberculosis drug in children living with or without HIV.

Pharmacokinetic (PK) studies in children are usually small and have ethical constraints due to the medical complexities of drawing blood in this special population. Often, population PK models for the drug(s) of interest are available in adults, and these models can be extended to incorporate the expected deviations seen in children. As a consequence, there is increasing interest in the use of optimal design methodology to design PK sampling schemes in children that maximize information using a small sample size and limited number of sampling times per dosing period. As a case study, we use the novel tuberculosis drug delamanid, and show how applications of optimal design methodology can result in highly efficient and model-robust designs in children for estimating PK parameters using a limited number of sampling measurements. Using developed population PK models based on available data from adults living with and without HIV, and limited data on children without HIV, competing designs for children living with HIV were derived and assessed based on robustness to model uncertainty.

Development and internal validation of a clinical prediction model for individualized dosing of BAY 81-8973, A full-length recombinant factor VIII, in pediatric patients with haemophilia A

BackgroundAs the most commonly used coagulation factor VIII (FVIII) concentrate in China, the individualized dosing prediction model of Kovaltry (BAY81–8973) is not fully investigated in pediatric patients. The prophylaxis tailored by population pharmacokinetic (PopPK) model can optimize dosing regimens. ObjectivesThis study aimed to develop PopPK models of BAY 81–8973 in pediatric patients, identify quantitative relationships of blood type (as a substitution for von Willebrand factor) on FVIII clearance and provide model-informed precision dosing (MIPD) procedures. MethodsPediatric patients with severe hemophilia A were enrolled and PK tests were conducted. The blood samples were collected at six time point. One-stage-based activated partial thromboplastin time was used for FVIII activity. Basic demographics and key covariates (blood type and von Willebrand factor antigen) were collected. A nonlinear mixed-effect modeling (NONMEM) approach was employed to establish PopPK model. Simulations were performed to evaluate current dosing regimens and present MIPD strategies. ResultsA total of 30 pediatric patients were included in the analysis. In the final model, Fat-free mass calculated from weight, age, and height was included as a size descriptor which affect FVIII apparent volume of distribution and clearance. Both von Willebrand factor antigen (VWF:Ag) and blood type accounted for the interindividual variability of FVIII clearance, but only one can retain in the final model. Therefore, two PopPK models based on VWF:Ag or blood type were developed. When the VWF:Ag value is doubled, the FVIII clearance is reduced by 35 %. Compared with blood type non-O, the clearance in pediatric patients with blood type O increased by 25.9 %. Weight-based dosing without regard to age and blood type resulted in large differences in FVIII trough activity. Patient demographics, dosing information, sparse blood samples and PopPK model together with Bayesian estimate constituted the MIPD workflow. Using it, the individual parameters and optimized dosing regimen could be achieved. ConclusionThis is the first predictive model designed to predict individualized dosing of BAY 81–8973 in pediatric patients with Hemophilia A. These results are useful in the PK-guided prophylaxis among pediatric patients and hold great potential to improve their long-term clinical outcomes.

Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates: A Pooled Population Pharmacokinetic Study.

There is a lack of evidence on oral amoxicillin pharmacokinetics and exposure in neonates with possible serious bacterial infection (pSBI). We aimed to describe amoxicillin disposition following oral and intravenous administration and to provide dosing recommendations for preterm and term neonates treated for pSBI. In this pooled-population pharmacokinetic study, 3 datasets were combined for nonlinear mixed-effects modeling. In order to evaluate amoxicillin exposure following oral and intravenous administration, pharmacokinetic profiles for different dosing regimens were simulated with the developed population pharmacokinetic model. A target of 50% time of the free fraction above the minimal inhibitory concentration (MIC) with an MICECOFF of 8 mg/L (to cover gram-negative bacteria such as Escherichia coli) was used. The cohort consisted of 261 (79 oral, 182 intravenous) neonates with a median (range) gestational age of 35.8 weeks (range, 24.9-42.4) and bodyweight of 2.6 kg (range, 0.5-5). A 1-compartment model with first-order absorption best described amoxicillin pharmacokinetics. Clearance (L/h/kg) in neonates born after 30 weeks' gestation increased with increasing postnatal age (PNA day 10, 1.25-fold; PNA day 20, 1.43-fold vs PNA day 3). Oral bioavailability was 87%. We found that a twice-daily regimen of 50 mg/kg/day is superior to a 3- or 4-times daily schedule in the first week of life for both oral and intravenous administration. This pooled population pharmacokinetic description of intravenous and oral amoxicillin in neonates provides age-specific dosing recommendations. We conclude that neonates treated with oral amoxicillin in the first weeks of life reach adequate amoxicillin levels following a twice-daily dosing regimen. Oral amoxicillin therapy could therefore be an adequate, cost-effective, and more patient-friendly alternative for neonates worldwide.

Clinical trial simulation to evaluate tenofovir disoproxil fumarate/emtricitabine HIV pre-exposure prophylaxis dosing during pregnancy.

To evaluate upward-adjustment of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) pre-exposure prophylaxis (PrEP) dosing during pregnancy in order to maintain target plasma concentrations associated with HIV protection. Population pharmacokinetic (PK) modeling and clinical trial simulation (CTS). We developed population pharmacokinetic models for TFV and FTC using data from the Partners Demonstration Project and a PK study of TDF/FTC among cisgender women by Coleman et al., and performed an in-silico simulation. Pregnancy-trimester was identified as a significant covariate on apparent clearance in the optimized final model. We simulated 1,000 pregnant individuals starting standard daily oral TDF/FTC (300 mg/200 mg) prior to pregnancy. Upon becoming pregnant, simulated patients were split into two study arms: one continuing standard-dose and the other receiving double standard-dose throughout pregnancy. Standard-dose trough TFV concentrations were significantly lower in pregnancy compared to pre-pregnancy, with 34.0%, 43.8%, and 65.1% of trough plasma concentrations below the lower bound of expected trough concentrations presumed to be the protective threshold in the 1st, 2nd, and 3rd trimesters, respectively. By comparison, in the simulated double-dose group, 10.7%, 14.4%, and 27.8% of trough concentrations fell below the estimated protective thresholds in the 1st, 2nd, and 3rd trimesters, respectively. The FTC trough plasma concentration during pregnancy was also lower than pre-pregnancy, with 45.2% of the steady-state trough concentrations below the estimated protective trough concentrations of FTC. In the pregnancy-adjusted double-dose group, 24.1% of trough plasma concentrations were lower than protective levels. Our simulation shows >50% of research participants on standard dosing would have 3rd trimester trough plasma TFV concentrations below levels associated with protection. This simulation provides the quantitative basis for the design of prospective TDF/FTC studies during pregnancy to evaluate the safety and appropriateness of pregnancy-adjusted dosing.

Population pharmacokinetics of apixaban in a real-life hospitalized population from the OptimAT study.

This study aimed to characterize apixaban pharmacokinetics (PKs) and its variability in a real-world clinical setting of hospitalized patients using a population PK (PopPK) approach. Model-based simulations helped to identify factors that affect apixaban exposure and their clinical significance. A classic stepwise strategy was applied to determine the best PopPK model for describing typical apixaban PKs in hospitalized patients from the OptimAT study (n = 100) and evaluating the associated variability and influencing factors. Apixaban exposure under specific conditions was assessed using the final model. A two-compartment model with first-order absorption and elimination best described the data. The developed PopPK model revealed a major role of renal function and a minor role of P-glycoprotein phenotypic (P-gp) activity in explaining apixaban variability. The final model indicated that a patient with stage 4 chronic kidney disease (creatinine clearance [CLcr] = 15-29 mL/min) would have a 45% higher drug exposure than a patient with normal renal function (CLcr >90 mL/min), with a further 12% increase if the patient was also a poor metabolizer of P-gp. A high interindividual variability in apixaban PKs was observed in a real-life setting, which was partially explained by renal function and by P-gp phenotypic activity. Target apixaban concentrations are reached under standard dosage regimens, but overexposure can rapidly occur in the presence of cumulative factors warranting the development of a predictive tool for tailoring apixaban exposure and its clinical utility in at-risk patients.

Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy.

Oxcarbazepine (OXC) is an antiepileptic drug whose efficacy is largely attributed to its monohydroxy derivative metabolite (MHD). Nevertheless, there exists significant inter-individual variability in both the pharmacokinetics and therapeutic response of this drug. The objective of this study is to explore the impact of patients' characteristics and genetic variants on MHD clearance in a population pharmacokinetic (PPK) model of Chinese pediatric patients with epilepsy. The PPK model was developed using a nonlinear mixed effects modeling method based on 231 MHD plasma concentrations obtained from 185 children with epilepsy. The one-compartment model and combined residual model were established to describe the pharmacokinetics of MHD. Forward addition and backward elimination were employed to evaluate the impact of covariates on the model parameters. The model was evaluated using goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. In the two final PPK models, age, estimated glomerular filtration rate (eGFR), and a combined genotype of six variants (rs1045642, rs2032582, rs7668282, rs2396185, rs2304016, rs1128503) were found to significantly reduce inter-individual variability for MHD clearance. The inter-individual clearance equals to 1.38 × (Age/4.74)0.29 × (eGFR/128.66)0.25 × eθABCB-UGT-SCN-INSR for genetic variants included model and 1.30 × (Age/4.74)0.30 × (eGFR/128.66)0.23 for model without genetic variants. The precision of all parameters was deemed acceptable, and the model exhibited good predictability while remaining stable and effective. Conclusion: Age, eGFR, and genotype may play a significant role in MHD clearance in children with epilepsy. The developed PPK models hold potential utility in facilitating oxcarbazepine dose adjustment in pediatric patients. What is Known: • The adjustment of the oxcarbazepine regimen remains difficult due to the considerable inter- and intra-individual variability of oxcarbazepine pharmacokinetics. • Body weight and co-administration with enzyme-inducing antiepileptic drugs emerge as the most influential factors contributing to the pharmacokinetics of MHD. What is New: • A positive correlation was observed between eGFR and the clearance of MHD in pediatric patients with epilepsy. • We explored the influence of genetic polymorphisms on MHD clearance and identified a combined genotype (ABCB-UGT-SCN-INSR) that exhibited a significant association with MHD concentration.

Development of a population pharmacokinetic model to characterize the pharmacokinetics of intrathecally administered tominersen in cerebrospinal fluid and plasma.

Tominersen is an intrathecally administered antisense oligonucleotide targeting huntingtin mRNA which leads to a dose-dependent, reversible lowering of cerebrospinal fluid (CSF) mutant huntingtin protein concentration in individuals with Huntington's disease. Nonlinear mixed-effect population pharmacokinetic (PopPK) modeling was conducted to characterize the CSF and plasma pharmacokinetics (PK) of tominersen, and to identify and quantify the covariates that affect tominersen PKs. A total of 750 participants from five clinical studies with a dose range from 10 to 120 mg contributed CSF (n = 6302) and plasma (n = 5454) PK samples. CSF PK was adequately described by a three-compartment model with first-order transfer from CSF to plasma. Plasma PK was adequately described by a three-compartment model with first-order elimination from plasma. Baseline total CSF protein, age, and antidrug antibodies (ADAs) were the significant covariates for CSF clearance. Body weight was a significant covariate for clearances and volumes in plasma. ADAs and sex were significant covariates for plasma clearance. The developed PopPK model was able to describe tominersen PK in plasma and CSF after intrathecal administration across a range of dose levels, and relevant covariate relationships were identified. This model has been applied to guide dose selection for future clinical trials of tominersen in patients with Huntington's disease.

Dabigatran Dosing Proposal for Adults With Atrial Fibrillation: Stress-Testing Renal Function Range in Real World Patients.

Dabigatran is the first of four direct-acting oral anticoagulants approved to prevent stroke in adult patients with atrial fibrillation using a fixed two-dose scheme compared with warfarin dosing adjusted to a prothrombin time range associated with optimal risk reduction in stroke and serious bleeding. The pivotal phase III trial found dabigatran, depending on dose, is superior to warfarin in stroke reduction and similar in bleeding risk while also showing dabigatran efficacy and safety correlate with steady-state plasma concentrations. Because the relationship between dabigatran dose and plasma concentration is highly variable, a previously developed population pharmacokinetic model of over 9,000 clinical trial patients was used as a basis for simulations comparing the performance of dosing via the drug label to other proposed doses and regimens. Assessment of dosing regimen performance was based on simulations of trough plasma levels within the therapeutic concentration range of 75-150 ng/mL over a renal function range of 15-250 mL/min creatinine clearance, representing extremes for real-world patients. An improved regimen that best achieves this therapeutic range was identified, requiring five different dosing schedules, corresponding to specified renal function ranges, compared with the two approved in the label. The discussion focuses on how this information could better inform patient outcomes and future dabigatran development.

Optimal dosing regimen of biapenem based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation in patients with febrile neutropenia and haematological malignancies

In the current study, a population pharmacokinetic (PPK) model was developed for biapenem in patients with febrile neutropenia (FN) and haematological malignancies. Through Monte Carlo simulation, optimal administration regimens were suggested based on the developed PPK model. In a prospective, single-centre, open-label study, 174 plasma samples from 120 Chinese patients with FN and haematological malignancies were analysed by chromatography, and PK parameters were analysed by NONMEM. The drug clearance process was influenced by crucial covariates, namely creatinine clearance (CLCR) and concomitant posaconazole (POS). The ultimate PPK model was as follows: CL (L/h)=29.81×(CLCR/121.38)0.806×(1-POS×0.297); volume of distribution (L)=114. For the target of ≥40% fT>minimum inhibitory concentration (MIC) (duration that the plasma level exceeds the MIC of the causative pathogen) and achieving the probability of target attainment ≥90%, the PK/pharmacodynamic breakpoint was 2 mg/L for the 2.4 g/day dosing regimen consisting of 600 mg q6h and 800 mg q8h. The breakpoint was 1 mg/L for the 1.2 g/day dosing regimen consisting of 300 mg q6h and 600 mg q12h. Empirical therapy would benefit from utilizing higher dosages and extended infusion durations. Therefore, it is suggested that patients with symptoms that are strongly suggestive of Pseudomonas aeruginosa or Acinetobacter baumannii infection may be suitable for combined treatment with other antibacterial drugs.

Variable Delta-9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics After Cannabis Smoking in Regular Users.

Despite its federally restricted status, cannabis is widely used medicinally and recreationally. The pharmacokinetics (PK) and central nervous system (CNS) effects of tetrahydrocannabinol (THC), the major psychoactive cannabinoid, are not well understood. The objective of this study was to develop a population PK model of inhaled THC, including sources of variability, and to conduct an exploratory analysis of potential exposure-response relationships. Regular adult cannabis users smoked a single cannabis cigarette containing 5.9% THC (Chemovar A) or 13.4% THC (Chemovar B) ad libitum. THC concentrations in whole blood were measured and used to develop a population PK model to identify potential factors contributing to interindividual variability in THC PK and to describe THC disposition. Relationships between model-predicted exposure and heart rate, change in composite driving score on a driving simulator, and perceived highness were evaluated. From the 102 participants, a total of 770 blood THC concentrations were obtained. A two-compartment structural model adequately fit the data. Chemovar and baseline THC (THC BL ) were found to be significant covariates for bioavailability, with Chemovar A having better THC absorption. The model predicted that heavy users-those with the highest THC BL -would have significantly higher absorption than those with lighter previous use. There was a statistically significant relationship between exposure and heart rate, and exposure and perceived highness. THC PK is highly variable and related to baseline THC concentrations and different chemovars. The developed population PK model showed that heavier users had higher THC bioavailability. To better understand the factors affecting THC PK and dose-response relationships, future studies should incorporate a wide range of doses, multiple routes of administration, and different formulations relevant to typical community use.

621. Pharmacokinetics Determinant and Risk Factors of Daptomycin Induced Eosinophilic Pneumonia and Muscular Toxicity: A Survival Analysis in patients treated for Bone and Joint Infection.

Abstract Background Daptomycin prescription for patients suffering from Bone and Joint infections increased in recent years. However, the implication between daptomycin exposure, concomitant factor, and the occurrence of either daptomycin-induced eosinophilic pneumonia (DIEP) or CPK elevation is not clearly understood. Methods All patients treated for a bone and joint infection (BJI) between 2014 and 2021 were screened and classified into cases if they experienced a CPK elevation or DIEP. The controls were randomly selected at a 1:3 ratio within the same period of inclusion. Daptomycin levels were obtained from routine therapeutic drug monitoring. In addition, demographic and biology data were also obtained from the computerized file of patients. Those data were used to compute the area under the concentration-time curve (AUC) of daptomycin using a previously developed population pharmacokinetic model. Finally, a univariate analysis was performed and all data with a p-value < 0.1 were included in the multivariate survival analysis using a proportional Cox hazard model. Results A total of 1130 patients were screened from which 16 patients with DIEP, 42 with CPK elevation, and 107 control were included in the final analysis. Age, CRP, Creatinine, Creatinine Clearance, Serum protein, AUC, and through concentrations were significantly different between case and controls. Summary of univariate analysis is available in table 1. After multivariate analysis, only 3 predictors remained significantly associated with the occurrence of DIEP or CPK elevation. The adjusted hazard ratio of developing DIEP of CPK elevation, were 3.1 (95% CI: 1.48 – 6.5, p < 0.001) for a daptomycin AUC > 939 mg.h/L, 9.8 (95% CI 3.94 – 24.5, p < 0.001) for CRP > 21.6mg/L and 2.4 (95% CI 1.02 – 5.65, p = 0.04] for Protein < 72g/L. Survival curves are shown in figure1. Variable identified in the whole population remained significant in DIEP or CPK subgroup analyses. Table 1.Patients characteristics at time of inclusionFigure 1.Survival analysis of the whole population according to AUC and CRP levels. Conclusion The risk of experiencing DIEP or CPK elevation was greater in patients with an AUC0-24 above 939 mg.h/L and a CRP > 21.6mg/L. Daptomycin Therapeutic drug monitoring should be performed and an AUC range of 666 to 939 mg.h/L should be targeted in order to maximize efficacy and minimize the risk of adverse events, especially for patients with an inflammatory syndrome. Disclosures All Authors: No reported disclosures.

Effect of Predicted Fludarabine Lymphodepletion Exposure on Clinical Outcomes in Myeloma Patients Undergoing BCMA-CAR-T: An Exploratory Analysis from CARTITUDE-1

Background: BCMA-targeted chimeric antigen receptor-engineered (anti-BCMA CAR) T-cell therapy has demonstrated favorable clinical outcomes in relapsed and refractory multiple myeloma (RRMM). Lymphodepleting (LD) chemotherapy including fludarabine (Flu) is hypothesized to promote expansion and persistence of CAR-T cells. Flu exhibits wide pharmacokinetic (PK) variability, with increased exposure as calculated by population PK model correlating with improved outcomes after anti-CD19+ CAR-T (Fabrizio VA, Blood Advances, 2022 & Dekker L. et al, Blood Advances, 2022). Using clinical data from patients enrolled in the CARTITUDE-1 clinical trial (NCT03548207, N=97), a phase 1b/2 study assessing ciltacabtagene autoleucel (cilta-cel) in patients with RRMM, we hypothesized that the developed population PK model may predict outcomes after cilta-cel in myeloma. Methods: Patients in the trial received a single cilta-cel infusion 5 to 7 days after fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for 3 consecutive days. Patients were excluded if they received any LD other than Flu/Cy or had any missing data needed to predict Flu exposure. Predicted exposure (pAUC) of Flu was determined by applying a population approach where eGFR is a covariate for Flu clearance and body weight is a covariate for Flu clearance and volume of distribution (Langenhorst JB, Clinical Pharmacokinetics, 2019). Individual Flu PK profiles and exposure metrics (Cmax, Ctrough and AUC0-72h) were simulated for each patient and were correlated with anti-BCMA CAR-T kinetics and efficacy (IMWG response, PFS and OS). Pearson/Spearman correlation coefficient was used to estimate the association between Flu PK parameters and LD effect, reflected by endogenous T cell changes (prior to versus post-LD), and CAR-T kinetics. Parametric t-test was used as the primary analysis and Mann-Whitney as the sensitivity analysis to determine if Flu AUC was associated with whether the patient can achieve stringent complete response (sCR) or not. PFS and OS rates were compared between 2 patient groups stratified by dichotomized LD exposure (AUC above and below the median). Results: We first investigated if there was variability in the two significant covariates of Flu PK in our cohort- body weight and eGFR. The eGFR distribution indicated large variability (mean=94.2, CV%=33.5) with 50 (51.5%) patients having renal dysfunction (eGFR <90 ml/min/1.73m2). Body weight ranged from 39 to 125.6 kg. The Flu pAUC in the entire population varied by 3.1-fold and the median was found to be 19.4 mg x h/L (IQR, 16.7-21.4; Figure 1A). No apparent association between Flu pAUC and CAR-T expansion and persistence was observed. Predicted peak Flu concentration (p=0.052) and AUC (p=0.058) appear to be slightly higher in sCR patients than non-sCR patients with significant overlapping (Figure 1B). Kaplan-Meier plot of PFS/OS (data cutoff: approximately 12 months of the last patient after CAR-T infusion) suggested no apparent association with LD exposure (p= 0.093 and 0.4 respectively). Analysis is ongoing to determine if there is an association between Flu pAUC and CRS/ICANS with results to be presented at the conference. Conclusions: Although we did not measure Flu blood levels, we report for the first time the application of a previously published population PK model to simulate Flu exposure in a prospective cohort of myeloma patients undergoing anti-BCMA CAR-T therapy. Predicted peak Flu concentration and AUC appears to be slightly higher in sCR patients than non-sCR patients and there was no apparent correlation with CART kinetics or PFS/OS. Our data suggests a trend in Flu exposure predicting PFS but this needs to be further validated with additional data and analysis. Because the actual individual Flu exposure may deviate from the predicted population mean, a definitive analysis will require measurement of Flu blood levels prospectively with lymphodepletion to confirm potential relationships between Flu AUC, CART expansion & persistence, and CART clinical activity. Figure 1. Distribution of Model-predicted Flu AUC0-72h (A). Boxplots of Peak Flu Concentration and Flu pAUC (B) with Stringent Complete Response. Boxplot shows the minimum, 25th quartile, median, 75th quartile, and maximum of the data. Symbols represent individual simulated data points in (B). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characterization of exposure–response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study

PurposeThe exposure–response relationships for efficacy and safety of ipatasertib, a selective AKT kinase inhibitor, were characterized using data collected from 1101 patients with metastatic castration-resistant prostate cancer in the IPATential150 study (NCT03072238).MethodsExternal validation of a previously developed population pharmacokinetic model was performed using the observed pharmacokinetic data from the IPATential150 study. Exposure metrics of ipatasertib for subjects who received ipatasertib 400 mg once-daily orally in this study were generated as model-predicted area under the concentration–time curve at steady state (AUCSS). The exposure–response relationship with radiographic progression-free survival (rPFS) was evaluated using Cox regression and relationships with safety endpoints were assessed using logistic regression.ResultsA statistically significant correlation between ipatasertib AUCSS and improved survival was found in patients with PTEN-loss tumors (hazard ratio [HR]: 0.92 per 1000 ng h/mL AUCSS, 95% confidence interval [CI] 0.87–0.98, p = 0.011). In contrast, an improvement in rPFS was seen in subjects receiving ipatasertib treatment (HR: 0.84, 95% CI 0.71–0.99, p = 0.038) but this effect was not associated with ipatasertib AUCSS in the intention-to-treat population. Incidences of some adverse events (AEs) had statistically significant association with ipatasertib AUCSS (serious AEs, AEs leading to discontinuation, and Grade ≥ 2 hyperglycemia), while others were associated with only ipatasertib treatment (AEs leading to dose reduction, Grade ≥ 3 diarrhea, and Grade ≥ 2 rash).ConclusionsThe exposure–efficacy results indicated that patients receiving ipatasertib may continue benefiting from this treatment at the administered dose, despite some variability in exposures, while the exposure–safety results suggested increased risks of AEs with ipatasertib treatment and/or increased ipatasertib exposures.

Comparison of Dose Adjustment Strategies for Obesity in High-dose Cyclophosphamide Among Adult Hematopoietic Cell Transplantation Recipients: Pharmacokinetic Analysis

Cyclophosphamide (CY) is an alkylating agent widely used in the field of oncology and hematopoietic cell transplantation (HCT). It is recommended to use an adjusted body weight with an adjustment factor of 0.25 (ABW25) for dosing of CY in obese patients undergoing HCT. However, evidence based on the pharmacokinetics (PK) of CY to support this recommendation is lacking. We aimed to identify a dosing strategy of CY that achieves equivalent exposures among obese and nonobese patients. The present study is a secondary analysis of a previously conducted observational PK study of phosphoramide mustard (PM), the final cytotoxic metabolite of CY. Data were collected from 85 adults with hematologic malignancy who received a single infusion of CY 50 mg/kg, fludarabine, ± anti-thymocyte globulin, and a single fraction of total body irradiation as HCT conditioning therapy. A previously developed population PK model in these patients was used for simulations. Using individualized PK parameters from that analysis, simulations were performed to assess cumulative exposures of PM (i.e., area-under-the-curve [AUC]) resulting from 8 different dosing strategies according to various measures of body size: (1) “mg/kg” by total body weight (TBW); (2) “mg/kg” by ideal body weight (IBW); (3) “mg/kg” by fat free mass; (4) “mg/m2” by body surface area (BSA); (5) “mg/kg” by TBW combined with ABW25 (TBW-ABW25); (6) “mg/kg” by IBW combined with ABW25 (IBW-ABW25); (7) “mg/kg” by TBW combined with ABW by adjustment factor of 0.50 (TBW-ABW50); and (8) “mg” by fixed-dose. We defined equivalent exposure as the effect of obesity on PM AUC within ±20% from the PM AUC in the nonobese group, where obesity is defined based on TBW/IBW ratio (i.e., nonobese, <1.2; mildly obese, 1.2-1.5; and moderately/severely obese, >1.5). Primary and secondary outcomes were PM AUC0-8hours and PM AUC0-infinity, respectively. In the 85 patients, with the median age of 63 years (range 21-75), 46% were classified as mildly and 25% were moderately/severely obese based on the TBW/IBW ratio. Negative correlations (i.e., higher the extent of obesity, lower the PM AUC) were shown when dosing simulations were based on IBW, TBW-ABW25, and fixed dosing (P < .05). Positive correlations were shown when dosing was simulated by TBW (P < .05). None of the 8 dosing strategies attained equivalent PM AUC0-8hours between patients with versus without obesity, whereas dosing by BSA and TBW-ABW50 attained equivalent PM AUC0-infinity (P < .05). Our study predicted that the recommended ABW25 dose adjustment may result in lower exposure of CY therapy in obese patients than in nonobese. A CY dosing strategy that would result in similar PM concentrations between obese and nonobese was not identified for early exposure (i.e., PM AUC0-8hours). The data suggest though that CY dosing based on “mg/m2” by BSA or “mg/kg” by TBW-ABW50 would result in similar total exposure (i.e., PM AUC0-infinity) and may minimize exposure differences in obese and nonobese patients.