Combined translational pharmacometrics approach to support the design and conduct of the first-in-human study of DWP16001.

AIMS: The objective of this study was to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, and predict efficacious doses for the first-in-human study using various translational approaches. METHODS: A mechanistic PK/PD model was developed for DWP16001 using nonlinear mixed-effect modelling to describe animal PK/PD properties. Using allometry and in silico physiologically based equations, human PK parameters were predicted. Human PD parameters were scaled by applying interspecies difference and in vitro drug-specific factors. Human parameters were refined using early clinical data. Model-predicted PK and PD outcomes were compared to observations before and after parameter refinement. RESULTS: The PK/PD model of DWP16001 was developed using a 2-compartment model with first-order absorption and indirect response. Efficacious doses of 0.3 and 2 mg of DWP16001 were predicted using human half-maximal inhibitory concentration values translated from Zucker Diabetic Fatty rats and normal rats, respectively. After parameter refinement, doses of 0.2 and 1 mg were predicted to be efficacious for each disease model, which improved the prediction results to within a 1.2-fold difference between the model prediction and observation. CONCLUSIONS: This study predicted efficacious human doses of DWP16001 using population PK/PD modelling and a combined translational pharmacometrics approach. Early clinical data allowed the methods used to translate in vitro and in vivo findings to clinical PK/PD values for DWP16001 to be optimized. This study has shown that a refinement step can be readily applied to improve model prediction and further support the study design and conduct of a first-in-human study.

An experience on the model-based evaluation of pharmacokinetic drug-drug interaction for a long half-life drug.

Fixed-dose combinations development requires pharmacokinetic drugdrug interaction (DDI) studies between active ingredients. For some drugs, pharmacokinetic properties such as long half-life or delayed distribution, make it difficult to conduct such clinical trials and to estimate the exact magnitude of DDI. In this study, the conventional (non-compartmental analysis and bioequivalence [BE]) and modelbased analyses were compared for their performance to evaluate DDI using amlodipine as an example. Raw data without DDI or simulated data using pharmacokinetic models were compared to the data obtained after concomitant administration. Regardless of the methodology, all the results fell within the classical BE limit. It was shown that the model-based approach may be valid as the conventional approach and reduce the possibility of DDI overestimation. Several advantages (i.e., quantitative changes in parameters and precision of confidence interval) of the model-based approach were demonstrated, and possible application methods were proposed. Therefore, it is expected that the model-based analysis is appropriately utilized according to the situation and purpose.

Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans.

It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan-rosuvastatin case, simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the Tmax changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (CmaxI/Cmax: 2.01, AUCI/AUC:1.18, Tmax: 5 h → 0.75 h). In the next case of cyclosporine-rosuvastatin, the simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CLint,BCRP,intestine of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin-telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin-cyclosporine interaction).

Retracted: Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans.

'Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans' by Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon and Dong-Seok Yim The above article, published online on 06 February 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, K. Sandy Pang, and John Wiley & Sons, Ltd. The authors retracted the paper due to errors associated with use of log D vs. log P of telmisartan as inputs of the PBPK model. The authors concluded that there are too many changes in the article to be resolved by an Erratum, and had requested a retraction. Reference Bae, S. H., Park, W.-S., Han, S., Park, G., Lee, J., Hong, T., Jeon, S., and Yim, D.-S. (2016) Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharm. Drug Dispos., doi: 10.1002/bdd.2060.

Simulation of PET scan timings for receptor occupancy studies of CNS drugs: a simple fixed-time design performed as well as scattered time point designs.

PURPOSE: This study aimed to determine the effect of PET scan timings on the reliability of occupancy parameter estimates and to identify the scan timing design that gives the most reliable occupancy parameter estimates. METHODS: We compared the performance of designs with various sets of sampling time points using the stochastic simulation and estimation method in Perl-speaks-NONMEM. Biases, relative standard errors, relative estimation errors, and root mean square errors were used to compare the performance of designs. RESULTS: Unlike the results of a previous report, we found that rather complicated designs where each subject or group of subjects are allocated to different scan timings were not superior to the simple, conventional fixed-time designs regardless of whether effect compartment or receptor binding models were used. CONCLUSIONS: We conclude that the conventional fixed-time designs that have been used so far may give robust PD parameter estimates for occupancy data obtained from human PET studies of CNS drugs.

Population pharmacokinetic analysis of piperacillin in burn patients.

Piperacillin in combination with tazobactam, a ß-lactamase inhibitor, is a commonly used intravenous antibiotic for the empirical treatment of infection in intensive care patients, including burn patients. The purpose of this study was to develop a population pharmacokinetic (PK) model for piperacillin in burn patients and to predict the probability of target attainment (PTA) using MICs and concentrations simulated from the PK model. Fifty burn patients treated with piperacillin-tazobactam were enrolled. Piperacillin-tazobactam was administered via infusion for approximately 30 min at a dose of 4.5 g (4 g piperacillin and 0.5 g tazobactam) every 8 h. Blood samples were collected just prior to and at 1, 2, 3, 4, and 6 h after the end of the infusion at steady state. The population PK model of piperacillin was developed using NONMEM. A two-compartment first-order elimination PK model was finally chosen. The covariates included were creatinine clearance (CLCR), day after burn injury (DAI), and sepsis. The final PK parameters were clearance (liters/h) (equal to 16.6 × [CLCR/132] + DAI × [-0.0874]), central volume (liters) (equal to 25.3 + 14.8 × sepsis [0 for the absence or 1 for the presence of sepsis]), peripheral volume (liters) (equal to 16.1), and intercompartmental clearance (liters/h) (equal to 0.636). The clearance and volume of piperacillin were higher than those reported in patients without burns, and the terminal half-life and PTA decreased with the increased CLCR. Our PK model suggests that higher daily doses or longer durations of infusion of piperacillin should be considered, especially for burn patients with a CLCR of ≥ 160 ml/min.

Modeling of the parathyroid hormone response after calcium intake in healthy subjects.

Plasma ionized calcium (Ca(2+)) concentrations are tightly regulated in the body and maintained within a narrow range; thus it is challenging to quantify calcium absorption under normal physiologic conditions. This study aimed to develop a mechanistic model for the parathyroid hormone (PTH) response after calcium intake and indirectly compare the difference in oral calcium absorption from PTH responses. PTH and Ca(2+) concentrations were collected from 24 subjects from a clinical trial performed to evaluate the safety and calcium absorption of Geumjin Thermal Water in comparison with calcium carbonate tablets in healthy subjects. Indirect response models (NONMEM Ver. 7.2.0) were fitted to observed Ca(2+) and PTH data, respectively, in a manner that absorbed but unobserved Ca(2+) inhibits the secretion of PTH. Without notable changes in Ca(2+) levels, PTH responses were modeled and used as a marker for the extent of calcium absorption.

Population pharmacokinetic analysis of colistin in burn patients.

Colistin is increasingly used as a salvage therapy for nosocomial infections caused by multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, the available pharmacokinetic (PK) data for colistin are limited to guide dosing. The aim of this study was to develop a population PK model of colistin and to identify the optimal dosage regimens for burn patients. Fifty patients with burns ranging from 4% to 85% of total body surface area who had been treated with colistimethate sodium (CMS) were studied. CMS, which is hydrolyzed in vivo to an active metabolite, was intravenously administered every 12 h. Blood samples were collected at 0, 1, 2, 4, 6, and 8 h after more than five infusions to measure the colistin concentration using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, v. 6.2). A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance for the relative fraction of CMS converted into colistin and the presence of edema for the turnover rate constant of CMS converted into colistin. A steady-state 24-h area under the concentration-time curve was simulated from 1,000 virtual patients receiving 150 mg colistin base activity every 12 h using the final model. Relative to previous studies with critically ill patients, the elimination half-life of colistin (6.6 h) was much shorter, and continuous renal replacement therapy was not a significant covariate for any PK parameters.

Population pharmacokinetic analysis of fluconazole to predict therapeutic outcome in burn patients with Candida infection.

The pharmacokinetic (PK) property of fluconazole might be significantly altered in major burn patients by medical interventions and physiologic changes. In this study, our aims were to investigate fluconazole PK in burn patients using a population approach and to recommend the optimal fluconazole regimen based upon the predicted therapeutic outcome. At steady state, blood samples for PK analysis were obtained from 60 burn patients receiving between 100 and ~400 mg fluconazole daily. A mixed-effect modeling was performed and the therapeutic outcome of antifungal therapy was predicted for 10,000 virtual patients using NONMEM (version 7.2). MIC values were sampled from the MIC distribution at the study site. An area under the free drug concentration-time curve (fAUC)/MIC measurement of >25 h was used as the criterion for therapeutic success. When the same dose was given, the plasma concentration of fluconazole was predicted to be lower in burn patients compared to the nonburn population because of the large PK parameter (clearance, volume of distribution) estimates and continuous renal replacement therapy (CRRT). This tendency was particularly predominant when the patients were within 30 postburn days. Based upon our findings, 400 mg/day fluconazole is recommended to obtain therapeutic successes in major burn patients.

Saturable human neopterin response to interferon-α assessed by a pharmacokinetic-pharmacodynamic model.

BACKGROUND: In this study, we developed a pharmacokinetic (PK)- pharmacodynamic (PD) model of a new sustained release formulation of interferon-α-2a (SR-IFN-α) using the blood concentration of IFN-α and neopterin in order to quantify the magnitude and saturation of neopterin production over time in healthy volunteers. The SR-IFN-α in this study is a solid microparticular formulation manufactured by spray drying of a feeding solution containing IFN-α, a biocompatible polymer (polyethylene glycol) and sodium hyaluronate. METHODS: The full PK and PD (neopterin concentration) datasets from 24 healthy subjects obtained after single doses of 9, 18, 27 and 36 MIU of subcutaneous SR-IFN-α were used to build the mixed-effect model using NONMEM (version 7.2) with the GFORTRAN compiler. RESULTS: A one-compartment model with first-order elimination and a mixture of zero- and first-order absorption was chosen to describe the PK of SR-IFN-α. The time-concentration profile of neopterin, the PD marker, was described by a turnover model combined with a single transit compartment. The saturable pattern of the neopterin response blurring the dose-response relationship of SR-IFN-α was addressed by introducing the concept of the EC50 increasing over time. CONCLUSIONS: The PK-PD model of SR-IFN-α developed in this study has presented a quantitative tool to assess the time-course of a saturable neopterin response in humans.

Pharmacokinetic-pharmacodynamic model of fimasartan applied to predict the influence of a high fat diet on its blood pressure-lowering effect in healthy subjects.

PURPOSE: Fimasartan is a non-peptide angiotensin II receptor antagonist which selectively blocks the AT(1) receptor. The aim of our study was to perform a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of fimasartan to evaluate the effect of food on the mechanistic PK-PD relationship. METHODS: This was a food-drug interaction single-center study involving 24 healthy subjects that was designed as a randomized, open-label, single-dosing, two-way crossover trial. Extensive PK data was obtained on blood samples collected at 0, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, and 24 h post-dosing and five systolic/diastolic blood pressure (BP) measurements made at 0, 4, 8, 12 and 24 h post-dosing and used to construct a mixed effect model (NONMEM, ver. 6.2). RESULTS: A two-compartment linear PK model with zero-order (fasted) or Weibull (fed with high-fat diet) absorption best described the PK of fimasartan. Relative bioavailability decreased by 37 % when the subjects were given a high-fat diet. CONCLUSIONS: The turnover PK-PD model combined with pre-defined cosine function for circadian rhythm described the BP changes measured within 24 h after dosing better than the effect compartment or transduction models. To predict the influence of a high-fat diet on the blood pressure-lowering effect of fimasartan in healthy subjects, we simulated changes in BP when fimasartan was given daily for 30 days. The overlapping pattern of simulated BP curves in the fasted versus fed group demonstrated that a high-fat diet would not cause a clinically significant reduction in the BP-lowering effect of fimasartan, despite a significant reduction in bioavailability.

Mixed-effect circadian rhythm model for human erythrocyte acetylcholinesterase activity--application to the proof of concept of cholinesterase inhibition by acorn extract in healthy subjects with galantamine as positive control.

PURPOSE: The aim of this study was to develop a non-linear mixed effect circadian rhythm model of acetylcholinesterase (AChE) activity variation and to evaluate the inhibitory effect of acorn extract (2 g) and galantamine (16 mg), used as positive control, on human AChE in red blood cells (RBC). METHODS: This was an open-label, randomized, three-way crossover study involving 12 healthy subjects who received one of the treatments in each study period: no treatment, acorn extract, and galantamine. RBC AChE activity was measured in peripheral blood samples collected at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16 and 24 h post-dose administration. Non-linear mixed effect modeling was performed using NONMEM (ver. 7.0). RESULTS: The circadian variation of AChE activity was best described using two mixed effect cosine functions, with periods of 24 and 12 h, respectively. When the inhibitory effect terms were added, the model was significantly improved for both acorn extract and galantamine. In terms of the effect, a 2-g single dose of acorn extract showed AChE inhibition (about 5%) similar to that of a 16-mg single dose of galantamine, in the first 24 h after administration. CONCLUSIONS: Based on the very pronounced inter- and intra-day variation in AChE activity in RBC, we conclude that the model-based approach is essential for the proof of concept and quantitation of AChE inhibition in human subjects.

Contribution of Trough Concentration Data in the Evaluation of Multiple-Dose Pharmacokinetics for Drugs with Delayed Distributional Equilibrium and Long Half-Life.

PURPOSE: The performance of "trough sampling before reaching steady-state" and "serial sampling beyond the interval between steady-state" in a multiple-dose pharmacokinetic evaluation was compared. Drugs with long half-lives, following multi-compartment pharmacokinetics, and whose distribution-related characteristics are less likely to be assessed within one dosing interval are focused. PATIENTS AND METHODS: Amlodipine pharmacokinetic data were collected from a human pharmacology study performed in Seoul St. Mary's Hospital (Seoul, Korea). Plasma concentration data until 144 hrs after a single administration was used. Nonlinear mixed-effects modeling was conducted to obtain the "true" model structure and pharmacokinetic parameter estimates. Then, stochastic simulation and estimation were performed using multiple-dose scenarios in various sampling strategies. Parameter accuracy and precision from each scenario were evaluated. RESULTS: A two-compartment model with first-order absorption followed by zero-order absorption with a lag time then first-order elimination was chosen as the final model and used in the stochastic simulation and estimation. In terms of parameter precision, the scenario incorporating data only within one dosing interval showed the worst results (V p /F = 313%, Q/F = 64.3%). Some scenarios including early trough samples yielded comparable outcomes (V p /F = 18.4%, Q/F = 32.1%) to the extended full-PK sampling scenario (V p /F = 15.9%, Q/F = 30.3%), which was the best case. The quality of distribution-related parameters was the major difference between scenarios. CONCLUSION: In multiple-dose studies on drugs with delayed distributional equilibrium, information from a few trough samples can augment the limit of serial sampling within the dosing interval for parameter estimation. With informative trough samples, extended hospitalization for serial sampling (until 3-5 half-lives after the last dose), which is particularly problematic for long half-life drugs, may be avoided. Trough samples obtained at the beginning of the repeated dose were more effective for mixed-effects modeling.

A Population Pharmacokinetic and Pharmacodynamic Model of CKD-519.

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang's distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia.

A review of three years' experience of the first pharmacometrics company in Korea.

As the pharmaceutical industry in Korea is reaching the golden era of drug discovery due to increased investments in research and development and government funds, the need for a more efficient tool for the quantitative analysis has emerged. Therefore, the demand for pharmacometrics (PMx) consultancy services increased. Higher quality service suitable for regulatory submission and out-licensing deals were desired. In this analysis, we compiled and summarized 3 years of experiences of Q-fitter, the first PMx consultancy service company providing PMx analysis to the pharmaceutical industry in Korea. The projects were organized by companies, company types, indications, therapeutic areas, drug development stages, purposes, and scope of services. Within each category, we subcategorized the sections and assessed proportions and a year-over-year trend. As a result, we observed an increase in the number of projects in an average of ~170% per year, with the most frequent types of companies collaborated being the domestic pharmaceutical companies. Among the projects, ~72% involved modeling and simulation using population pharmacokinetic (PK) models, and the other included non-compartmental analysis (NCA), drug-drug interaction (DDI) prediction, and interpretation of the modeling results. The most sought-after purpose in PMx analysis was first-in-human (FIH) dose prediction followed by PK analysis, next clinical trial prediction, and scenario-based simulation. Oncology has been the top therapeutic area of interest every year consisting of ~38% of total projects, followed by Neurology (~13%). From this review, we were able to characterize the PMx service needs and spot the trend of current PMx practices in Korea.

Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP).

CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were developed using mixed effect modeling analysis for exploration, and an interspecies model where allometric scaling was applied was developed based on the integrated animal PK data to predict the human PK profile. PD parameters and profile were predicted using in vitro potency and same-in-class drug information. The two-compartment first-order elimination model with Weibull-type absorption and bioavailability following the sigmoid Emax model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the Emax model of the same-in-class drug. The predicted PK/PD profile and parameters were used to simulate the human PK/PD profiles for different dose levels, and based on the simulation result, the appropriate efficacious dose was estimated as 25 mg in a 60 kg human. However, there were some discrepancies between the predicted and observed human PK/PD profiles compared to the phase I clinical data. The huge difference between the observed and predicted bioavailability suggests that there is a hurdle in predicting the absorption parameter only from animal PK data.

Population pharmacokinetic analysis of metformin administered as fixed-dose combination in Korean healthy adults.

Metformin, an oral antihyperglycemic agent, is widely used as the first-line pharmacotherapy for type 2 diabetes mellitus (T2DM). It has been in use for several decades as numerous different formulations. However, despite its use, population pharmacokinetic (PK) modeling of metformin is not well developed. The aim of the present study was to evaluate the effect of formulation on PK parameters by developing a population PK model of metformin in Koreans and using this model to assess bioequivalence. We used a comparative PK study of a single agent and a fixed-dose combination of metformin in 36 healthy volunteers. The population PK model of metformin was developed using NONMEM (version 7.3). Visual predictive checks and bootstrap methods were performed to determine the adequacy of the model. The plasma concentration-time profile was best described by a two-compartment, first-order elimination model with first-order absorption followed by zeroorder absorption with lag time. From the covariate analysis, formulation had significant effect (p < 0.01) on relative bioavailability (F = 0.94) and first-order absorption constant (Ka = 0.83), but the difference was within the range of bioequivalence criteria. No other covariate was shown to have significant effect on PK parameters. The PK profile of the disposition phase was consistent with the published literature. However, in the present study, the multiple peaks found during the absorption phase implied the possible diversity of absorption PK profile depending on formulation or population. Unlike traditional bioequivalence analysis, the population PK model reflects formulation differences on specific parameters and reflected simulation can be performed.

Erratum: Population Pharmacokinetic Analysis of Metformin Administered as Fixed-Dose Combination in Korean Healthy Adults.

[This corrects the article on p. 25 in vol. 26.].

Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis.

Fimasartan is a nonpeptide angiotensin II receptor blocker. In a previous study that compared the pharmacokinetics (PK) of fimasartan between patients with hepatic impairment (cirrhosis) and healthy subjects, the exposure to fimasartan was found to be higher in patients, but the decrease of blood pressure (BP) was not clinically significant in those with moderate hepatic impairment. The aims of this study were to develop a population PK-pharmacodynamic (PD) model of fimasartan and to evaluate the effect of hepatic function on BP reduction by fimasartan using previously published data. A 2-compartment linear model with mixed zero-order absorption followed by first-order absorption with a lag time adequately described fimasartan PK, and the effect of fimasartan on BP changes was well explained by the inhibitory sigmoid function in the turnover PK-PD model overlaid with a model of circadian rhythm (NONMEM version 7.2). According to our PD model, the lower BP responses in hepatic impairment were the result of the increased fimasartan EC50 in patients, rather than from a saturation of effect. This is congruent with the reported pathophysiological change of increased plasma ACE and renin activity in hepatic cirrhosis.

Comparison of oral absorption models for pregabalin: usefulness of transit compartment model.

Pregabalin is an anticonvulsant used for the treatment of neuropathic pain and partial seizure in adults. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the absorption characteristics of pregabalin given fasted or after meals. Data from five healthy subject PK studies (n=88) of single- or multiple-dose pregabalin (150 mg) were used. Pregabalin was administered twice daily, without meals or 30 min after a meal (regular or high-fat diet) in the morning and 30 min or 4 h after a meal (regular diet) in the evening. Serial plasma samples were collected up to 24 h after the last dose for PK analysis. Because the peak concentrations were not properly modeled by a conventional first-order absorption model, Erlang frequency distribution, Weibull-type absorption, and transit compartment models were tested on a two-compartment linear PK model using a nonlinear mixed-effects method (NONMEM; version 7.3). The transit compartment model best described the absorption characteristics of pregabalin regardless of meal status. We conclude that the absorption model should be carefully chosen based on the principle of model development and validation and not by following a conventional first-order absorption model for its popularity and simplicity, especially when the PK dataset includes densely sampled absorption-phase data.