Objective The purpose of this study was to characterize escitalopram population pharmacokinetics (PK)in patients treated for major depression in a cross-national, U.S.-Italian clinical trial. Methods Data from the two sites participating in this trial, conducted at Pittsburgh (USA) and Pisa (Italy) were utilized. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed-effects modeling (NONMEM) was used to model the PK characteristics of escitalopram. One and two compartment models with various random effect implementations were evaluated during model development. Objective function values (OFV) and goodness of fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, BMI, sex, race, and clinical site were evaluated as possible covariates. Results 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A one-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 BMI affected estimated V/F. Pisa, Italy patients had significantly lower clearances than Pittsburgh patients that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Post-processed 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 30-50 years (n=84) and greater than 50 years of age (n=43), respectively. Conclusions CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. Patients with heterogeneous or homogeneous CYP2C19*2 or *3 genotype had significantly lower clearances than patients with other genotypes. CL/F significantly decreased with either increasing age or decreasing body weight. These variables may affect patient tolerance of this antidepressant and, consistent with the NIH emphasis on personalized treatment, may provide important information in the effort to tailor treatments to patients’ individual needs.
RO7049389, an inhibitor of hepatitis B virus (HBV) capsid assembly, is being developed for the treatment of patients with chronic HBV infection. The objectives of this first-in-human study are to assess the safety, tolerability, pharmacokinetics (PK), food effect, inhibitory effect on CYP3A, and effect on QT of RO7049389 in healthy participants. Five components, single ascending doses (SAD) cohorts, multiple ascending doses (MAD) cohorts, food effect assessment, drug-drug interaction assessment, and concentration-QT analysis were integrated in one study (five-in-one). Participants randomly received a single dose of 150-2500 mg RO7049389 or placebo in SAD cohorts (n = 41), or multiple doses of 200-800 mg RO7049389 or placebo in MAD cohorts (n = 42). A single doses of 450 mg RO7049389 was administrated under fasted and fed condition. The micro-dose of midazolam was administrated before and after multiple dosing of RO7049389. Safety and tolerability were monitored throughout the study. Serial blood and urine samples were collected for the PK analysis. RO7049389 was safe and well tolerated in healthy participants. Absorption and elimination of RO7049389 occurred rapidly in plasma with minimal recovery in urine. Greater than dose-proportional increases in plasma exposure were observed. Exposure of RO7049389 (450 mg) increased by ∼2 fold when administered with a high fat meal. The inhibition effect of RO7049389 on CYP3A was weak (< 20%). No effect on QT interval was observed up to a single dose of 2500 mg. RO7049389 displayed a favorable safety, tolerability and PK profile suitable for further clinical development.
The goal of the study was to characterize population pharmacokinetics (PPK) for perphenazine in patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Patients (n = 156) received 8–32 mg of perphenazine daily for 14 to 600 days for a total of 421 plasma concentrations measurements. Nonlinear mixed-effects modeling was used to determine PPK characteristics of perphenazine. One-and two-compartment models with various random effect implementations and mixture distributions were evaluated. Objective function values and goodness of fit plots were used as model selection criteria. Age, weight, sex, race, smoking, and concomitant medications were evaluated as covariates. A one-compartmental linear model with proportional error best described the data. The population mean clearance and volume of distribution for perphenazine were 483 L/h and 18,200 L, respectively. Race and smoking status had significant impacts on perphenazine clearance estimates. In addition, the estimated population mean clearance was 48% higher in nonsmoking African Americans than in nonsmoking other races (512 L/h versus 346 L/h). Active smokers eliminated perphenazine 159 L/h faster than nonsmokers in each race. Clearances for smoking African Americans versus smokers in other races were 671 L/h versus 505 L/h, respectively.
The objective of this study was to compare population pharmacokinetic (PPK) models of escitalopram developed from dosage times recorded by a medication event monitoring system (MEMS) versus the reported times from patients with diagnosed depression. 73 patients were prescribed doses of 10,15 or 20 mg of escitalopram daily. Sparse blood samples were collected at weeks 4, 12, 24 and 36 with 185 blood samples obtained from the 73 patients. NONMEM was used to develop a PPK model based on dosing records obtained from MEMS prior to each blood sample time. A separate PPK analysis using NONMEM was performed for the same population using the patient reported last dosing time and assuming a steady state condition as the model input. Objective function values (OFV) and goodness of fit plots were used as model selection criteria. The absolute mean difference in the last dosing time between MEMS and patient reported times was 4.48 ± 10.12 hrs. A one compartment model with first-order absorption and elimination was sufficient for describing the data. Estimated oral clearance (CL/F) to escitalopram was statistically insensitive to reported dosing methods, (MEMS vs. patient reported: 25.5 (7.0%) vs. 26.9 (6.6%) L/hr). However, different dosing report methods resulted in significantly different estimates on the volume of distribution (V/F) (MEMS vs. Patient reported: 1000 (17.3%) vs. 767 (17.5%) L) and the absorption rate constant Ka (MEMS vs. Patient reported: 0.74 (45.7%) vs. 0.51 (35.4%) hr −1 ) for escitalopram. Furthermore, the parameters estimated from the MEMS method were similar to literature reported values for V/F (∼1100L) and Ka (∼ 0.8−0.9 hr −1 ) arising from traditional PK approaches.
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