Population Pharmacokinetic Characteristics Research Articles

Population Pharmacokinetic Analyses for Belzutifan to Inform Dosing Considerations and Labeling.

Belzutifan (Welireg, Merck & Co, Inc.) is an oral, potent inhibitor of hypoxia-inducible factor (HIF) 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors (pNET). It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM® v7.3, based on demographics/PK data from 3 clinical pharmacology (food effect, formulation bridging, genotype/race effect) and 2 clinical (phase 1 dose escalation/expansion in RCC and other solid tumors; phase 2 in VHL patients) studies. Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear 2-compartment model with first-order absorption and elimination. For VHL patients, the predicted geometric mean (% coefficient of variation [CV]) apparent clearance (CL/F) was 7.3 L/hr (51%), apparent total volume of distribution (Vd/F) was 130 L (35%); and half-life was 12.39 hours (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model dual UGT2B17 and CYP2C19 poor metabolizers (PM) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve (AUC) compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in overall- and sub-populations for belzutifan labeling.

Population Pharmacokinetic Model of AST-001, L-Isomer of Serine, Combining Endogenous Production and Exogenous Administration in Healthy Subjects.

AST-001 is an L-isomer of serine that has protective effects on neurological disorders. This study aimed to establish a population pharmacokinetic (PK) model of AST-001 in healthy Korean to further propose a fixed-dose regimen in pediatrics. The model was constructed using 648 plasma concentrations from 24 healthy subjects, including baseline endogenous levels during 24 h and concentrations after a single dose of 10, 20, and 30 g of AST-001. For the simulation, an empirical allometric power model was applied to the apparent clearance and volume of distribution with body weight. The PK characteristics of AST-001 after oral administration were well described by a two-compartment model with zero-order absorption and linear elimination. The endogenous production of AST-001 was well explained by continuous zero-order production at a rate of 0.287 g/h. The simulation results suggested that 2 g, 4 g, 7 g, 10 g, and 14 g twice-daily regimens for the respective groups of 10–14 kg, 15–24 kg, 25–37 kg, 38–51 kg, 52–60 kg were adequate to achieve sufficient exposure to AST-001. The current population PK model well described both observed endogenous production and exogenous administration of AST-001 in healthy subjects. Using the allometric scaling approach, we suggested an optimal fixed-dose regimen with five weight ranges in pediatrics for the upcoming phase 2 trial.

Establishing combination PAC‐1 and TRAIL regimens for treating ovarian cancer based on patient‐specific pharmacokinetic profiles using in silico clinical trials

AbstractOvarian cancer is commonly diagnosed in its late stages, and new treatment modalities are needed to improve patient outcomes and survival. We have recently established the synergistic effects of combination tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and procaspase activating compound (PAC‐1) therapies in granulosa cell tumors (GCT) of the ovary, a rare form of ovarian cancer, using a mathematical model of the effects of both drugs in a GCT cell line. Here, to understand the mechanisms of combined TRAIL and PAC‐1 therapy, study the viability of this treatment strategy, and accelerate preclinical translation, we leveraged our mathematical model in combination with population pharmacokinetics (PKs) models of both TRAIL and PAC‐1 to expand a realistic heterogeneous cohort of virtual patients and optimize treatment schedules. Using this approach, we investigated treatment responses in this virtual cohort and determined optimal therapeutic schedules based on patient‐specific PK characteristics. Our results showed that schedules with high initial doses of PAC‐1 were required for therapeutic efficacy. Further analysis of individualized regimens revealed two distinct groups of virtual patients within our cohort: one with high PAC‐1 elimination and one with normal PAC‐1 elimination. In the high elimination group, high weekly doses of both PAC‐1 and TRAIL were necessary for therapeutic efficacy; however, virtual patients in this group were predicted to have a worse prognosis when compared to those in the normal elimination group. Thus, PAC‐1 PK characteristics, particularly clearance, can be used to identify patients most likely to respond to combined PAC‐1 and TRAIL therapy. This work underlines the importance of quantitative approaches in preclinical oncology.

Population pharmacokinetics of polymyxin B and dosage strategy in critically ill patients with/without continuous renal replacement therapy

Polymyxin B is served as a last-line agent for Carbapenem-resistant organisms (CRO) infections. This study aimed to establish a population pharmacokinetic (PK) model in patients with/without continuous renal replacement therapy (CRRT), to investigate the relationship between clinical covariates and polymyxin B PK parameters, and to optimize polymyxin B dosing regimens. Blood samples were obtained for each patient at steady state. The plasma concentrations of polymyxin B were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Population PK models were developed using Pirana program and Monte Carlo simulations were conducted. A total of 63 patients accounting for 189 blood samples were included and divided into modeling (n = 49) and validation (n = 14) groups. A two-compartment model described the data well. CRRT, creatinine clearance (CLCR) and Sequential Organ Failure Assessment (SOFA) score were identified as significant covariates of polymyxin B clearance. Monte Carlo simulations indicated that a maintain dose of 75–100 mg q12h was required to meet the target drug exposure in patients receiving CRRT with SOFA ≤ 11 (minimum inhibitory concentration ≤ 1 mg·L−1). For patients without CRRT, dosage strategy should be adjusted on the basis of different renal functions and SOFA scores. This is the first population PK study that demonstrated CRRT, CLCR and SOFA score had significant effects on polymyxin B clearance in critically ill patients with/without CRRT. More PK data are urgently needed to clarify polymyxin B PK characteristics in patients with/without CRRT.

Population pharmacokinetics analysis of guselkumab in healthy subjects and patients with psoriatic arthritis, plaque psoriasis and palmoplantar pustulosis.

Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin 23, is approved for the treatment of plaque psoriasis (PsO) and psoriatic arthritis (PsA), palmoplantar pustulosis (PPP), generalized pustular psoriasis, and erythrodermic psoriasis in various countries. The purpose of this analysis was to develop a comprehensive population pharmacokinetic (PK) model for guselkumab to determine whether PK differs across different disease populations and healthy subjects. A nonlinear mixed-effects modelling approach was used to analyse 23 097 serum PK samples obtained from 2623 healthy subjects and patients with PsO, PsA and PPP across 9 phase 1-3 clinical trials. Guselkumab concentrations were adequately described by a 2-compartment linear PK model with first-order absorption and elimination. Clearance (CL), central and peripheral volume of distribution, intercompartmental flow, absorption rate constant and absolute bioavailability estimates were 0.255 L/d, 3.60 L, 1.78 L, 0.369 L/d, 0.313 d-1 and 49.2%, respectively, for a subject weighing 70 kg. Terminal half-life was estimated to be approximately 14.6days. Body weight was the primary factor affecting CL and central volume of distribution. CL of guselkumab was similar among patients with PsA, PsO and PPP, but CL in disease populations was 11-17% lower than that in healthy subjects after other covariate effects such as body weight were considered. The population pharmacokinetic analysis indicated that, after other covariate effects were taken into account, patients with PsO, PsA and PPP had similar PK characteristics, with CL in these disease populations being slightly lower than in healthy individuals.

Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

PurposeAppropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK) model of gentamicin in CRRT patients and to infer the optimal dosing regimen for gentamicin.MethodsFourteen CRRT patients dosed with gentamicin were included to establish a population PK model to characterize the variabilities and influential covariates of gentamicin. The pharmacokinetic/pharmacodynamic (PK/PD) target attainment and risk of toxicity for different combinations of gentamicin regimens (3–7 mg/kg q24h) and CRRT effluent doses (30–50 mL/h/kg) were evaluated by Monte Carlo simulation. The probability of target attainment (PTA) was determined for the PK/PD indices of the ratio of drug peak concentration/minimum inhibitory concentration (Cmax/MIC > 10) and the ratio of area under the drug concentration–time curve/MIC over 24 h (AUC0-24h/MIC > 100), and the risk of toxicity was estimated by drug trough concentration thresholds (1 and 2 mg/L).ResultsA one-compartment model adequately described the PK characteristics of gentamicin. Covariates including body weight, age, gender, and CRRT modality did not influence the PK parameters of gentamicin based on our dataset. All studied gentamicin regimens failed to achieve satisfactory PTAs for pathogens with an MIC ≥2 mg/L. A good balance of PK/PD target attainment and risk of toxicity (>2 mg/L) was achieved under 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose for an MIC ≤1 mg/L. CRRT dose intensity had a significant impact on the target attainment of AUC0-24h/MIC >100 and risk of toxicity.ConclusionA combination of 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose might be considered as a starting treatment option for CRRT patients, and drug monitoring is required to manage toxicity.

Population pharmacokinetic characteristics of cemiplimab in patients with advanced malignancies

Cemiplimab, a human monoclonal antibody targeting programmed cell death-1 (PD-1) receptor, demonstrated antitumor activity in patients with advanced malignancies and a safety profile comparable to other anti–PD-1 therapies. This population pharmacokinetics (PopPK) analysis of cemiplimab included 11,178 pharmacokinetics (PK) observations from 548 patients pooled from a first-in-human study (Study 1423; NCT02383212) in advanced malignancies and a Phase 2 study (Study 1540; NCT02760498) in advanced cutaneous squamous cell carcinoma (CSCC). Most patients (80.3%) received cemiplimab 3 mg/kg every 2 weeks (Q2W) intravenously (IV). A PopPK model was developed by evaluating two-compartment linear models with an empirical non-linear function describing time-varying change in cemiplimab clearance and covariates that improved goodness-of-fit. PopPK simulations were used to describe cemiplimab exposure generated by a fixed 350 mg every 3 weeks (Q3W) IV dose regimen. PopPK modeling showed that a two-compartment model with zero-order IV infusion rate and first-order elimination rate well described individual concentrations of cemiplimab. Although several covariates, including baseline body weight and albumin concentrations, had a modest impact on cemiplimab exposure, the magnitude of influence was within the typical observed PK variability of approximately 30%. Based on PopPK simulation results, the 350 mg Q3W dose regimen was selected for further studies in advanced malignancies, including advanced CSCC. Similarity in observed cemiplimab exposure at the fixed 350 mg Q3W and the weight-based 3 mg/kg Q2W dose regimens confirmed this fixed dose selection. A robust PopPK model was developed to describe cemiplimab concentrations and supported use of the fixed 350 mg Q3W IV dose regimen.

Pharmacologic effects of oseltamivir in immunocompromised adult patients as assessed by population PK/PD analysis and drug-disease modelling for dosing regimen optimization.

AimPharmacologic effects were analysed to determine a dose recommendation for oseltamivir in immunocompromised (IC) adults with influenza.MethodsQuantitative clinical pharmacology methods were applied to data from 160 adult IC patients (aged 18‐78 years) from two studies (NV20234, 150 patients; NV25118, 10 patients) who received oseltamivir 75‐200 mg twice daily for up to 10 days. An established population‐pharmacokinetic (PK) model with additional effects on oseltamivir and oseltamivir carboxylate (OC) clearance described the PK characteristics of oseltamivir in IC patients versus otherwise healthy (OwH) patients from previous clinical trials. Estimated PK parameters were used to evaluate exposure‐response relationships for virologic endpoints (time to cessation of viral shedding, viral load measures and treatment‐emergent resistance). A drug‐disease model characterized the viral kinetics of influenza accounting for the effect of OC on viral production.ResultsOseltamivir clearance was 32.5% lower (95% confidence interval [CI], 26.1‐38.8) and OC clearance was 33.7% lower (95% CI, 23.2‐44.1) in IC versus OwH patients. No notable exposure‐response relationships were identified for exposures higher than those achieved after conventional dose oseltamivir 75 mg, which appeared to be close to the maximum effect of oseltamivir. Simulations of the drug‐disease model predicted that initiating treatment within 48 hours of symptom onset had maximum impact, and a treatment duration of 10 days was favourable over 3‐5 days to limit viral rebound.ConclusionsOur findings support the use of conventional‐dose oseltamivir 75 mg twice daily for 10 days in the treatment of IC adult patients with influenza.

Pharmacokinetic-pharmacodynamic (dipeptidyl peptidase-4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once-weekly administered omarigliptin.

To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment. PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participating in Phase 1, 2 and 3 studies examining single- or multiple-dose weekly administration of omarigliptin at doses ranging from 0.25 to 400 mg. Population PK and PD analyses were performed using nonlinear mixed effect modelling. A semi-mechanistic 2-compartment model with linear unbound clearance and concentration-dependent binding of omarigliptin to the DPP-4 enzyme in both the central and peripheral compartments adequately described omarigliptin PK. Key covariates on omarigliptin PK included reduced unbound clearance with renal impairment. A direct effect sigmoid maximum inhibitory efficacy model adequately described the relationship between omarigliptin plasma concentrations and DPP-4 inhibition. These models supported the current Japan label instructions that the approved omarigliptin 25-mg once-weekly dose be halved in patients with severe renal impairment and in those with end-stage renal disease. Also, if patients missed a dose, the next dose of omarigliptin should be taken as soon as remembered up to and including the day before the next scheduled dose. No other clinically important covariates were identified. The models in the present analysis adequately described PK and PD characteristics of omarigliptin and supported the dosing and administration section of the omarigliptin label.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants.

Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software (version 7.2.0). Fifty-one infants (age range, 0.1 to 2.0 years) were included. Sparse pharmacokinetic samples (n = 90) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CLCR) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg/kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT>MIC), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.

Population Pharmacokinetic Characteristics of Amikacin in Suspected Cases of Neonatal Sepsis in a Low-Resource African Setting: A Prospective Nonrandomized Single-Site Study

BackgroundAmikacin exhibits marked pharmacokinetic (PK) variability and is commonly used in combination with other drugs in the treatment of neonatal sepsis. There is a paucity of amikacin PK information in neonates from low-resource settings. ObjectivesTo determine the PK parameters of amikacin, and explore the influence of selected covariates, including coadministration with aminophylline, on amikacin disposition in neonates of African origin. MethodsNeonates with suspected sepsis admitted to an intensive care unit in Accra, Ghana, and treated with amikacin (15 mg/kg loading followed by 7.5 mg/kg every 12 hours), were recruited. Serum amikacin concentration was measured at specified times after treatment initiation and analyzed using a population PK modeling approach. ResultsA total of 419 serum concentrations were available for 247 neonates. Mean (SD) trough amikacin concentration (from samples collected 30 minutes before the fourth dose) among term (n = 25), and preterm (<37 weeks’ gestation n = 36) neonates were 6.2 (3.4) and 9.2 (5.7) µg/mL, respectively (P = 0.02). A 1-compartment model best fitted amikacin disposition, and birth weight was the most important predictor of amikacin clearance (CL) and distribution (V). The population CL and V of amikacin were related as CL (L/h) = 0.153 (birth weight/2.5)1.31, V (L) = 2.94 (birth weight/2.5)1.18. There was a high between-subject variability (58.9% and 50.7%) in CL and V, respectively. CL and V were 0.058 L/h/kg and 1.15 L/kg, respectively, for a mean birth weight of 2.1 kg, and the mean half-life (based on 1-compartment model), was 13.7 hours. ConclusionsThe V and half-life of amikacin in this cohort varied from that reported in non-African populations, and the high trough and low peak amikacin concentrations in both term and preterm neonates suggest strategies to optimize amikacin dosing are required in this population.

Population pharmacokinetic characteristics of sirolimus in healthy Chinese subjects and renal transplant patients

To identify the factors affecting the pharmacokinetics (PKs) of sirolimus in healthy Chinese subjects and renal transplant patients. A population PK model of sirolimus was constructed using dense data from 22 healthy volunteers and sparse data from 105 renal transplant patients. The data were well described by a two-compartment model with first-order absorption. The estimates of absorption rate constant (Ka), clearance (CL/F), and central volume of distribution (V2/F) were 0.24 h(-1), 8.81 L/h, and 676 L, respectively. The CL/F in renal transplant patients was 45.5% lower than that in healthy subjects. Based on the final model, CL/F decreased significantly with increasing cyclosporine (CsA) daily dose and age. A decrease of 7.3% in CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in CL/F for every 20-year increase in age was observed. Moreover, V2/F increased significantly with increasing serum creatinine in our study. However, the range of serum creatinine concentration and the interindividual variability for V2/F are large. This is the first study to characterize the population PKs of sirolimus using a two-compartment model in healthy Chinese subjects and renal transplant patients. A decrease of 7.3% in the sirolimus CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in the sirolimus CL/F for every 20-year increase in age was observed, which allowed us to better optimize sirolimus dosing regimens in Chinese renal transplant patients.

Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors.

Sonidegib (Odomzo) selectively inhibits smoothened and suppresses the growth of hedgehog pathway-dependent tumors. A population pharmacokinetic (PK) analysis of sonidegib in healthy subjects and patients with advanced solid tumors was conducted to characterize PK, determine variability, and estimate covariate effects. PK data from five phase 1 or 2 studies (N=436) in the dose range from 100 to 3000mg were analyzed using NONMEM. A two-compartment base model with first-order absorption, lag time, linear elimination, and bioavailability that decreased with dose was updated to describe the PK of sonidegib. Covariate analyses were performed and were incorporated into the population PK full model. The base and full models were robust with a good fit to the study data. Population-predicted geometric means (inter-individual variability, CV%) of apparent oral clearance, apparent volume of distribution at steady state, accumulation ratio, and elimination half-life were 9.5L/h (71.4%), 9163L (74.9%), 21 (131%) and 29.6days (109%). Clinically relevant covariate effects were: A high-fat meal increased sonidegib bioavailability fivefold, healthy volunteers had threefold higher clearance, sonidegib bioavailability decreased with increasing dose levels, and PPI coadministration reduced sonidegib bioavailability by 30%. Sonidegib PK was not significantly impacted by baseline age, weight, total bilirubin, alanine aminotransferase, albumin, creatinine clearance, gender, and ethnicity (Western countries versus Japanese). No dose adjustment is needed for mild hepatic impairment, mild and moderate renal impairment, age, weight, gender, or ethnicity. This population PK model adequately characterizes sonidegib PK characteristics and can be used for various simulations and applications.

Study of the Population Pharmacokinetic Characteristics of Nimorazole in Head and Neck Cancer Patients Treated in the DAHANCA-5 Trial

AimsTo study the pharmacokinetic characteristics of the hypoxic radiosensitiser nimorazole in patients with head and neck squamous cell carcinoma. Materials and methodsThe pharmacokinetics of the hypoxic radiosensitiser nimorazole were studied in 63 patients treated in the DAHANCA-5 trial. After the first day of treatment, serial venous blood samples were taken and plasma concentrations of nimorazole measured by high pressure liquid chromatography (HPLC). Plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using validated PC-based software. The different pharmacokinetic parameters were calculated and correlated with the different patient- and treatment-related variables. ResultsHPLC measurements showed a linear relationship between peak plasma concentration and administered dose. The mean peak concentration adjusted for dose (in g/m2) was 32.2 ± 0.9 μg/ml. The time of peak concentration ranged between 30 and 180 min (median 60 min). Plasma elimination occurred with a mean half-life of 3.35 ± 0.09 h and was not significantly altered as a function of dose. There was a well-established linear–linear relationship between area under the concentration–time curve (AUC; mean 191 ± 6 μg·h/ml) and administered dose, especially when expressed as g/m2. The mean apparent volume of distribution was 0.77 ± 0.02 l/kg. A statistically significant longer elimination half-life in men relative to women (mean difference 0.40 h; 95% confidence interval 0.77–0.03; P 0.03) was detected. Nimorazole was well tolerated; with 67% of patients reporting no toxicity; nausea/vomiting was the most reported toxicity in the remaining patients. ConclusionThe study supports the current nimorazole dose scheduling in patients.

Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake

The aim of the study was to better understand blonanserin population pharmacokinetic (PK) characteristics in Chinese healthy subjects. Data from two studies with 50 subjects were analyzed to investigate the population PK characteristics of blonanserin at single dose (4, 8, and 12 mg) under fasting, multidose (4 mg bid or 8 mg qd for 7 days) and under food intake condition (single dose, 8 mg). Blonanserin plasma concentrations were detected using the high performance liquid chromatography tandem mass spectrometry (LC/MS/MS). A nonlinear mixed-effects model was developed to describe the blonanserin concentration-time profiles. A two compartment model with first-order absorption was built to describe the time-course of blonanserin. The population-predicted system apparent clearance (CL/F), volume of apparent distribution in center (V(1)/F), and the first-order absorption rate constant (Ka) of blonanserin under fasting was 1230 L/h, 9500 L, and 3.02 h(-1), respectively. Food intake decreased Ka of blonanserin to 0.78 h(-1). The relative bioavailability between fasting and food intake estimated by the final model was 55%. No clinically significant safety issues were identified. This is the first study assessing the PK profile of blonanserin with population PKs method. The results can be used for simulation in further clinical trial and optimize individual dosage regimens using a Bayesian methodology in patients.

Study of the Population Pharmacokinetic Characteristics of Once-Daily Trospium Chloride 60 mg Extended-Release Capsules in Patients with Overactive Bladder and in Healthy Subjects

Overactive bladder is a common disorder that affects approximately 34 million adults in the United States. Anticholinergic (antimuscarinic) agents are the most widely used pharmacological option for overactive bladder. This study set out to identify and characterize the influence of a number of intrinsic characteristics on the pharmacokinetics of the anticholinergic agent trospium chloride (Sanctura(®)) 60 mg extended release (XR), and to evaluate the correlation between trospium chloride exposure and key efficacy and safety outcomes in subjects and patients. Pharmacokinetic data were obtained from three studies in which a total of 349 subjects received trospium chloride XR for up to 12 weeks. Plasma trospium chloride concentration data were pooled and a population pharmacokinetic model was derived using non-linear mixed-effects modelling. Demographic factors were assessed for influence on the model. The correlation between trospium chloride exposure and key efficacy variables was evaluated. Correlations between exposure and safety outcomes were also assessed. Trospium chloride XR 60 mg once daily for 10 days in healthy volunteers or trospium chloride 60 mg XR once daily for either 2 weeks or 12 weeks in patients with overactive bladder. The best population pharmacokinetic model was determined to be a two-compartment model with zero-order release into the depot compartment and first-order absorption. Body surface area (BSA) was the only covariate to significantly (P < 0.05) impact trospium chloride 60 mg XR pharmacokinetics. Significant relationships (P < 0.05) were observed between exposure [maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve from time zero to 24 h (AUC(24))] and efficacy outcomes in the <65-year age group for change in average number of voids/day, change in number of incontinence episodes, and change in urgency severity, and in the ≥65-year age group statistical significance (P < 0.05) was achieved for C(max), but not for AUC(24), for these same three efficacy measures. Statistically significant relationships (P < 0.004) were also observed between exposure and both dry mouth and constipation, with increased benefit and increased incidence of adverse events (AEs) associated with higher concentrations; the correlation coefficients were low against the aggregate of AEs of interest (0.19 for AUC(24) and 0.18 for C(max)), indicating only mild strength of association. This population pharmacokinetic analysis demonstrated that the only demographic characteristic associated with trospium chloride pharmacokinetics was BSA. Thus, treatment of most patients with overactive bladder with once-daily trospium chloride 60 mg XR should not require consideration of key intrinsic demographic parameters. Furthermore, while efficacy and tolerability outcomes were found to be correlated with trospium chloride exposure, the strength of the association was modest in this study.

Population pharmacokinetic (PK) analysis supports fixed dosing for the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) administered intravenously in patients with advanced solid tumors.

2586 Background: Monoclonal antibody therapeutics in oncology are most frequently dosed using body weight (BW)-based dosing, which may be due to the perception that BW-based dosing may be more precise. MEGF0444A is a huMAb that targets and inhibits the epidermal growth factor-like domain 7 (EGFL7) and has anti-vascular, and anti-re-growth effects on tumor vasculature and anti-tumor activity, particularly in combination with anti-VEGF. The objective of this analysis was to characterize MEGF0444A PK from two Phase I studies in patients (pts) with solid tumors and to evaluate the potential for using fixed dosing in Phase II studies. Methods: Noncompartment and population analyses were performed using pt data from the Phase Ia (0.3, 1, 3, 7.5, and 15 mg/kg q3wk) and Ib (2, 5, and 10 mg/kg q2wk) studies. Pt demographic data and other clinical relevant covariates were incorporated in the population analysis. PK simulation of 1000 subjects with a BW distribution was performed to compare the inter-individual variability of MEGF0444A exposure following fixed or BW-based dosing. Results: MEGF0444A was characterized by linear PK in the dose range tested. The clearance (CL) and volume of distribution (Vd) values were consistent with those of a typical huMAb. The elimination half-life was approximately 2 weeks. BW effect on CL and Vd was found to be minor to moderate, which appeared to be smaller when compared with other oncology MAbs. PK simulations suggest that fixed dosing may result in less inter-individual variability in MEGF0444A exposure compared with BW-based dosing. In addition, under- and over-exposure in extreme BW pts tended to be reduced with fixed dosing. Conclusions: PK characteristics support dosing of MEGF0444A every 2 or 3 weeks to maintain desired drug exposure. Population PK analysis results support fixed dosing of MEGF0444A at the equivalent 5 mg/kg q2 wk doses (400mg q2 or 600mg q3 wks) in future studies. The current analysis provides valuable insights on fixed dosing for oncology MAbs.

Population pharmacokinetics (PK) and association of PK and clinical outcomes of rituximab in patients with non-Hodgkin's lymphoma.

e13108 Background: Rituximab is effective and widely used in NHL. To increase our understanding of its PK characteristics and relation to clinical outcomes, we analyzed data from the rituximab pivotal trial (IDEC102-05) in patients with relapsed low-grade or follicular B-cell NHL who were treated with 4 weekly rituximab doses. Methods: Population PK (POP-PK) of rituximab was performed based on 1,848 serum samples from 161 patients using nonlinear mixed-effects modeling (NONMEM VI) software. The association of rituximab PK with response and time to progression (TTP) in the follicular lymphoma (FL) subgroup was evaluated by logistic and Cox regression, respectively. Results: Rituximab clearance was best described by a two-compartment model with time varying clearance comprised of two terms—a target-independent pathway as with other endogenous IgG antibodies, which is unchanged throughout treatment, and a target-mediated pathway that decreases from its initial value following infusion at a constant decay rate related to the extent of B cell/tumor-burden at baseline. In the FL subgroup (N=111), a positive association of rituximab serum concentrations pre-second infusion with overall response rate and TTP was observed among patients with low concentrations (< 35 ug/ml): odds ratio =1.72 (95% CI: 1.14-2.60, p=0.009) for response and HR=0.75 (95% CI: 0.64-0.91, p=0.0032) for TTP (per 5 ug/ml). In contrast, no association with TTP or OR was seen for the FL patients with higher serum concentrations (≥ 35 ug/ml). Similar results were observed for timpoints at 1 and 3 mo post-treatment, and the association is not qualitatively affected by baseline characteristics or disease factors. Conclusions: POP-PK studies suggest that the lower rituximab serum levels are associated with the larger tumor burden and/or antigen load. Among FL patients, higher rituximab concentrations are associated with better clinical outcomes only on those with serum concentrations in a low range. Further studies would be necessary to identify the threshold of rituximab level sufficient to override the effects of tumor burden for FL patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Roche

Effect of age, weight, and CYP2C19 genotype on escitalopram exposure.

The purpose of this study was to characterize escitalopram population pharmacokinetics (PK) in patients treated for major depression in a cross-national, US-Italian clinical trial. Data from the 2 sites participating in this trial, conducted at Pittsburgh (United States) and Pisa (Italy), were used. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed effects modeling was used to model the PK characteristics of escitalopram. One- and 2-compartment models with various random effect implementations were evaluated during model development. Objective function values and goodness-of-fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, body mass index, sex, race, and clinical site were evaluated as possible covariates. In total, 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A 1-compartmental model with linear elimination and proportional error best described the data. Apparent clearance (CL/F) and volume of distribution (V/F) for escitalopram without including any covariates in the patient population were 23.5 L/h and 884 L, respectively. CYP2C19 genotype, weight, and age had a significant effect on CL/F, and patient body mass index affected estimated V/F. Patients from Pisa, Italy, had significantly lower clearances than patients from Pittsburgh that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Postprocessed individual empirical Bayes estimates on clearance for the 172 patients show that patients without allele CYP2C19(*)2 or (*)3 (n = 82) cleared escitalopram 33.7% faster than patients with heterogeneous or homogeneous (*)2 or (*)3 ((*)17/(*)2, (*)17/(*)3, (*)1/(*)2, (*)1/(*)3, (*)2/(*)2, (*)2/(*)3, and (*)3/(*)3, n = 46). CL/F significantly decreased with increasing patient age. Patients younger than 30 years (n = 45) cleared escitalopram 20.7% and 42.7% faster than patients aged 30 to 50 years (n = 84) and older than 50 years of age (n = 43), respectively. CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. These variables may affect patient tolerance of this antidepressant and may provide important information in the effort to tailor treatments to patients' individual needs.

Population approaches in paediatrics

Population pharmacokinetic (PK) approach is now often used to evaluate PK characteristics of a new compound during its clinical development. Recently, new legislation governing the development and authorization of medicines for use in children aged 0-17 years was introduced in the European Union. Among the strategies proposed in relation to clinical aspects, use of population PKs is stated. In this manuscript, comparison between standard PK and population PK methods will be briefly addressed to understand why the second is particularly adapted to perform PK studies in paediatrics. Then, specific patients' characteristics (covariates) in paediatrics will be presented. Examples of PK and PK-pharmacodynamic (PK-PD) studies will be finally given. The number of population PK studies published still exceeds largely those of PK-PD.