Nonlinear Mixed Effects Model Program Research Articles

Optimal exposure to docetaxel in adjuvant chemotherapy for early-stage breast cancer.

Drug-induced neutropenia is the main reason for the dose limitation of docetaxel in patients with breast cancer. The area under the drug concentration-time curve (AUC) of docetaxel is associated with neutropenia. However, the optimal exposure to docetaxel for receiving postoperative adjuvant chemotherapy remains unclear. Therefore, we aimed to evaluate the relationship between the docetaxel AUC and neutropenia, identify potential influencing factors, and explore the best monitoring target for docetaxel when treating patients with early-stage breast cancer using a population pharmacokinetic (PopPK) model. Docetaxel plasma concentration, demographics, clinical data, and related laboratory data were collected. PopPK analyses were performed using a nonlinear mixed-effect modelling program. The docetaxel AUC was determined using the maximum a posteriori Bayesian (MAPB) method. The docetaxel exposure-toxicity threshold measured from the AUC for neutropenia was determined using the receiver operating characteristic (ROC) curve. The correlation between docetaxel exposure and neutropenia was analysed using multivariable logistic regression. Among the 70 participants, 47 (67.1%) developed severe neutropenia. The PopPK analysis showed that the typical drug clearance (CL) rate was 37.4L/h. Age was a significant covariate of CL rate, and aspartate aminotransferase and albumin levels were covariables of the volume of distribution. The multivariable regression analysis showed that AUC >3.0mg.h/L (odds ratio [OR], 5.940; 95% confidence interval [CI], 1.693-20.843; P=0.005), platinum use (OR, 0.156; 95% CI, 0.043-0.562; P=0.005) and baseline haemoglobin level (OR, 0.938; 95% CI, 0.887-0.993; P=0.027) were significant factors influencing the occurrence of grade 3/4 neutropenia. The AUC of first cycle may not predict the occurrence rates of grade 3/4 neutropenia in later cycles. We developed a docetaxel PopPK model for patients with early-stage breast cancer. Age and AST and ALB levels were significant covariates. AUC estimated using the MAPB method can predict the toxicity of docetaxel in patients with breast cancer. Docetaxel AUC >3.0mg.h/L, absence of platinum use and low baseline haemoglobin level were risk factors for docetaxel-induced grade 3/4 neutropenia. Chinese Clinical Trial Center Registry (ChiCTR2200056460).

Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics.

Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post-liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixed-effect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post-hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model-building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post-hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R2 =0.330, p < 0.0001). The estimation accuracy in pediatric patients was considerably high, except for one infant out of 13 patients. In conclusion, population pharmacokinetic analysis clarified several significant covariates for everolimus pharmacokinetics in liver transplant patients. Everolimus pharmacokinetics moderately correlated with tacrolimus pharmacokinetics and could be extrapolated from adult to pediatric patients by body size correction, except for infants.

Population Pharmacokinetics Modeling of Lamotrigine in Jordanian Epileptic Patients Using Dried Blood Spot Sampling.

To characterize the population pharmacokinetics of lamotrigine in Jordanian epileptic patients and to identify factors affecting therapeutic parameters. A population pharmacokinetics model for lamotrigine was established based on a prospectively collected data of 52 steady-state concentrations from 38 adult and pediatric patients with epilepsy. Lamotrigine concentrations were determined by a dried blood spot liquid chromatography method. Data were analyzed according to a one-compartment model with first-order absorption and elimination using the nonlinear mixed effect modeling program. The covariates effect of total body weight, gender, age, and co-medication with topiramate, carbamazepine, phenytoin, phenobarbital, and valproic acid on lamotrigine clearance were investigated using a stepwise forward addition followed by a stepwise backward elimination. The final population pharmacokinetics model for lamotrigine clearance was as follows: CL/Fpop=θ1*exp (θ3*age)*exp (θ5*carbamazepine)*exp (θ6*valproic acid) , where θ1 is the relative clearance (L/hr) estimated, and θ3, θ5, and θ6 are the fixed parameters relating to age and co-medication with carbamazepine and valproic acid, respectively.The population mean value of lamotrigine total clearance generated in the final model (with covariates) was 2.12 L/hr. Inter-individual variability and residual unexplained variability expressed as the coefficient of variation was 37.1 and 26.1%, respectively. Lamotrigine total clearance in the Jordanian patients is comparable to that reported by others for Caucasian patients. Age and concomitant therapy with carbamazepine and valproic acid significantly affected lamotrigine clearance, and accounted for 48% of its inter-individual variability.

Population Pharmacokinetics of Erlotinib in Patients With Non–small Cell Lung Cancer: Its Application for Individualized Dosing Regimens in Older Patients

PurposeErlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non–small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib. Methods: A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups. FindingsA total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h−1. The external validation showed a negligible bias of −4% (95% CI, −7 to −1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure. ImplicationsThis large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities.

Clinical pharmacokinetics and drug exposure-toxicity correlation study of docetaxel based chemotherapy in Chinese head and neck cancer patients.

BackgroundArea under time-concentration curve (AUC) of docetaxel is related with its toxicity and efficacy. The aim of this study is to investigate the target range of docetaxel AUC in Chinese head and neck cancer (HNC) patients.MethodsEligible HNC patients were enrolled and received at least 2 cycles of docetaxel-based chemotherapy. A simplified pharmacokinetic (PK) strategy (2 monitored samples) was developed to simulate docetaxel AUC using the nonlinear mixed-effect modelling program. Preliminary target range of AUC was pre-set as 2.5–3.7 µg·hr/mL according to pooled analysis from 8 previous studies. Fisher exact test was used to analyze the relationship between AUC with neutropenia and efficacy, and to verify the target range.ResultsThirty-nine eligible patients were enrolled. Grade 3-4 and grade 4 neutropenia rate in 1st cycle was 64% and 36%, respectively. AUC simulation by simplified PK strategy was acceptable compared to full sampling method from the analysis of archived 300 patients’ data, with −5.67% of mean prediction error (MPE). Median AUC of all patients was 2.58 µg·hr/mL (range from 1.28 to 9.39). A significant correlation (P=0.007) was detected between AUC and body surface area (BSA)-dosage, but BSA contributed only 18.3% of AUC inter-individual variability. Docetaxel AUC was significantly related with the severity (grade 3–4) of neutropenia (correlation of coefficient was 0.452, P=0.004). Fourteen patients (36%) were within the target AUC range. Patients with AUC above the target experienced more severe neutropenia (grade 3–4 rate 100% vs. 56%, P=0.036; grade 4 rate 86% vs. 25%, P=0.005). No significant difference of response rate was found between patients within the target or not.ConclusionsA simplified samples PK strategy was developed for docetaxel AUC simulation. The target range of docetaxel AUC in Chinese HNC patients was suggested at 2.5–3.7 µg·hr/mL for reduced toxicity without compromising efficacy of docetaxel treatment.

Population Pharmacokinetics and Pharmacodynamics of Apixaban Linking Its Plasma Concentration to Intrinsic Activated Coagulation Factor X Activity in Japanese Patients with Atrial Fibrillation.

Apixaban is used in the prevention and treatment of patients with deep vein thrombosis or pulmonary embolism, and in the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). In this study, we aimed to elucidate intrinsic factors affecting efficacy of apixaban by conducting population pharmacokinetic and pharmacodynamic analysis using data from 81 Japanese AF patients. The intrinsic FXa activity was determined to assess the pharmacodynamic effect of apixaban. The pharmacokinetic and pharmacodynamic profiles were described based on a one-compartment model with first-order absorption and a maximum inhibitory model, respectively. Pharmacokinetic and pharmacodynamic analysis was conducted using a nonlinear mixed effect modeling program. The population pharmacokinetic parameters of apixaban were fixed at the reported values in our recent study. The population mean of half-maximal inhibitory concentration (IC50) of apixaban was estimated to be 45.3ng/mL. The population mean IC50 decreased 27.7% for patients with heart failure, but increased 55% for patients with a medical history of cerebral infarction. In contrast, no covariates affected the population mean of baseline of intrinsic FXa activity (BASE) and maximum effect (Imax) value of apixaban. The population mean of BASE and Imax value were estimated to be 40.2 and 38.4nmol/min/mg protein, respectively. The present study demonstrates for the first time that the co-morbidity of heart failure as well as the medical history of cerebral infarction are an intrinsic factor affecting the pharmacodynamics of apixaban.

Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7-1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix). 31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded. Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban. Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2 and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using a nonlinear mixed effect modelling (NONMEM™) program. The nonlinear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70mlmin-1 ) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06lh-1 . When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7l. The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

Population pharmacokinetics of vancomycin from severe in patients with lower respiratory tract infection

Objective: To develop a population pharmacokinetic (PPK) model of vancomycin in Chinese inpatients with severe lower respiratory tract infection. Methods: We gathered serum concentrations of vancomycin from inpatients who received vancomycin during Nov 2011 to Nov 2012.Vancomycin serum concentrations was measured by high performance liquid chromatography. Vancomycin PPK analysis was performed using nonlinear mixed effects model (NONMEM) program. Results: We gathered the data of 70 inpatients with lower respiratory tract infection at respiratory ward or respiratory intensive care unit(RICU) between Nov 2011 to Nov 2012 [58 males, 12 females; 78(23-91) years old; the mean of APACHⅡ score was 16.4±4.8]. A total of 267 concentrations of vancomycin were gathered from 70 patients. A 2-compartment model fit the concentration data best. The final vancomycin PPK model was: CL(i)=1.67×e(η1), V(1i)=33.04×[1-0.199×(60/Scr)] ×e(η2), Q(i)=7.08×2.053(AI)×e(η3), V(2i)=19.29×e(η4).(CL: vancomycin clearance; V(1): distribution volume of the central compartment; Q: intercompartment clearance; V(2): distribution volume of the intercompartment). The population mean values were 1.67 L/h, 33.04 L; 7.08 L/h and 19.29 L respectively. Serum creatinine was the covariate to affect vancomycin apparent distribution volume of the central compartment. Intercompartment clearance was 2.053 times larger in patients with albumin infusion than that in patients without. Conclusions: We found that a 2-compartment model fit the concentration data best in Chinese patients with severe lower respiratory tract infection. Serum creatinine and albumin infusion were the most significant covariates to affect vancomycin PK.

Population pharmacokinetic models of lamotrigine in different age groups of Chinese children with epilepsy.

The study aims to establish population pharmacokinetic (PPK) models of lamotrigine (LTG) in different age groups of epileptic children by nonlinear mixed effect modelling(NONMEM), and provide essential tools and theoretical basis for individualised optimal drug dose. Cases of 473 epileptic children were divided into infant, toddler and preschool age (≤6years) (n=211), school age (6-12years) (n=171) and adolescence age (>12years) (n=81). A total of 625 steady-state serum trough concentration samples were extracted. The clinical information included demography, medication, serum concentration data and blood biochemical parameters. PPK models of LTG were established by NONMEM program, using first-order absorption and elimination. Demography and drug combination was investigated for influence on apparent clearance (CL) and apparent volume of distribution (Vd). To assess the accuracy and precision of the different ages and whole-age model, the mean prediction error (MPE), mean absolute error (MAE) and root mean squared error (RMSE) were compared. The final model of LTG in different ages stage and whole age was as follows: (1) infant, toddler and preschool age CL=0.715×[(WEIG/16.25)0.655]×(0.458VPA)×(1.99IND), V=10.4; (2) school age CL(L/h)=1.01×(WEIG/30)0.399×0.465VPA×1.98IND, Vd(L)=17.7; (3) adolescence age CL(L/h)=1.49×(WEIG/51.5)0.509×0.498VPA×1.7IND, Vd(L)=23.1; (4) whole age CL=0.945×[(WEIG/25)0.645]×(0.463VPA)×(1.94IND), V=16.7×(WEIG/25)0.919 (WEIG, total body weight; VPA, combination with valproate, yes=1, no=0; IND, combination with enzyme inducer, yes=1, no=0). The values of MPE, MAE and RMSE in age-stage-specific models were less than the ones in the whole-age model, which suggests the age-stage-specific models have better precision and accuracy than the whole-age model. PPK models of LTG in different age groups of epileptic children were successfully established. Weight and combination therapy were identified as significant covariates on LTG clearance. Compared with the whole-age model, the age-specific models are more reliable.

Population pharmacokinetics of exenatide.

AimThe aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate‐release (IR) exenatide, which can be used in subsequent analyses of novel sustained‐release formulations.MethodsData from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed‐effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks.ResultsThe pharmacokinetics of IR exenatide was described by a two‐compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero‐order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr−1. The nonlinear elimination was quantified with a Michaelis–Menten constant (K m) of 567 pg ml−1 and a maximum rate of metabolism (V max) of 1.6 μg h−1. For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero‐order process, and the remaining 63% via the nonlinear pathway.ConclusionsThe present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained‐release exenatide formulations.

Population pharmacokinetics of thrombomodulin alfa in pediatric patients with hematological malignancy and disseminated intravascular coagulation

Thrombomodulin alfa (TM-α) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM-α and determine the optimal dose in pediatric patients with hematological malignancy and DIC. Pediatric patients with hematological malignancy and DIC were administered TM-α at a dose of 0.06 mg/kg (380 U/kg) over 30 min every 24 hr. Blood samples were taken at steady state before the start, immediately after the end, and 24 hr after the start of the sixth administration. Population pharmacokinetic analysis was performed using sparse samples with the nonlinear mixed-effect modeling program NONMEM® , version 7.3. The actual and predicted plasma concentrations of TM-α based on the final population pharmacokinetic model showed a good linear correlation. Clearance and volume of distribution of TM-α were affected by body weight. The clearance of TM-α in pediatric patients with hematological malignancy and DIC was higher than that in adults as previously reported. Six of eight patients did not achieve the target trough concentration at steady state. Furthermore, the pharmacokinetic simulation based on the estimated pharmacokinetic parameters from the final model demonstrated that TM-α administered at a dose of 0.06 mg/kg every 24 hr also failed to achieve the target trough concentration at steady state in the majority of pediatric patients. Our study shows that further dose adjustment of TM-α is necessary considering the higher clearance per body weight in pediatric patients with hematological malignancy and DIC.

Population pharmacokinetics of ramosetron.

Ramosetron is a selective serotonergic 5-hydroxy-tryptamine receptor 3 antagonist that is used to prevent and treat postoperative nausea and vomiting. This study aimed to characterize the population pharmacokinetics of ramosetron in patients undergoing surgery with general anesthesia. Patients aged 19-80 years received a single intravenous bolus of ramosetron (0.3, 0.45, or 0.6 mg) 30 min before the end of surgery. Blood samples were collected, and plasma concentrations of ramosetron were measured by high performance liquid chromatography-tandem mass spectrometry. Pooled data from 50 patients and 479 pharmacokinetic samples were used for population pharmacokinetic analysis using the nonlinear mixed effect modeling program (NONMEM(®)). The pharmacokinetics of ramosetron was best described by a three-compartment mammillary model with first-order elimination. Based on allometric principles, body weight was incorporated in the base model, along with fixed allometric exponents. The typical value of clearance was 0.19 L/h in a 60-kg subject, and it decreased approximately 3% for every year of age, starting at age of 57. The bootstrap method and visual predictive check showed that the final pharmacokinetic model was appropriate. A population pharmacokinetic model of ramosetron was constructed in adult surgical patients, providing a foundation for further defining the relationship between ramosetron dose and postoperative nausea and vomiting.

Modeling approach for multiple transporters-mediated drug–drug interactions in sandwich-cultured human hepatocytes: Effect of cyclosporin A on hepatic disposition of mycophenolic acid phenyl-glucuronide

A lower exposure of mycophenolic acid (MPA) in patients receiving MPA-mofetil in combination with cyclosporin A (CsA) is thought to be due to the inhibition of enterohepatic circulation of phenyl-glucuronide of MPA (MPAG). This study aimed to evaluate the interaction of CsA with hepatic disposition of MPA and MPAG in sandwich-cultured human hepatocytes (SCHH) by a mathematical modeling approach. In addition, the inhibition of CsA for glucuronidation of MPA to MPAG was examined in human liver microsomes. Inhibitory parameters of CsA for hepatic disposition of MPAG were estimated using a non-linear mixed effect model program, NONMEM. As a result, CsA did not influence the conversion of MPA to MPAG in either SCHH or human liver microsomes. In contrast, CsA inhibited the basolateral uptake of MPAG with an estimated maximum inhibitory effect (Imax) of 32.4%. CsA also inhibited basolateral efflux and biliary excretion of MPAG formed in SCHH, and the concentration producing 50% of Imax (IC50) for biliary excretion was lower than that for basolateral efflux. Our modeling approach suggests that CsA inhibits both basolateral uptake and biliary excretion of MPAG and leads to changes in systemic exposure of MPA and MPAG in humans.

Establishment of population pharmacokinetic models with valproic acid in different age groups of Chinese epileptic children

Objective To establish population pharmacokinetic (PPK) models with valproic acid(VPA) in different age groups(infant and toddler, preschool age, school age and adolescence) of Chinese epileptic children by nonlinear mixed effect modeling(NONMEM), and provide evidence for individualized drug therapy. Methods Cases of 518 epileptic children were collected from 2010 to 2013 in the Pediatric Outpatient Clinics of the First Hospital, Peking University.The clinical information included demographic data, medication, serum concentration data and blood biochemical parameters.The patients were divided into infants and toddlers (n=191), children at preschool age(n=172) and children at school and adolescence age(n=155). A total of 665 steady-state serum trough concentration samples were extracted.Population pharmacokinetic models of VPA were established by NONMEM program by using first-order absorption and elimination.Demography and drug combination was investigated for influence on apparent clearance (CL/F) and apparent volume of distribution (V/F). The reliability and stability of the PPK models were evaluated by 1 000 times of Bootstrap procedure.To assess the accuracy and precision of the different age groups models and whole age model, the average prediction error (MPE), average absolute error (MAE) and average root variance (RMSE) were compared. Results The final model of VPA in different age groups and whole age group were: 1.the infant and toddler's age group CL/F(L/h)=0.154×(WEIG/11.5)1.31, V/F(L)=3.32×(WEIG/11.5)2.49. 2.preschool age group CL/F(L/h)=0.211×(WEIG/18)0.534, V/F(L)=4.08. 3.school and adolescence age group CL/F(L/h)=0.287×(WEIG/29.75)0.464, V/F(L)=7.05. 4.whole age group CL/F(L/h)=0.197×(WEIG/18)0.648×1.09GEND, V/F(L)=4.25×(WEIG/18)0.714(GEND was gender, male=1, female=0; WEIG was weight). The results of Bootstrap procedure were corresponding to the estimates from NONMEM.The values of the different age groups model MPE, MAE, RMSE were less than ones of the whole age group, which suggested the different age groups models had better precision and accuracy than the whole age group models. Conclusions PPK models of VPA in different age groups of Chinese epileptic children by NONMEM were successfully established.Weight was identified as a significant cova－riate on VPA clearance.Compared with the whole age group models，the different age groups models are more reliable. Key words: Valproic acid; Population pharmacokinetics; Epilepsy; Different age groups

Clinical pharmacokinetics of tacrolimus in Iranian liver transplant recipients.

Tacrolimus, a cornerstone of immunosuppressive therapy in solid organ transplantation, has a narrow therapeutic range with considerable inter-individual and intra-individual pharmacokinetic variability. To date, there is no information on the pharmacokinetics of tacrolimus in Iranian liver transplant recipients. This study was designed to determine pharmacokinetic properties of orally administered tacrolimus in Iranian adult liver transplant recipients. Tacrolimus doses and steady state whole blood trough concentrations as well as patient demographic and clinical data were obtained retrospectively using the 30 included patients' medical records. Pharmacokinetic parameters were estimated by using a nonlinear mixed effect model program (Monolix version 3.1). Absorption rate constant was fixed at two hours(-1). Drug apparent clearance (CL/F), apparent volume of distribution (Vd/F), and elimination half life (t½β) were calculated. The administered dose of tacrolimus to the patients ranged from 0.02 to 0.14 mg/Kg/day. Tacrolimus blood trough concentrations varied widely within the range of 1.8 to 30 ng/mL. The mean values of CL/F, Vd/F, and t½β were found to be 9.3 ± 0.96 L/h, 101 ± 29 L, and 7.5 hours, respectively. The pharmacokinetics of tacrolimus was highly variable among our patients. CL/F, Vd/F, and t½β of tacrolimus in this study were comparable to reported values from Italian heart transplant patients but somewhat different from reported ones from other solid organ transplant populations.

Population pharmacokinetic study of Cyclosporine in the hematopoietic stem cell transplant recipients

The aim of this study is to investigate the population pharmacokinetics (PopPK) of cyclosporine (CsA) in the Chinese hematopoietic stem cell transplantation (HSCT) recipients for promoting the individualization of CsA administration. A total of 887 retrospective drug monitoring data points were collected from 58 HSCT recipients. Whole blood samples were collected at predose (C0) and 2 hours (C2) post dose. The administration of CsA was intermittent intravenous infusion, continuous intravenous infusion and oral. Population modeling was performed using the NONMEM (nonlinear mixedeffect modeling) program. A one compartment pharmacokinetic model was used to fit the data. Body surface area (BSA), administration route and postoperative days were identified as significant covariates for clearance (CL) according to the final model: CL = 31.0 × (BSA/1.59)0.761 × (ROUT) × (POD), where ROUT was 1.91 if the administration route was intravenous infusion, otherwise it is equal to 1. The POD was 0.818, 0.753, 0.539, and 0.509 for posttransplant Days 0 - 10, 11 - 20, 21 - 30 and more than 30 days, respectively. Administration route was a significant covariate for volume (V) according to the final model: V = 192 × (ROUT), where ROUT was 4.10, 3.63 and 1 when the administration route was continuous intravenous infusion, intermittent intravenous infusion and oral. The other covariates were not identified as a significant effect on CsA pharmacokinetic parameters. Body surface area, administration route and postoperative days should be considered in individual pharmacotherapy of cyclosporine for HSCT patient to achieve the desired therapeutic target.

Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats

To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats. Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 μg/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments. Exenatide exhibited rapid absorption with k(a)=4.45 h(-1), and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated S(m1) of 0.822 and SC(50) of 4.02 μg/L. It was demonstrated that insulin stimulated glucose dissipation (S(m2)=0.0513) and inhibited the production of glucose (I(m)=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed. The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.

Abstract 3792: Population Pharmacokinetic (PPK) modeling of ProLindac™ (AP5346), a nanopolymer prodrug of diaminocyclohexane (DACH)-platinum (Pt) in recurrent advanced ovarian cancer (AOC) patients

Abstract Background: ProLindac™ (PL) is a 25 kDa hydroxypropylmethacrylamide copolymer linked to a DACH-Pt. The DACH-Pt complex is thought to be biologically inert while attached to the polymer, with slow in vivo Pt release accelerated in low pH environments (extracellular space of hypoxic tumor and intracellular lysosomal compartment). Methods: 9/35 patients (pts) with recurrent OAC treated with single-agent PL via 2-h IV infusion at doses of 900 mg/m*2 q2w (3 pts), 1400 mg/m*2 q3w (3 pts) and 1680 mg/m*2 q3w (3 pts) were assessable for full PK analysis. 8 time point samples were collected on cycle 1, and 2 samples at cycles 2, 3 and 4. The ultrafiltration procedure used Ultra-4 filters (Amicon) with 50 kDa for unbound PL (U-PL) and 3 kDa for unbound Pt (U-Pt) cut-off. Urine was collected every 6 h from day 1 to 5 of dosing 1. Pt levels were measured by a validated Flameless Atomic Absorption Spectrometry Method (concentration range: 12.5 - 500 ng/mL). PPK was modeled using a nonlinear mixed effect model program (Monolix version 3.1s) by computing the maximum likelihood estimation of the parameters without any approximation of the model. Results: A 3-compartment open model adequately described the total PL time-concentration curve with linear elimination while a 2-compartment model satisfactorily described U-PL and U-Pt time-concentration curves with linear elimination. Mean PPK parameters with SD are summarized below: The mean recovery of PL dose in urine was at least 60% within 5 days. Conclusion: The central Vd for total PL Pt is rather small, close to the circulating blood volume suggesting that the major part of parent drug is restrained in the circulatory space with weak tissue diffusion probably due to a high protein binding rate. However, for U-PL and U-Pt, the Vd is much higher suggesting: 1) a significant tissue diffusion of active species (free-Pt), 2) PL is bound to plasma proteins with low-energy bonds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3792. doi:1538-7445.AM2012-3792