A Comparison of the Charlson and Elixhauser Methods for Predicting Nursing Indicators in Gastrectomy with Gastric Cancer Patients.

Background: Comorbidity indices such as Charlson's (CCI) and Elixhauser's (ECI) are used to adjust the patient's care, depending on the severity of their condition. However, no study has compared these indices' ability to predict nursing-sensitive outcomes (NSOs). We compared the performance of CCI and ECI in predicting NSOs in gastric cancer patients' gastrectomy. Methods: Gastric cancer patients with gastrectomy, aged 19 years or older and admitted between 2015 and 2016, were selected from the Korea Insurance Review and Assessment Service database. We examined the relationships between NSOs and CCI or ECI while adjusting patient and hospital characteristics with logistic regression. Results: The ECI item model was the best in view of the C-statistic and Akaike Information Criterion for total NSO, physiologic/metabolic derangement, and deep vein thrombosis, while the Charlson item model was the best for upper gastrointestinal tract bleeding. For the C-statistic, the ECI item model was the best for in-hospital mortality, CNS complications, shock/cardiac arrest, urinary tract infection, pulmonary failure, and wound infection, while the CCI item model was the best for hospital-acquired pneumonia and pressure ulcers. Conclusions: In predicting 8 of 11 NSOs, the ECI item model outperformed the others. For other NSOs, the best model varies between the ECI item and CCI item model.

Likelihood interval for nonlinear regression.

Wald confidence interval has been used as the conventional method of interval estimation for the parameters in nonlinear models. Because Wald confidence interval is symmetric around the point estimate, it does not reflect the asymmetry of the likelihood profile in nonlinear regression. In contrast, a likelihood interval is estimated directly from the likelihood profile and does reflect the shape of the likelihood profile. However, the lack of software for the estimation of likelihood intervals and visualization of likelihood profiles posed an obstacle to the use of likelihood intervals in nonlinear models. There was a need for software implementation to tackle these tasks. Likelihood interval estimation and likelihood profile plotting for nonlinear models had not been previously implemented in R software. This article describes the implementation of likelihood interval estimation and likelihood profile plotting in the wnl R software package. To demonstrate the usage of implemented functions, an example of fitting a nonlinear pharmacokinetic model to concentration-time data is presented.

Pharmacokinetic Interactions Between Bazedoxifene and Cholecalciferol: An Open-Label, Randomized, Crossover Study in Healthy Male Volunteers.

Purpose: The combined administration of bazedoxifene, a tissue-selective estrogen receptor modulator, and cholecalciferol can be a promising therapeutic option for postmenopausal osteoporosis patients. This study aimed to examine the pharmacokinetic interactions between these two drugs and the tolerability of their combined administration in healthy male subjects. Patients and Methods: Thirty male volunteers were randomly assigned to one of the six sequences comprised of three treatments: bazedoxifene 20 mg monotherapy, cholecalciferol 1600 IU monotherapy, and combined bazedoxifene and cholecalciferol therapy. For each treatment, a single dose of the investigational drug(s) was administered orally, and serial blood samples were collected to measure the plasma concentrations of bazedoxifene and cholecalciferol. Pharmacokinetic parameters were calculated using the non-compartmental method. The point estimate and 90% confidence interval (CI) of the geometric mean ratio (GMR) were obtained to compare the exposures of combined therapy and monotherapy. The pharmacokinetic parameters compared were the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast). The safety and tolerability of the combined therapy were assessed in terms of the frequency and severity of adverse events (AEs). Results: For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.9263-1.1765) for Cmax and 1.1329 (1.0232-1.2544) for AUClast. For baseline-adjusted cholecalciferol, the GMR (90% CI) of the combined therapy to monotherapy was 0.8543 (0.8005-0.9117) for Cmax and 0.8056 (0.7445-0.8717) for AUClast. The frequency of AEs observed was not significantly different between the combined therapy and monotherapy, and their severity was mild in all cases. Conclusion: A mild degree of pharmacokinetic interaction was observed when bazedoxifene and cholecalciferol were administered concomitantly to healthy male volunteers. This combined therapy was well tolerated at the dose levels used in the present study.

Comparison of Pharmacodynamics between Tegoprazan and Dexlansoprazole Regarding Nocturnal Acid Breakthrough: A Randomized Crossover Study.

Background/Aims: Tegoprazan, a novel potassium-competitive acid blocker, is expected to overcome the limitations of proton pump inhibitors and effectively control nocturnal acid breakthrough. To evaluate the pharmacodynamics of tegoprazan versus dexlansoprazole regarding nocturnal acid breakthrough in healthy subjects. Methods: In a randomized, open-label, single-dose, balanced incomplete block crossover study, 24 healthy male volunteers were enrolled and randomized to receive oral tegoprazan (50, 100, or 200 mg) or dexlansoprazole (60 mg) during each of two administration periods, separated by a 7- to 10-day washout period. Blood samples were collected for pharmacokinetic parameter analysis; gastric monitoring was performed for pharmacodynamic parameter evaluation. Results: All 24 subjects completed the study. Average maximum plasma concentration, area under the plasma concentration-time curve, and mean time with gastric pH >4 and pH >6 for tegoprazan demonstrated dose-dependent incremental increases. All the tegoprazan groups reached mean pH ≥4 within 2 hours, whereas the dexlansoprazole group required 7 hours after drug administration. Based on pharmacodynamic parameters up to 12 hours after evening dosing, 50, 100, and 200 mg of tegoprazan presented a stronger acid-suppressive effect than 60 mg of dexlansoprazole. Moreover, the dexlansoprazole group presented a comparable acid-suppressive effect with the tegoprazan groups 12 hours after dosing. Conclusions: All the tegoprazan groups demonstrated a significantly faster onset of gastric pH increase and longer holding times above pH >4 and pH >6 up to 12 hours after evening dosing than the dexlansoprazole group.

Association between nurse staffing levels and rotavirus infection in neonatal intensive care units: A retrospective observational study.

OBJECTIVES: To explore the relationship between nurse staffing levels and rotavirus infection in neonatal intensive care units. RESEARCH METHODOLOGY: This study adopted a retrospective observational design with data from the Health Insurance Review and Assessment Service (2018) database in South Korea. Participants were 35,308 infants in neonatal intensive care units. Multiple logistic regression analyses were employed to examine the association between nurse staffing levels and rotavirus infection in neonatal intensive care units after adjusting for confounding variables such as patient and hospital-related characteristics. RESULTS: A total of 1,514 (4.3%) infants developed rotavirus infection. Among the confounding variables, infectious disease, and being admitted from January to March and in December significantly increased the risk of rotavirus infection, whereas low birth weight, cardiovascular disorders, neonatal jaundice, receiving breastmilk, central line insertion, and ventilator usage significantly decreased the risk. Neonatal intensive care units with a grade 5 nurse staffing level (compared with grades 1-4) had a higher risk of rotavirus infection. CONCLUSIONS: The results suggest that neonatal intensive care units with higher (vs lower) nurse staffing levels are associated with lower rotavirus infection rates among infants. High-risk infants are extremely susceptible to hospital-acquired infections, and more intensive nursing care that differs from that provided to adult or paediatric patients is required. Therefore, nurse staffing levels with less than a 2:1 patient-to-nurse ratio are needed to control and prevent rotavirus infection in neonatal intensive care units.

Implementation of Miettinen-Nurminen score method with or without stratification in R.

Analysis of a 2 × 2 table for clinical data involves computing the point estimate and confidence interval for risk difference, relative risk, or odds ratio. While point estimates of these comparative parameters are uniquely defined, several statistical methods have been proposed to estimate the confidence interval for each parameter. The Miettinen-Nurminen (MN) score method is expected to be used increasingly over traditional interval estimation methods. The MN score method has not been previously implemented in R software for data with stratification. There is a need for a comprehensive software implementation of the MN score method. This article describes the implementation of the MN score method in the sasLM R software package. To demonstrate the usage of the sasLM functions introduced, recently published clinical data are provided as examples.

A simple time-to-event model with NONMEM featuring right-censoring.

In healthcare situations, time-to-event (TTE) data are common outcomes. A parametric approach is often employed to handle TTE data because it is possible to easily visualize different scenarios via simulation. Not all pharmacometricians are familiar with the use of non-linear mixed effects models (NONMEMs) to deal with TTE data. Therefore, this tutorial simply explains how to analyze TTE data using NONMEM. We show how to write the code and evaluate the model. We also provide an example of a hands-on model for training.

Population Pharmacokinetic and Pharmacodynamic Analysis of Polmacoxib in Healthy Volunteers and Patients With Osteoarthritis.

PURPOSE: Polmacoxib, a new coxib dually inhibiting cyclooxygenase-2 and carbonic anhydrase I/II, was recently approved for osteoarthritis treatment in South Korea. This study explored the population pharmacokinetic and pharmacodynamic characteristics of polmacoxib. METHODS: Nonlinear mixed-effects modeling was performed using pooled pharmacokinetic data from a Phase I study in healthy individuals and pharmacokinetic properties and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) data from a Phase IIb study in patients with osteoarthritis. Pharmacodynamic models for WOMAC were sequentially fit using individual pharmacokinetic parameter estimates. FINDINGS: Polmacoxib concentrations in whole blood were adequately described by the 2-compartment model, with mixed zero- and first-order absorption kinetics. Iron concentration was the significant covariate associated with clearance of polmacoxib. The relationship between the whole blood concentration of polmacoxib and WOMAC was best described by a 2-effect compartment model that consisted of central and peripheral compartments with the rate constant of 0.408 min-1 for distribution to the central effect compartment. A decrease in WOMAC was linked to the central effect site compartment concentration through an ordinary maximum effect model with an effect site concentration needed to achieve 50% of the maximum effect of 508 ng/mL. IMPLICATIONS: The current model accurately characterized the pharmacokinetic and pharmacodynamic properties of polmacoxib and could provide a basis for individualized drug therapy.

Acetaminophen-induced anaphylaxis: a case report.

Acetaminophen is known to be generally safe, and the occurrence of anaphylaxis due to acetaminophen has been rarely reported. We report a case of acetaminophen-induced anaphylaxis in a healthy male subject who participated in a clinical trial on the pharmacokinetics of ibandronate. The subject had not experienced an allergic reaction to acetaminophen prior to this incident. The patient received 1300 mg oral acetaminophen at about 12 hours after receiving 150 mg ibandronate. After about 10 minutes, the subject developed whole-body urticaria and hypotension. The temporal association suggested that the anaphylaxis was due to acetaminophen and not ibandronate. Anaphylaxis could occur due to acetaminophen even in the absence of allergic reactions in the first dosing.

Effect of Food on the Pharmacokinetics and Pharmacodynamics of a Single Oral Dose of Tegoprazan.

PURPOSE: Tegoprazan is a potassium-competitive acid blocker (P-CAB) that is designed to treat acid-related diseases through a fundamentally different mechanism than that of proton pump inhibitors (PPIs). Because PPIs inhibit only activated parietal cell H+/K+ adenosine triphosphatase, stimulation of parietal cells by a meal is necessary for optimal results. In contrast, P-CABs can inactivate proton pumps without acid activation and bind to both activated and inactivated adenosine triphosphatase. This study evaluates the effect of food consumption on the pharmacokinetic and pharmacodynamic properties of tegoprazan after a single oral dose in healthy men. METHODS: In this open-label, 2-period crossover study, 24 healthy men were randomized to 1 of 2 treatment sequence groups: administration of tegoprazan under the fasting condition and administration of tegoprazan under the fed condition. The dosing periods of both sequence groups were separated by a washout period of 7 days. At each dosing period, the participants received a single dose of 200 mg of tegoprazan followed by pharmacokinetic and pharmacodynamic analysis. FINDINGS: After the oral administration of 200 mg tegoprazan, the Cmax was decreased and delayed under the fed condition compared with that of the fasting condition. However, no significant differences were observed in the AUC and the time of gastric acid suppression (inhibition of integrated acidity) during 24 hours. IMPLICATIONS: The pharmacokinetic and pharmacodynamic properties of tegoprazan are independent of food effect; thus, tegoprazan could be administered regardless of the timing of food consumption in patients. ClinicalTrials.gov identifier: NCT01830309.

First-in-Human, Double-Blind, Randomized Controlled Trial of an Oral Dose of GnRH Antagonist TU2670 in Healthy Women.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TU2670, a novel orally active, nonpeptide gonadotropin-releasing hormone (GnRH) antagonist administered to healthy female participants. METHODS: This was a first-in-human, multicenter, phase 1, randomized, double-blind, placebo-controlled, single-dose ascending trial that took place in multiple medical centers. A total of 16 healthy premenopausal women (23 to 45 years of age) were randomized and received 20, 40, 80, and 160 mg TU2670 (GnRH antagonist) or placebo 7 days (±1 day) after the onset of menstrual bleeding. We performed a noncompartmental analysis for pharmacokinetic parameters and calculated relative minimum concentration values (Cmin, % Baseline) of serum pharmacodynamic (PD) markers (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and estradiol). RESULTS: There were no significant differences among treatments with respect to vital signs, electrocardiography, adverse events, ovulation test results, and ultrasonography. The median Tmax of TU2670 occurred 0.75 to 1.00 hours after dosing, and concentrations then declined, with a mean apparent half-life (t1/2) of 3.0 to 5.9 hours. AUClast (17.7-417.9 ng·h/mL) and Cmax (8.1-95.4 ng/mL) increased in a dose-dependent manner. The PD analysis after a single administration of TU2670 revealed dose-dependent suppression of LH, FSH, and estradiol. Maximal suppression of the pre-dose baseline (%) was 58% to 82% at 6 to 8 hours for LH, 28% to 39% at 6 to 12 hours for FSH, and 34% to 82% at 12 to 24 hours for estradiol. CONCLUSION: The single administration of TU2670 in healthy premenopausal women was well tolerated and resulted in the dose-dependent suppression of LH, FSH, and estradiol, suggesting rapid and significant inhibition of pituitary and ovarian hormones.

First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of a Neuroprotective Poly (ADP-ribose) Polymerase-1 Inhibitor, JPI-289, in Healthy Volunteers.

BACKGROUND: Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor has therapeutic potential for acute ischemic stroke by suppressing microglial activation and facilitating neuroprotection. In this first-in-human study, we investigate the safety, tolerability and pharmacokinetics (PK) of JPI-289 in healthy male volunteers. SUBJECTS AND METHODS: In single ascending dose (SAD) study, 35, 75, 150, 300, 600 mg JPI-289 or placebo was infused intravenously over 30 minutes to 40 subjects. In multiple ascending dose (MAD) study, 150, 300, 450 mg JPI-289 or placebo was infused over 1 hour every 12 hours to each of 24 subjects for 3.5 days (7 times). The plasma and urine concentrations of JPI-289 and its metabolites were determined. RESULTS: In the SAD study, AUClast and Cmax tended to increase supra-proportionally especially at higher doses in SAD study. However, Cmax showed dose-proportionality in the range of 75-600mg. JPI-289 reached a mean Tmax within 0.50 hour after dosing and a mean elimination half-life (t1/2) was 2.18 to 3.21 hours. In the MAD study, observed accumulation index ranged from 1.52 to 1.76. The effective half-life of JPI-289 was 1.88 to 3.05 hours, indicating that the plasma JPI-289 concentration rapidly reaches steady state. % recovered of JPI-289 measured in urine was 1.59-9.05%. In both studies, concentration of metabolites was less than 10% of JPI-289. Adverse events reported in the study were all mild in intensity and resolved without any sequelae. CONCLUSION: The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be useful in further clinical development of JPI-289.

Validation of "sasLM," an R package for linear models with type III sum of squares.

The general linear model (GLM) describes the dependent variable as a linear combination of independent variables and an error term. The GLM procedure of SAS® and the "car" package in R calculate the type I, II, or III ANOVA (analysis of variance) tables. In this study, we validated the newly-developed R package, "sasLM," which is compatible with the GLM procedure of SAS®. The "sasLM" package was validated by comparing the output with SAS®, which is the current gold standard for statistical programming. Data from ten books and articles were used for validation. The results of the "sasLM" and "car" packages were compared with those in SAS® using 194 models. All of the results in "sasLM" were identical to those of SAS®, whereas more than 20 models in "car" showed different results from those of SAS®. As the results of the "sasLM" package were similar to those in SAS® PROC GLM, the "sasLM" package could be a viable alternative method for calculating the type II and III sum of squares. The newly-developed "sasLM" package is free and open-source, therefore it can be used to develop other useful packages as well. We hope that the "sasLM" package will enable researchers to conveniently analyze linear models.

Pharmacokinetic Evaluation by Modeling and Simulation Analysis of a Donepezil Patch Formulation in Healthy Male Volunteers.

INTRODUCTION: This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation. METHODS: PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software. RESULTS: A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application. CONCLUSION: PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.

Bioequivalence data analysis.

SAS® is commonly used for bioequivalence (BE) data analysis. R is a free and open software for general purpose data analysis, and is less frequently used than SAS® for BE data analysis. This tutorial explains how R can be used for BE data analysis to generate comparable results with SAS®. The main SAS® procedures for BE data analysis are PROC GLM and PROC MIXED, and the corresponding R main packages are "sasLM" and "nlme" respectively. For fixed effects only or balanced data, the SAS® PROC GLM and R "sasLM" provide good estimates; however, for a mixed-effects model with unbalanced data, the SAS® PROC MIXED and R "nlme" are better for providing estimates without bias. The SAS® and R scripts are provided for convenience.

Pharmacokinetic modeling analysis of cilostazol and its active metabolites (OPC-13015 and OPC-13213) after multiple oral doses of cilostazol in healthy Korean volunteers.

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.

Randomised clinical trial: safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of tegoprazan (CJ-12420), a novel potassium-competitive acid blocker, in healthy male subjects.

BACKGROUND: Tegoprazan (CJ-12420) is a potassium-competitive acid blocker (P-CAB) with therapeutic potential for gastro-oesophageal reflux disease (GERD) by reversibly suppressing gastric H+ /K+ -ATPase. AIMS: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of tegoprazan METHODS: A phase I, randomised, double-blind and placebo-controlled clinical trial was conducted in 56 healthy male subjects without Helicobacter pylori infection. In the single ascending dose study, 50, 100, 200 and 400 mg tegoprazan were administered to 32 subjects. In the multiple ascending dose study, 100 and 200 mg tegoprazan were administered every 24 hours to each of the eight subjects for 7 days. In the comparative pharmacodynamics study, 40 mg esomeprazole was administered to eight subjects every 24 hours for 7 days. The assessment included safety, tolerability, pharmacodynamics through monitoring of 24-hour gastric pH and pharmacokinetics of tegoprazan in plasma and urine. RESULTS: Tegoprazan was generally well tolerated. Most adverse events reported in the study were mild in intensity and resolved without any sequelae. Exposure to tegoprazan increased in a dose-proportional manner. Multiple dosing with tegoprazan showed no accumulation in plasma on day 7. The pharmacodynamic analysis revealed that tegoprazan showed rapid, dose-dependent gastric acid suppression. CONCLUSIONS: Tegoprazan was well tolerated and showed rapid and potent gastric acid suppression. This supports the further development of tegoprazan as a treatment for acid-related disorders.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of CTB-001, a Recently Developed Generic of Bivalirudin.

PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.

Disease Progression Modeling Analysis of the Change of Bone Mineral Density by Postoperative Hormone Therapies in Postmenopausal Patients With Early Breast Cancer.

The osteoporosis incidence in postmenopausal patients on aromatase inhibitors (AI) is much higher than in those on tamoxifen, and adverse effects other than musculoskeletal disorders are less on AI than on tamoxifen. In this study we performed disease-progression modeling in postmenopausal patients with early breast cancer who had received 5 years of postoperative hormone therapy. Clinical data from postmenopausal patients who had received postoperative hormonal therapy and met the predefined selection criteria were retrospectively collected in an anonymized way. Disease-progression modeling and simulations were performed using NONMEM version 7.42. A first-order deterioration model with a combination of a symptomatic model (when a drug effect provides a transient bad effect by offsetting the severity of the disease) and a disease-modifying model (when a drug affects the disease progression rate) was used. Vitamin D supplementation was found to have a disease-modifying effect in osteoporosis, whereas AI decreased the bone mineral density by a t score of -0.21. However, after stopping the AI, the estrogen level reverted to normal, thereby reexercising protective effects against bone loss. In the simulation the probability of osteoporosis increased by 10% in the AI group compared with the other groups (tamoxifen, no-treatment group) during the medication period. Tamoxifen showed no significant effects in the final model.

Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline.

Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty-four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25-mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline.