S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults.

PURPOSE: S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. METHODS: In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >-5 to <5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%. RESULTS: S-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R2, %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE. CONCLUSIONS: Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.

Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults.

We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2-compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single- or 2-time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration-time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single- and 2-time point limited sampling models estimated area under the plasma concentration-time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4- and 6-hour limited sampling model had acceptable limits of r2 , bias, and precision. Consequently, development of a single- or 2-time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.

Alcohol use disorder and alcohol withdrawal syndrome in Vietnamese hospitalized patients.

AIMS: To identify the extent to which patients admitted to a general hospital in Vietnam meet the criteria for risky alcohol drinking, alcohol use disorder (AUD), and alcohol withdrawal syndrome (AWS), describe problems and behavior of alcohol use such as types and quantity of alcohol drinking in a hospitalized population in Vietnam, and investigate the association among age, disease-related factors, and alcohol consumption with AWS. METHODS: This study was conducted prospectively in 1340 patients admitted to a general hospital. All patients were screened for risky alcohol drinking. Risky alcohol drinkers were assessed by using the Alcohol Use Disorder Identification Test (AUDIT) to identify AUD patients. The diagnosis of AWS was based on criteria defined by Diagnostic and Statistical Manual of Mental Disorders, version 5. The AWS scale was used to quantitate AWS severity level. RESULTS: Prevalence of risky alcohol drinkers, AUD patients, and AWS patients among hospitalized patients was 15.5%, 13.1%, and 7.3%, respectively. All of the AUD and AWS patients were male. The majority of risky alcohol drinkers, patients with AUD, and patients with AWS were 40-60-year-old men. Almost all patients (98.3%) drank homemade alcohol. Hospitalized patients were more likely to develop AWS if they had liver disease or past experience with AWS. CONCLUSIONS: AUD and AWS are common in hospitalized patients. Formulating a protocol to identify and care for patients with alcohol-related disorders is urgent.

Population Pharmacokinetic Analyses for Ertapenem in Subjects with a Wide Range of Body Sizes.

Despite a number of studies reporting that ertapenem pharmacokinetic parameters differ considerably in obese patients from those in healthy volunteers, functions describing the relationships between this agent's pharmacokinetics and indicators of body size have not been developed. The aim of this analysis was to develop an ertapenem population pharmacokinetic model using data from a previously described study in normal-weight, obese, and morbidly obese healthy volunteers. A single ertapenem 1-g dose administered intravenously was evaluated in 30 subjects within different body mass index (BMI) categories. The population pharmacokinetic model was developed using the first-order conditional estimation method with interaction (FOCE-I) algorithm within NONMEM. The ability of age, sex, renal function, and various body size measures (total body weight, height, body mass index, ideal body weight, fat-free mass, and body surface area [BSA]) to explain a portion of the interindividual variability on select pharmacokinetic parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The data were best described using a linear three-compartment model with total body weight as a covariate on clearance (CL = 1.79 · [weight/95.90]0.278) and BSA as a covariate on central volume (Vc = 4.76 · [BSA/2.06]1.86). After accounting for fixed effects, the estimated interindividual variability was very low (<10% for all clearance and volume terms). Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. Using the developed population pharmacokinetic model and simulation, reliable estimates of ertapenem serum exposures, which can be utilized to evaluate various dosing regimens in subjects with a wide range of body sizes, are expected.

Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults.

BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach.

Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2 ) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.

S-Warfarin Limited Sampling Models to Estimate Area Under the Concentration Versus Time Curve for Cytochrome P450 2C9 Baseline Activity and After Induction.

BACKGROUND: Phenotyping cytochrome P450 (CYP) 2C9 activity using S-warfarin has routinely required extensive blood sampling over at least 96 hours after dose to estimate the area under the concentration time curve from zero to infinity (AUC). Alternatively, S-warfarin limited sampling models (LSMs) using one or 2 concentration timepoints have been proposed to estimate AUC. This study evaluated whether S-warfarin LSMs accurately estimate CYP2C9 baseline and induction conditions in healthy adults and in advanced-stage cancer patients. METHODS: Plasma S-warfarin concentrations from healthy adults (n = 92) and in advanced-stage cancer patients (n = 22) were obtained from 6 published studies where a single 10 mg dose of oral warfarin was administered at CYP2C9 baseline and induction conditions. S-warfarin observed AUC was determined by noncompartmental analysis, whereas estimated AUC was calculated from the LSMs. Bias and precision were assessed by percent mean prediction error, percent mean absolute error, and percent root mean square error. RESULTS: Different results were observed for S-warfarin LSMs in estimating CYP2C9 baseline activity, with most studies resulting in unacceptable bias and precision. The percent mean prediction error, percent mean absolute error, and/or percent root mean square error exceeded acceptable limits for LSMs in patients with advanced-stage cancer and during CYP2C9 induction with lopinavir/ritonavir. CONCLUSIONS: The differing results during CYP2C9 baseline conditions, as well as unacceptable bias and precision in patients with advanced cancer and during CYP2C9 induction, considerably limit the widespread use of previously published S-warfarin LSMs.

Limitations of S-warfarin truncated area under the concentration-time curve to predict cytochrome P450 2c9 activity.

OBJECTIVE: Phenotyping cytochrome P450 (CYP) 2C9 activity with S-warfarin requires extensive blood sampling to characterize area under the concentration-time curve (AUC). This retrospective data analysis was conducted to determine if truncated S-warfarin AUCs can be used to measure CYP2C9 activity. METHODS: S-warfarin plasma concentrations were obtained from healthy adults (n = 84) genotyped as CYP2C9 extensive metabolizers (EMs) from 6 published studies. Subjects received a single 10 mg oral warfarin dose during baseline and treatment conditions. AUC zero to infinity (AUCINF) and truncated AUCs at 48 h (AUC(48)), at 72 h (AUC(72)) and at 96 h (AUC(96)) were determined by noncompartmental analysis. Equivalence was determined via least squares geometric mean ratios (LS-GMRs) with 90% confidence intervals (CI) within 0.8-1.25. RESULTS: A lack of equivalence was observed for AUC(48) and AUC(72) compared to AUC(INF) during baseline conditions in all evaluated studies and during treatment conditions in 5 of 6 studies. Equivalence was observed for AUC(96) compared to AUC(INF) during all baseline and treatment conditions. Results were consistent across all evaluated AUCs between baseline and treatment without a CYP2C9-mediated drug-drug interaction and during induction with an oral contraceptive. During inhibition with fluvastatin, a lack of equivalence was observed with AUC(INF)(LS-GMR [90%CI] = 1.25 [1.16-1.34]) and AUC(96) (1.2 [1.13=1.27]). In contrast, equivalence was observed for AUC(48)(1.15 [1.08-1.22]) and AUC(72) (1.18 [1.11-1.24]). CONCLUSIONS: S-warfarin truncated AUC(48) and AUC(72) poorly characterize AUC(INF) and are unable to detect weak CYP2C9 inhibition with fluvastatin. S-warfarin phenotyping parameters need to ensure blood sampling of at least 96 h to characterize AUC and thus CYP2C9 activity.