Final Population Pharmacokinetic Model Research Articles

Population pharmacokinetic study of caffeine citrate in Chinese premature infants with apnea.

Caffeine citrate is a commonly used methylxanthine for pharmacologic treatment of apnea of prematurity. The aim of this study was to develop and verify a population pharmacokinetic (PPK) model, which can provide a reference for individualized caffeine citrate treatment of apnea in Chinese premature infants. A total of 88 serum concentration measurements from 46 preterm patients (median gestational age 29weeks) were retrospectively collected and the relevant clinical data of patients were recorded. The PPK analysis was performed by non-linear mixed-effect modelling method using NONMEM. Allometric scaling was applied in the PPK analysis, and the final model was evaluated by graphic and statistical methods, including goodness-of-fit plots, normalized prediction distribution errors plots and bootstrap procedures. A one-compartment model with first-order elimination was successfully fitted to the data. The typical scaled values for the parameters clearance and volume of distribution (V) were 0.268L/h and 109L per 70kg, respectively. The weight at the time of blood collection (CW) and post-natal age were identified as important predictors for pharmacokinetic parameters of caffeine. The evaluation process showed good stability and predictability of the final PPK model. This is a complete PPK study of caffeine citrate in Chinese premature infants with apnea, which complements caffeine pharmacokinetic data of the premature from China. A final PPK model was developed which may serve as a beneficial tool for the use of caffeine citrate in the treatment of apnea in Chinese preterm infants.

Dosing Recommendations Based on Population Pharmacokinetics of Lamotrigine in Mexican Adult Patients With Epilepsy

Dose individualization is essential in epilepsy treatment, especially in antiepileptic drugs that present high interindividual variability such as lamotrigine. We aimed an observational study to develop a population pharmacokinetic model for quantitative evaluation of the factors that influence lamotrigine pharmacokinetics in Mexican adults with epilepsy. Patients on stable treatment with lamotrigine therapy were included, plasma concentrations were analyzed by a high-performance liquid chromatography method and UGT2B7–161C > T polymorphism was determined. The data were analyzed by NONMEM® 7.3, model validation was performed using bootstrap approach and visual predictive check. Finally, stochastic simulations were carried out to propose dosage regimens. A total of 73 lamotrigine plasma concentrations from 2 h after last dose and up to 0.5 h prior to next administration were fitted to a one-compartment open model. The final population pharmacokinetic model for lamotrigine indicates that concomitant treatment with valproic acid and carbamazepine should be considered to individualize epilepsy treatment with this drug. Based on this model, we proposed dosage regimens to achieve trough lamotrigine concentrations within reference interval (2.5–15 mg/L). These results provide clinical useful data to give more rational anticonvulsant therapy in our population.

Population pharmacokinetic/pharmacodynamic modelling of nifekalant in healthy Chinese volunteers

Nifekalant is a class III antiarrhythmic drug, and its major adverse effect is prolongation of the QT interval. This study analysed data generated from a pharmacokinetic (PK) study to develop a population PK/pharmacodynamics (PD) model for describing the relationship between plasma concentrations and prolongation of the QT interval over time following intravenous administration of nifekalant. This open-labelled, phase I clinical study comprised two dose level groups of eight healthy Chinese volunteers. Concentrations of nifekalant in plasma samples collected at set time-points were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. A PK/PD model was constructed using a non-linear mixed-effects approach (Phoenix NLME 8.1). Furthermore, demographic covariates of the model were investigated and a concentration factor (ConcƟ) was introduced as the only covariate which improved the performance of the model. The final population PK model exhibited one-order elimination with two-compartment distribution and adequately described nifekalant plasma concentrations over time. The QT interval prolongation was best described by an indirect effect model with an inhibition build-up effect, representing the relationship between plasma concentrations and effect. The final population PK/PD model may facilitate more accurate predictions of the drug profile in clinical settings in the future.

Initial dosage optimization of ciclosporin in pediatric Chinese patients who underwent bone marrow transplants based on population pharmacokinetics.

Bone marrow transplants (BMT) are an established therapeutic strategy for patients with severe aplastic anemia, acute lymphoblastic leukemia, acute myeloid leukemia or chronic myeloid leukemia. However, the successful application of BMT is limited by graft-vs.-host disease (GVHD). Ciclosporin has been widely used for treating GVHD in pediatric patients who underwent BMT. The present study aimed to optimize the dosage of ciclosporin for safety and effectiveness based on population pharmacokinetics. A non-linear mixed-effects model was used to analyze the clinical data of pediatric patients who underwent BMT between September 2016 and September 2019 at the Children's Hospital of Fudan University. Monte Carlo simulations were used to identify the optimal dose of ciclosporin. The final population pharmacokinetic model indicated that body weight and days post-transplant influenced the clearance of ciclosporin in pediatric patients who underwent BMT. The present study indicated that the optimal initial dose of ciclosporin for pediatric patients weighing 5-30 kg who underwent BMT was 6 mg/kg/day split into 2 doses.

Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women.

This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase2/3 studies. Data from multiple phase1 (P005, P025, and P014), phase2b (P004 and P022), and phase3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase1, 514 from phase2b, and 664 from phase3) who received weekly oral odanacatib doses ranging from 3 to 100mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3-mg oral dose to 24.5% for a 100-mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high-fat breakfast, and a study effect on F1. All fixed- and random-effects parameters were estimated with good precision (%standard error of the mean ≤29.5%). This population PK analysis provides insights into intrinsic- and extrinsic-factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic-factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80-1.21) even in subjects aged >80 years, or in subsets with multiple combinations of factors.

Population Pharmacokinetics of IV Phenobarbital in Neonates After Congenital Heart Surgery.

To develop a population pharmacokinetic model for IV phenobarbital in neonates following cardiac surgery and perform simulations to identify optimal dosing regimens. Retrospective single-center pharmacokinetic study. Cardiac ICU at Children's Hospital of Philadelphia. Consecutive neonates who received greater than or equal to one dose of IV phenobarbital and had greater than or equal to one phenobarbital concentration drawn per standard of care from June 15, 2012, to October 15, 2018. None. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model variables. Optimal phenobarbital loading doses were determined based on attainment of peak and maintenance concentrations between 20 and 40 mg/L. A total of 37 neonates contributed 159 pharmacokinetic samples. The median (range) weight, postmenstrual age, and postnatal age were 3.2 kg (1.3-3.8), 39 2/7 weeks (28 2/7 to 42 6/7), and 5 days (0-26 d), respectively. Twelve patients (32%) were on extracorporeal membrane oxygenation. An one-compartment model best described the data. The final population pharmacokinetic model included (1) weight and postnatal age for clearance and (2) weight, extracorporeal membrane oxygenation, and albumin for volume of distribution. In neonates not on extracorporeal membrane oxygenation, loading doses of 30 and 20 mg/kg reached goal concentration with albumin values less than or equal to 3 and 3.5 mg/dL, respectively. Loading doses of 30 mg/kg reached goal concentration on extracorporeal membrane oxygenation regardless of albumin values. Maintenance doses of 4-5 mg/kg/d reached goal concentration in all neonates. In neonates following cardiac surgery, phenobarbital clearance increased with postnatal age. Volume of distribution increased with extracorporeal membrane oxygenation and lower albumin values. Loading doses of 30 mg/kg on extracorporeal membrane oxygenation and 20-30 mg/kg without extracorporeal membrane oxygenation were needed to reach goal concentration based on simulations.

Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia.

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen–minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration–time curve over 24 h ≥ 96 μg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75–101) years, were investigated. The plasma-concentration–time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 μg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50–60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

Pharmacokinetic interaction of Forsythia suspensa extract and azithromycin injection after single and co-intravenous administration in rats.

Azithromycin and Chinese medicine forsythia are often used together to treat pediatric mycoplasma infections in China. We aimed to investigate the pharmacokinetic interaction of Forsythia suspensa extract and azithromycin after single and co-intravenous administration in rats. Male Sprague-Dawley rats received single (Forsythia suspensa extract or azithromycin) treatment or co-administration of Forsythia suspensa extract and azithromycin. Blood samples were collected at scheduled times, and drug concentrations were determined by HPLC-UV or HPLC-MS/MS methods. Both non-compartmental analyses and nonlinear mixed-effects modeling approaches were applied to fit pharmacokinetic data and evaluate the impact of co-administration. Pharmacokinetic analysis showed that the area under the curve of azithromycin and forsythiaside increased, and clearance decreased significantly (P < 0.05), after co-administration. The in vivo behavior of both azithromycin and forsythiaside could be appropriately described by the two-compartmental model. The final population pharmacokinetic model indicated that co-administration decreased the central volume of azithromycin and forsythiaside clearance significantly. Co-administration of Forsythia suspensa extract and azithromycin significantly decreased the clearance and increased exposure for both drugs. Pharmacokinetic data suggest that drug co-administration may increase efficiency.

Population pharmacokinetics of high‐dose methotrexate in Chinese pediatric patients with medulloblastoma

Methotrexate (MTX) pharmacokinetics has substantial inter-individual variability and toxicity. In children with medulloblastoma treated with high-dose methotrexate (HD-MTX), the pharmacokinetic properties of methotrexate have not been established. A total of 660 serum samples from 105 pediatric patients with medulloblastoma were included in a population pharmacokinetic (PPK) analysis of methotrexate by using the nonlinear mixed-effects modeling method. The basic one-compartment population pharmacokinetic model was established by NONMEM software and the first-order conditional estimation (FOCE) method, and the final covariate model was obtained by the stepwise regression method. Weight (WT), creatinine clearance (CrCL), and whether the treatment was combined with dexamethasone (DEX) were covariates that had significant effects on the clearance rate (CL) of the model. The pharmacokinetic equation of CL in the final covariate model was as follows: CLi = 9.23× (1 + 0.0005× (θCrCL -105.78)) × (1 + 0.0017× (θWT -16)) × eηcl,i (L/h), IF (θDEX ) CLi = 1.19× CLi (L/h). The estimation accuracy of all pharmacokinetic parameters were acceptable (relative standard error < 14.74%). The goodness-of-fit diagram and bootstrap tests indicated that the final PPK model was stable with acceptable predictive ability. The PPK model may be useful for determining personalized medication levels in pediatric medulloblastoma patients undergoing HD-MTX therapy.

Pharmacokinetic Modeling, Simulation, and Development of a Limited Sampling Strategy of Cycloserine in Patients with Multidrug-/Extensively Drug-Resistant Tuberculosis.

Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokinetic model of cycloserine to assess drug exposure and to develop a limited sampling strategy for cycloserine exposure monitoring. Patients with multidrug-/extensively drug-resistant tuberculosis who were treated for > 7days with cycloserine were eligible for inclusion. Patients received cycloserine 500mg (body weight ≤ 50kg) or 750mg (body weight > 50kg) once daily. MW/Pharm 3.83 (Mediware, Groningen, The Netherlands) was used to parameterize the population pharmacokinetic model. The model was compared with pharmacokinetic values from the literature and evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset. Monte Carlo simulations were used to develop a limited sampling strategy. Cycloserine plasma concentration vs time curves were obtained from 15 hospitalized patients (nine male, six female, median age 35years). Mean dose/kg body weight was 11.5mg/kg (standard deviation 2.04mg/kg). Median area under the concentration-time curve over 24h (AUC0-24h) of cycloserine was 888h mg/L (interquartile range 728-1252h mg/L) and median maximum concentration of cycloserine was 23.31mg/L (interquartile range 20.14-33.30mg/L). The final population pharmacokinetic model consisted of the following pharmacokinetic parameters [mean (standard deviation)]: absorption constant Ka_po of 0.39 (0.31) h-1, distribution over the central compartment (Vd) of 0.54 (0.26) L/kg LBM, renal clearance as fraction of the estimated glomerular filtration rate of 0.092 (0.038), and metabolic clearance of 1.05 (0.75) L/h. The population pharmacokinetic model was successfully evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset of Chinese patients (difference of 14.6% and 19.5% in measured and calculated concentrations and AUC0-24h, respectively). Root-mean-squared-errors found in predicting the AUC0-24h using a one- (4h) and a two- (2h and 7h) limited sampling strategy were 1.60% and 0.14%, respectively. This developed population pharmacokinetic model can be used to calculate cycloserine concentrations and exposure in patients with multidrug-/extensively drug-resistant tuberculosis. This model was successfully validated by internal and external validation methods. This study showed that the AUC0-24h of cycloserine can be estimated in patients with multidrug-/extensively drug-resistant tuberculosis using a 1- or 2-point limited sampling strategy in combination with the developed population pharmacokinetic model. This strategy can be used in studies to correlate drug exposure with clinical outcome. This study also showed that good target attainment rates, expressed by time above the minimal inhibitory concentration, were obtained for cycloserine with a minimal inhibitory concentration of 5 and 10mg/L, but low rates with a minimal inhibitory concentration of 20 and 32.5mg/L.

Population pharmacokinetics and pharmacodynamics of dobutamine in neonates on the first days of life.

AimsTo describe the pharmacokinetics (PK) and concentration‐related effects of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=535 in critically ill neonates in the first days of life, using nonlinear mixed effects modelling.MethodsDosing, plasma concentration and haemodynamic monitoring data from a dose‐escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5–20 μg kg−1 min−1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors.ResultsTwenty‐eight neonates with median (range) gestational age of 30.4 (22.7–41.0) weeks and birth weight (BW) of 1618 (465–4380) g were included. PK data were adequately described by 1‐compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h−1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model.ConclusionIn the postnatal transitional period, PK of dobutamine was described by a 1‐compartmental linear model, CL related to BW and PMA. A concentration–response relationship with haemodynamic variables has been established.

Pharmacometric Analysis of IgPro10 in Japanese and Non-Japanese Patients With Primary Immunodeficiency

PurposeImmunoglobulin (Ig) G replacement therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is the standard treatment in patients with primary immunodeficiencies (PID). We aimed to characterize the pharmacokinetic (PK) characteristics of serum IgG following administration of IgPro10 every 3 or 4 weeks in Japanese patients with PID, and compare with PK in non-Japanese patients. A previously developed population PK (PPK) model was validated, and predicted parameters were compared with the results from the clinical study. MethodsThe previously developed PPK model, containing IgG concentration data from 5 non-Japanese studies, was supplemented with data from 3 Japanese studies of IgPro10 or IgPro20 to compare the IgG PK parameters between Japanese and non-Japanese patients. The model was externally validated by simulating IgG concentration–time profiles in Japanese patients to predict serum IgG PK characteristics and to compare them with observed Japanese PK data from Study IgPro10_3004. FindingsThe analysis included 4502 serum IgG concentration values (from 34 Japanese and 168 non-Japanese patients). PPK estimates from the current analysis demonstrated a clearance (CL) of 0.139 L/d, central volume (V2) of 4.01 L, inter-compartmental clearance (Q) of 0.30 L/d, and peripheral volume of 3.51 L. These results were consistent with those from the previously published PPK model, with similar bootstrap means and 95% CIs. Goodness-of-fit criteria indicated that the final PPK model was consistent with observed data, with no systemic bias in model prediction. Prediction-corrected visual predictive checks confirmed a good description of data on both SCIG and IVIG. PK parameters were equivalent between Japanese and non-Japanese patients. Body weight was determined to be a significant covariate on both CL and V2. Simulated and observed AUC and maximum and minimum serum IgG concentrations were similar, with 90% CIs overlapping between simulated and observed IgG concentrations in Japanese patients. ImplicationsPK parameter estimates of serum IgG were similar between Japanese and non-Japanese patients with PID. The PPK model, updated with Japanese data, was consistent with the previously published PPK model and could accurately predict both individual and population serum IgG concentration–time profiles following IgPro10 IV infusions every 3 or 4 weeks. EudraCT identifier: 2016-001631-12.

Population Pharmacokinetic Modeling of Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma or Adult T-Cell Lymphoma.

Cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATL) are rare non-Hodgkin lymphomas commonly expressing C-C chemokine receptor 4 (CCR4). Mogamulizumab is a humanized monoclonal antibody against CCR4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sézary syndrome, the most common forms of CTCL. Pharmacokinetic (PK) and clinical study data from 444 adult patients with ATL or CTCL collected during 6 clinical trials of mogamulizumab were used to construct a population PK model, which was best described by a 2-compartment model with linear clearance. Albumin, aspartate aminotransferase, mild-to-moderate hepatic impairment, and sex were statistically significant predictors of clearance; albumin was also a statistically significant predictor of peripheral volume of distribution; and body surface area was a statistically significant predictor for central volume of distribution. None of the other covariates-for example, age, body weight, body mass index, bilirubin, creatinine clearance, disease type (ATL and CTCL), ATL subtype (acute, lymphoma, and chronic), CTCL subtype (mycosis fungoides and Sézary syndrome), CCR4 expression (status or degree), race (Japanese and non-Japanese), renal impairment (normal, mild, moderate, and severe), or performance status-had a statistically significant impact. Performance of the final population PK model was acceptable. This model will be valuable for guiding further studies of mogamulizumab.

Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer

To investigate the exposure–safety relationships of afatinib in Japanese population, we performed population pharmacokinetics (PK) analysis of afatinib in Japanese advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutation. Plasma samples were collected at 0.5–1, 2–3, 8–12, and 24 h after oral afatinib (40 mg) administration on day 1 and day 8. Plasma afatinib concentrations were determined using high-performance liquid chromatography. Data was analyzed following the population approach and using the software Phoenix® NLMETM Version 7.0 software (Certara USA, Inc., Princeton, NJ, USA). From 34 patients, a total of 354 afatinib plasma concentration values were available for the population PK analysis. Significant covariates in the population PK model included aspartate aminotransferase and creatinine clearance on CL/F, and age and body mass index on V/F. Results of simulation based on final PK model indicated that hepatic impairment had a significant effect on afatinib levels in plasma after multiple dosing. Afatinib trough plasma concentrations on day 8 were higher in patients with adverse events of grade 3 or higher. The population PK analysis showed that hepatic impairment affected afatinib PK parameters and contributed to the high inter-patient variability and high plasma concentrations of afatinib following multiple treatments.

Population Pharmacokinetics of Ruxolitinib in Patients with aGVHD Who Had an Inadequate Response to Corticosteroids

Background: Jakafi® (ruxolitinib) is currently approved for the treatment of adult patients with intermediate- and high-risk myelofibrosis (MF) and for the treatment of adult patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant to hydroxyurea. A prospective, open-label, single-cohort, Phase 2 study (REACH1) was conducted to evaluate the safety and efficacy of Jakafi® (ruxolitinib) in patients with acute graft versus host disease (aGVHD) who have had an inadequate response to corticosteroids. A population PK analysis was employed to characterize the PK of ruxolitinib in this patient population. Patients and Methods: REACH1, Study INCB 18424-251, and COMFORT-I are the 3 studies supporting the population PK of ruxolitinib; the first study is in participants with aGVHD who have had an inadequate response to corticosteroids, and the other 2 studies are in participants with MF. First, the final PK model for ruxolitinib in patients with MF was applied to the data in patients with MF and aGVHD. When significant biases were observed in this validation process, new population PK models were developed based on the pooled data. The accuracy and robustness of the final population PK model were assessed using a predictive check method. Results: An under-prediction bias was observed at the population level when existing PK model in MF was applied to pooled data in patients with MF and aGVHD. A new model was developed to account for the under prediction bias at the population level. The final population PK model for ruxolitinib was a 2 compartment disposition model with first order absorption, absorption lag time, and linear elimination. Body weight and gender were significant predictors of the volume of distribution of the central compartment and oral clearance, respectively. Patients with aGVHD showed lower oral clearance (66.7%) and slower rate of absorption (~28%) than that in patients with MF. The stage of liver involvement in GVHD and use of moderate or potent CYP3A4 inhibitors were identified as covariates for ruxolitinib CL. Conclusion: The population PK analysis supports the proposed dose regimen in patients with aGVHD who had an inadequate response to corticosteroids as well as dose recommendations for DDI and subjects with organ dysfunction. Disclosures Chen: Incyte Research Institute: Employment. Liu:Incyte Research Institute: Employment. Wang:Incyte Research Institute: Employment. Yeleswaram:Incyte Research Institute: Employment.

Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia.

To develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient. A prospective study was developed in 50 children (1-15years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central "Dr. Ignacio Morones Prieto" and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX. A two-compartment open model was selected to describe concentration-time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (L) = 3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model. The establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients' outcomes.

Population pharmacokinetics of vactosertib, a new TGF-β receptor type Ι inhibitor, in patients with advanced solid tumors.

Vactosertib, a novel inhibitor of transforming growth factor-β type Ι receptor, is under development for the treatment of various cancers. The objective of this study was to characterize the population pharmacokinetics of vactosertib in patients with solid tumors. Vactosertib population pharmacokinetics was assessed by nonlinear mixed-effects modelling of plasma concentration-time data obtained from a first-in-human phase 1 trial conducted in patients with advanced solid tumors. The final population pharmacokinetic model was constructed by assessing the effect of covariates on pharmacokinetic parameters including demographic characteristics, laboratory values, hepatic and renal function, and concomitant medications. The robustness of the final model was evaluated using a bootstrap method as well as visual predictive check based on Monte Carlo simulations and goodness-of-fit plots. A total of 559 concentrations from 29 patients were available for pharmacokinetic analysis. A two-compartment linear model with first-order absorption and absorption lag time adequately described the population pharmacokinetics of vactosertib. The estimates of apparent clearance (CL/F) and volume of central compartment (Vc/F) were 31.9 L/h (inter-individual variability, 0.481) and 82.9 L (inter-individual variability, 0.534), respectively. The mixture model accounts for both typical absorption profile in the majority of patients and distinct profile in some patients with uncommon gastrointestinal conditions. Body mass index was significantly associated with Vc/F. The model developed in this study adequately describes the population pharmacokinetics of vactosertib in patients with advanced solid tumors. The pharmacokinetic characteristics assessed using the model would provide useful quantitative information to assist the future clinical development of vactosertib.

The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model–based pediatric dose estimation

Mirabegron, a selective β3-adrenoreceptor agonist, is a well-established alternative to antimuscarinics in adults with overactive bladder (OAB) symptoms and is under development for use in pediatric patients. Understanding drug pharmacokinetics (PK) in pediatric patients is needed to determine appropriate dosing. Conducting these studies is ethically complex, particularly as regulatory guidance requires that PK is assessed in pediatric patients with a therapeutic need for the drug. It is also vital to evaluate the safety/tolerability and palatability/acceptability of pediatric formulations. The purpose of the study was to characterize the PK of mirabegron in pediatric patients with neurogenic detrusor overactivity or idiopathic OAB, to provide a basis for a weight-based dosing algorithm, and to evaluate the safety, tolerability, and palatability/acceptability of the formulations. A preliminary population PK model constructed from adult data with allometric scaling was used to predict single weight-adjusted mirabegron doses. This was developed to achieve exposures in pediatric patients in two phase 1 studies that were consistent with steady state in adults following once-daily 25mg ('low dose') and 50mg ('high dose') dosing. In study 1, adolescents (12-<18 years) and children (5-<12 years) received a single tablet under fed or fasted conditions. In study 2, children (3-<12 years) received a single oral suspension dose under fed conditions. The PK data were used to assess the predictive value of the preliminary PK model and to update it to analyze mirabegron PK in pediatric patients. The safety/tolerability and palatability/acceptability of the formulations were evaluated. Forty-three patients comprised six study cohorts: adolescents, low-dose tablets, fed (n=7); children, low-dose tablets, fed (n=7); adolescents, high-dose tablets, fed (n=8); children, high-dose tablets, fed (n=6); children, high-dose tablets, fasted (n=6); and children, high-dose oral suspension, fed (n=9). The population PK model-based doses for tablets and oral suspension achieved exposures that were typically consistent with steady state in adults. The final population PK model was used to describe the PK for mirabegron in pediatric patients (Table). Both formulations were well tolerated, and there were no reports of bad taste or swallowing difficulties for the tablets, although some found the oral suspension unpleasant. The single, weight-adjusted pediatric mirabegron doses were successfully predicted by population PK modeling to achieve drug exposures comparable with steady state in adults. The finalized PK model used to characterize the pediatric PK of mirabegron will be utilized to develop a weight-based dosing algorithm. The single mirabegron doses were well tolerated.

Population Pharmacokinetics of Cis-, Trans-, and Total Cefprozil in Healthy Male Koreans.

Cefprozil, one of cephalosporin antibiotics, has been used extensively in clinics. However, pharmacokinetic (PK) information on cefprozil is still very limited. There have been no reports of population pharmacokinetics (PPKs). A PPK model for cefprozil will be a great advantage for clinical use. Thus, the aim of this study was to develop a PPK model for cefprozil for healthy male Koreans. Clinical PK and demographic data of healthy Korean males receiving cefprozil at a dose of 1000 mg were analyzed using Phoenix® NLME™. A one-compartment model with first-order absorption with lag-time was constructed as a base model. The model was extended to include covariates that influenced between-subject variability. Creatinine clearance significantly influenced systemic clearance of cefprozil. The final PPK model for cis-, trans-, and total cefprozil was established and validated. PPK parameter values of cis- and total cefprozil were similar to each other, but different from those of trans-isomer. Herein, we describe the establishment of accurate PPK models of cis-, trans-, and total cefprozil for healthy male Koreans for the first time. It may be useful as a dosing algorithm for the general population. These results might also contribute to the development of stereoisomeric cefprozil.

The Evolution of Population Pharmacokinetic Model of Oral Phenytoin for Early Seizure Prophylaxis Post-Craniotomy.

This study aimed to re-establish a Population Pharmacokinetic (PPK) model of oral phenytoin to further optimize the individualized medication regimen based on our previous research. Patients with intracranial malignant tumor requiring craniotomy were prospectively enrolled according to the inclusion criteria. Genotypes of CYP2C9*1 or *3 and CYP2C19*1, *2 or *3 were determined by real time PCR (TaqMan probe) method. Serum concentrations of phenytoin on the 4th and 7th day after oral administration were determined using fluorescence polarization immunoassay. The PPK parameters were estimated using Nonlinear Mixed Effects Models (NONMEM) and internal validation was performed using bootstraps. The predictive performance of the final model was evaluated by Normalized Predictive Distribution Errors (NPDEs) and diagnostic goodness- of-fit plots. A total of 390 serum samples were collected from 170 patients in PPK model building group. The population typical values for Vm, Km and the apparent volume of distribution (V) in the final model were 17.5 mg/h, 6.41 mg/L and 54.8 L, respectively. Internal validation by bootstraps showed that the final model was stable and reliable. NPDEs with a normal distribution and a scatterplot with symmetrical distribution showed that the final model had good predictive capability. Individualized dose regimens of additional 40 patients in the external validation group were designed by the present final PPK model. The percentages of patients with serum concentrations within the therapeutic range were 61.53% (24/39) on the 4th day and 94.87% (37/39) on the 7th day, which were higher than the 39.33% (59/150) and 52.10% (87/167) of above 170 patients (P < 0.0001). The present PPK final model for oral phenytoin may be used to further optimize phenytoin individualized dose regimen to prevent early seizure in patients after brain injury if patient characteristics meet those of the population studied.