Characterizing the time-course of antihypertensive activity and optimal dose range of fimasartan <i>via</i> mechanism-based population modeling

Bulitta, Jü,rgen B.,Paik, Soo Heui,Chi, Yong Ha,Kim, Tae Hwan,Shin, Soyoung,Landersdorfer, Cornelia B.,Jiao, Yuanyuan,Yadav, Rajbharan,Shin, Beom Soo Elsevier 2017 European journal of pharmaceutical sciences Vol.107 No.-

<P><B>Abstract</B></P> <P>Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan <I>via</I> a new population pharmacokinetic/pharmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers. Patients received placebo, 20, 60, or 180mg fimasartan every 24h for 28days and healthy volunteers received placebo or 20 to 480mg as a single oral dose or as seven doses every 24h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 10.1±7.5 (12.6±9.2; mean±SD)mmHg for 20mg, 14.2±7.0 (15.1±9.3) mmHg for 60mg, and 15.9±6.8 (11.5±9.9)mmHg for 180mg daily relative to placebo. The model explained the saturation of antihypertensive activity by counter-regulation at high fimasartan concentrations. Drug effect was maximal at approximately 23ng/mL fimasartan for diastolic and 12ng/mL for systolic blood pressure. The proposed mechanism-based population model characterized the circadian rhythm of ABPM data and the antihypertensive effect of fimasartan. After internal and external model validation, 30 to 60mg oral fimasartan given once daily was predicted as optimal dose range.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Two Mechanisms of Killing of <i>Pseudomonas aeruginosa</i> by Tobramycin Assessed at Multiple Inocula via Mechanism-Based Modeling

Bulitta, Jü,rgen B.,Ly, Neang S.,Landersdorfer, Cornelia B.,Wanigaratne, Nicholin A.,Velkov, Tony,Yadav, Rajbharan,Oliver, Antonio,Martin, Lisandra,Shin, Beom Soo,Forrest, Alan,Tsuji, Brian T. American Society for Microbiology 2015 Antimicrobial Agents and Chemotherapy Vol.59 No.4

<P>Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three <I>Pseudomonas aeruginosa</I> strains. At low-intermediate tobramycin concentrations (<4 mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (≥8 mg/liter). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 10<SUP>8.9</SUP> CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens.</P>

Novel extended <i>in vitro-in vivo</i> correlation model for the development of extended-release formulations for baclofen: From formulation composition to <i>in vivo</i> pharmacokinetics

Kim, Tae Hwan,Bulitta, Jü,rgen B.,Kim, Do-Hyung,Shin, Soyoung,Shin, Beom Soo Elsevier 2019 International journal of pharmaceutics Vol.556 No.-

<P><B>Abstract</B></P> <P> <I>In vitro-in vivo</I> correlation (IVIVC), a predictive mathematical model between the <I>in vitro</I> dissolution and the <I>in vivo</I> pharmacokinetics has been utilized for the development of new extended release (ER) formulations. The aim of the present study was to extend the IVIVC approach, which correlates among the formulation composition, the <I>in vitro</I> dissolution, and the plasma drug concentration, to predict plasma drug concentrations from a given composition of the formulation, and vice versa, using baclofen as a model drug. Baclofen ER tablets with different dissolution rates were prepared by varying the composition of hydroxypropyl methylcellulose (HPMC). First, the HPMC compositions and the corresponding <I>in vitro</I> dissolutions parameters were correlated, and then the <I>in vitro</I> dissolution parameters were correlated with the <I>in vivo</I> dissolution parameters extracted from the pharmacokinetic profiles of the baclofen ER formulations <I>via</I> population pharmacokinetic modeling. The final extended IVIVC model linked the composition of the formulation, the <I>in vitro</I> dissolution, and the <I>in vivo</I> plasma concentration profile and was successfully applied for the prediction of <I>in vivo</I> pharmacokinetics from the amount of HPMC in baclofen ER formulations. The present approach holds great promise for designing optimal compositions of ER formulations to present desired plasma concentration profile.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Population Pharmacokinetics of a Novel Histone Deacetylase Inhibitor, Cyclo{(2S)-2-Amino-8-[(Aminocarbonyl)Hydrazono] Decanoyl-1-<i>L</i>-Tryptophyl-<i>L</i>-Isoleucyl-(2R)-2-Piperidinecarbonyl} (SD-2007), and Its Metabolic Conversion to Apicidin after I

Shin, Beom Soo,Bulitta, Jü,rgen B.,Hong, Deok Ki,Kim, Hye Youn,Kim, Min Ki,Choi, Yohan,Lee, Jong Bong,Hwang, Sang Wook,Lee, Mann Hyung,Yoo, Sun Dong S. Karger AG 2011 Chemotherapy Vol.57 No.3

<P>Abstract</P><P><I>Background:</I> This study assessed the population pharmacokinetics and metabolic conversion of a novel histone deacetylase (HDAC) inhibitor, SD-2007, into its active metabolite, apicidin, in rats. <I>Methods:</I> SD-2007 was given to rats by intravenous injection (4 mg/kg) and oral administration (40 mg/kg). Serum concentrations of SD-2007 and apicidin were determined by LC-MS/MS. All concentrations were analyzed using a population pharmacokinetic model with 9 compartments in S-ADAPT. <I>Results:</I> The area under the curve for apicidin was 96 ± 16 mg·h/ml after 4 mg/kg administered intravenously and 2,455 ± 1,211 mg·h/ml after 40 mg/kg given orally. The population pharmacokinetic model described all profiles well. After oral administration of SD-2007, the median absolute bioavailability of SD-2007 was 6.67% (range 3.83–9.89) and the median apparent bioavailability was 22.3% (range 15.7–35.8) for apicidin, whereas only a median of 8.85% (range 7.57–9.34) of an intravenous SD-2007 dose was converted to apicidin. <I>Conclusions:</I> Oral SD-2007 displayed a substantial presystemic metabolism to active apicidin. The high serum concentrations of apicidin after oral administration of SD-2007 may cause significant HDAC inhibition.</P><P>Copyright © 2011 S. Karger AG, Basel</P>

Development of a Physiologically Relevant Population Pharmacokinetic <i>in Vitro</i>–<i>in Vivo</i> Correlation Approach for Designing Extended-Release Oral Dosage Formulation

Kim, Tae Hwan,Shin, Soyoung,Bulitta, Jü,rgen B.,Youn, Yu Seok,Yoo, Sun Dong,Shin, Beom Soo American Chemical Society 2017 Molecular Pharmaceutics Vol.14 No.1

<P>Establishing a level A in vitro in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used, as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively. An in vitro dissolution test in various pH conditions showed that loxoprofen dissolution was faster at higher pH. The in vivo pharmacokinetics of loxoprofen was assessed following oral administration of the different loxoprofen formulations to Beagle dogs (n = 22 in total). Secondary peaks or shoulders were observed in many of the individual plasma concentration vs time profiles after ER tablet administration, which may result from secondary absorption in the intestine due to a dissolution rate increase under intestinal pH compared to that observed at stomach pH. In addition, in vivo oral bioavailability was found to decrease with prolonged drug dissolution, indicating site-specific absorption. Based on the in vitro dissolution and in vivo absorption data, a POP-PK IVIVC model was developed using S-ADAPT software. pH dependent biphasic dissolution kinetics, described using modified Michaelis Menten kinetics with varying V-max and site-specific absorption, modeled using a changeable absorbed fraction parameter, were applied to the POP-PK IVIVC model. To experimentally determine the biphasic dissolution profiles, of the ER tablets, another in vitro dissolution test was conducted by switching dissolution medium pH based on an in vivo estimate of gastric emptying time. The model estimated, using linear regression, that in vivo initial maximum dissolution rate (Vmax(0)(in vivo)) was highly correlated (r(2) > 0.998) with in vitro (V-max(0)(in vitro)), indicating that in vivo dissolution profiles obtained from POP-PK modeling could be converted to in vitro dissolution profiles and vice versa. Monte Carlo simulations were performed for model validation, and prediction errors for C-max and AUC were all within the acceptable range (90 to 110%) according to the FDA guidelines. The developed model was successfully applied for the prediction of in vivo pharmacokinetics of a loxoprofen double-layered tablet using the in vitro dissolution profile. In conclusion, a level A IVIVC approach was developed and validated using population modeling that accounted for pH-dependent dissolution and site-specific absorption. Excellent correlations were observed between in vitro and in vivo dissolution profiles. This new approach holds great promise for the establishment of IVIVCs for drug and formulation development where absorption kinetics strongly depend on complex physiologically absorption processes.</P>

Assessment of bisphenol A exposure in Korean pregnant women by physiologically based pharmacokinetic modeling.

Shin, Beom Soo,Hwang, Sang Wook,Bulitta, Jurgen B,Lee, Jong Bong,Yang, Seung Du,Park, Joong San,Kwon, Min Chang,Kim, Do Jung,Yoon, Hae-Seong,Yoo, Sun Dong Taylor Francis 2010 Journal of toxicology and environmental health. Pa Vol.73 No.21

<P>The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 관g/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.</P>

Physiologically Based Pharmacokinetics of Zearalenone

Shin, Beom Soo,Hong, Seok Hyun,Bulitta, Jü,rgen B.,Lee, Jong Bong,Hwang, Sang Wook,Kim, Hyoung Jun,Yang, Seung Du,Yoon, Hae-Seong,Kim, Do Jung,Lee, Byung Mu,Yoo, Sun Dong Informa UK (TaylorFrancis) 2009 Journal of toxicology and environmental health. Pa Vol.72 No.21

<P>The objectives of this study were to (1) develop physiologically based pharmacokinetic (PBPK) models for zearalenone following intravenous (i.v.) and oral (p.o.) dosing in rats and (2) predict concentrations in humans via interspecies scaling. The model for i.v. dosing consisted of vein, artery, lung, liver, spleen, kidneys, heart, testes, brain, muscle, adipose tissue, stomach, and small intestine. To describe the secondary peak phenomenon observed after p.o. administration, the absorption model was constructed to reflect glucuronidation, biliary excretion, enterohepatic recirculation, and fast and slow absorption processes from the lumenal compartment. The developed models adequately described observed concentration-time data in rats after i.v. or p.o. administration. Upon model validation in rats, steady-state zearalenone concentrations in blood and tissues were simulated for rats after once daily p.o. exposures (0.1 mg/kg/d). The average steady-state blood zearalenone concentration predicted in rat was 0.014 ng/ml. Subsequently, a daily human p.o. dose needed to achieve the same steady-state blood concentration found in rats (0.014 ng/ml) was determined to be 0.0312 mg/kg/d or 2.18 mg/70 kg/d. The steady-state zearalenone concentration-time profiles in blood and tissues were also simulated for human after multiple p.o. administrations (dose 0.0312 mg/kg/d). The developed PBPK models adequately described the pharmacokinetics in rats and may be useful in predicting human blood and tissue concentrations for zearalenone under different p,o, exposure conditions.</P>

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

Shin, Beom Soo,Yoo, Sun Dong,Kim, Tae Hwan,Bulitta, Jurgen B.,Landersdorfer, Cornelia B.,Shin, Jeong Cheol,Choi, Jin Ho,Weon, Kwon-Yeon,Joo, Sang Hoon,Shin, Soyoung American Society for Pharmacology and Experimental 2014 Drug metabolism and disposition: the biological fa Vol.42 No.6

<P>Apicidin, a potential oral chemotherapeutic agent, possesses potent anti-histone-deacetylase activity. After oral administration, the total bioavailability of apicidin is known to be low (14.2%–19.3%). In the present study, we evaluated the factors contributing to the low bioavailability of apicidin by means of quantitative determination of absorption fraction and first-pass metabolism after oral administration. Apicidin was given to rats by five different routes: into the femoral vein, duodenum, superior mesenteric artery, portal vein, and carotid artery. Especially, the fraction absorbed (<I>F</I><SUB>X</SUB>) and the fraction that is not metabolized in the gut wall (<I>F</I><SUB>G</SUB>) were separated by injection of apicidin via superior mesenteric artery, which enables bypassing the permeability barrier. The <I>F</I><SUB>X</SUB> was 45.9% ± 9.7%, the <I>F</I><SUB>G</SUB> was 70.9% ± 8.1% and the hepatic bioavailability (<I>F</I><SUB>H</SUB>) was 70.6% ± 12.3%, while the pulmonary first-pass metabolism was minimal (<I>F</I><SUB>L</SUB> = 102.8% ± 7.4%), indicating that intestinal absorption was the rate-determining step for oral absorption of apicidin. The low <I>F</I><SUB>X</SUB> was further examined in terms of passive diffusion and transporter-mediated efflux by in vitro immobilized artificial membrane (IAM) chromatographic assay and in situ single-pass perfusion method, respectively. Although the passive diffusion potential of apicidin was high (98.01%) by the IAM assay, the in situ permeability was significantly enhanced by the presence of the P-glycoprotein (P-gp) inhibitor elacrider. These data suggest that the low bioavailability of apicidin was mainly attributed to the P-gp efflux consistent with the limited <I>F</I><SUB>X</SUB> measured in vivo experiment.</P>

Pharmacokinetics and metabolite profiling of fimasartan, a novel antihypertensive agent, in rats

Kim, Tae Hwan,Shin, Soyoung,Bashir, Mohammad,Chi, Yong Ha,Paik, Soo Heui,Lee, Joo Han,Choi, Hyuk Joon,Choi, Jin Ho,Yoo, Sun Dong,Bulitta, Jü,rgen B.,Ma, Eunsook,Joo, Sang Hoon,Shin, Beom Soo Informa UK Ltd. 2014 Xenobiotica Vol.44 No.10

<P>1. <?ri?>The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats.</P><P>2. <?ri?>Unlabeled fimasartan or radiolabeled [<SUP>14</SUP>C]fimasartan was dosed by intravenous injection or oral administration to rats. Concentrations of unlabeled fimasartan in the biological samples were determined by a validated LC/MS/MS assay. Total radioactivity was quantified by liquid scintillation counting and the radioactivity associated with the metabolites was analyzed by using the radiochemical detector. Metabolite identification was conducted by product ion scanning using LC/MS/MS.</P><P>3. <?ri?>After oral administration of [<SUP>14</SUP>C]fimasartan, total radioactivity was found primarily in feces. In bile duct cannulated rats, 58.8 ± 14.4% of the radioactive dose was excreted via bile after oral dosing. Major metabolites of fimasartan including the active metabolite, desulfo-fimasartan, were identified, yet none represented more than 7.2% of the exposure of the parent drug. Fimasartan was rapidly and extensively absorbed and had an oral bioavailability of 32.7-49.6% in rats. Fimasartan plasma concentrations showed a multi-exponential decline after oral administration. Double peaks and extended terminal half-life were observed, which was likely caused by enterohepatic recirculation.</P><P>4. <?ri?>These results provide better understanding on the pharmacokinetics of fimasartan and may aid further development of fimasartan analogs.</P>