Adv Drug Deliv Rev 2001; 50: S4167. Keywords: bisoprolol, whole-body physiologically based pharmacokinetic model, drug absorption, drug distribution, renal function impairment Correlations were demonstrated between creatinine clearance and elimination half-life, mean residence time, area under the curve, total clearance and maximum concentration in those with renal dysfunction. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. For the prediction in patients with impaired renal function, renal function and age differences were taken into account. Human Rbp (blood-to-plasma concentration ratio) was estimated using the ADMET PredictorTM module and then fitted to correct for the steady-state volume of distribution (Vss)15 within the range 0.81 (ADMET PredictorTM) and 1.36 (rat value45). FOIA In our patients, a total daily dose of bisoprolol ranged from 1.25 to 10 mg. Prior simulations of the potential exposure and disposition in individuals with renal impairment may help in the selection of a safe and effective dosage regimen. (A) parameter sensitivity analysis of the Tmax; (B) parameter sensitivity analysis of the Cmax; (C) parameter sensitivity analysis of the AUC after 10 mg bisoprolol single oral administration. The model successfully predicted the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in different normal human populations and patients with impaired renal function. Jones HM, Gardner IB, Watson KJ . J Pharm Sci 2005; 94: 123748. Therefore, the WB-PBPK model was able to accurately simulate the plasma concentration-time profile following intravenous administration using the in silico data, in vitro data, predicted Kp values and predicted clearances as inputs to the model, as shown in Figure 2 and Table 5. The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency. Bisoprolol: a new beta-adrenoceptor blocking drug. PMC In the virtual trial for the 8 healthy subjects, it can be noted that all but one of the clinical observations lie within the 90% confidence intervals of the simulation (Figure 8A). Physiological modeling and assessments of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible. Cb,v is the venous blood concentration. Damman K, Voors AA, Hillege HL, Navis G, Lechat P, van Veldhuisen DJ, et al. Brophy CM, Moore JG, Christian PE, Egger MJ, Taylor AT. Unable to load your collection due to an error, Unable to load your delegates due to an error. The pharmacokinetics of bisoprolol are independent of the dose in the range from 2.5 to 100 mg. 19.79. Physiological parameters in laboratory animals and humans. Hudachek SF, Gustafson DL . The input properties used for the intravenous simulation were fixed for the simulation of the oral profile. Tahara K, Kagawa Y, Takaai M, Taguchi M, Hashimoto Y . Epub 2013 Sep 25. 2022 Jan;39(1):391-404. doi: 10.1007/s12325-021-01958-6. Application of PBPK modelling in drug discovery and development at Pfizer. Therefore, these models have been recognized as a means of bridging healthy adult and patients' studies and for predicting doses and drug exposures in patients. J Pharm Sci 2006; 95: 123857. The mass balance for the rate of change in bisoprolol concentration in a non-eliminating tissue was equal to the product of tissue blood flow rate and the difference between the concentrations in the arterial and venous bloods. government site. The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics. Experiments for obtaining Kps are usually difficult and labor-intensive and also require conducting numerous animal studies to ensure accuracy 60. If the observed value is greater than the predicted value, fold-error=observed/predicted; If observed value is less than the predicted value, fold-error=predicted/observed; To examine the agreement between the predicted concentrations and the corresponding measured concentrations, the mean absolute error (MAE) and the root mean square error (RMSE), which represent accuracy and precision, were calculated using the following formulas35,58: The WB-PBPK model for bisoprolol was constructed according to the scheme presented in Figure 1. Beta-blockers and heart failure. Blood Press. Jones HM, Parrott N, Jorga K, Lav T . Parrott N, Davies B, Hoffmann G, Koerner A, Lave T, Prinssen E, et al. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Figure 5 and Figure 6 show that the oral pharmacokinetics of bisoprolol after the 20 mg and 5 mg doses in different populations of healthy adults were correctly predicted by adjusting the value of stomach transit time to 0.6 h. As WB-PBPK modeling allows integration of disease-related changes in physiology, it is valuable for the prediction of differences in the pharmacokinetics between healthy subjects and special patient populations13,14,63. Each compartment was defined by an associated tissue blood flow rate, volume and a tissue-to-plasma partition coefficient. The approach integrated drug-specific parameters such as logP, pKa, solubility and permeability and in vitro data such as plasma protein binding and blood-to-plasma concentration ratio, was able to simulate the pharmacokinetics of bisoprolol (for both intravenous and oral doses) across multiple dose levels in different human populations with suitable accuracy. Drugs R D. 2014 Dec;14(4):325-32. doi: 10.1007/s40268-014-0073-5. Tissue distribution was predicted using established tissue-composition equations. Drug Metab Dispos 1995; 22: 100821. The predictions of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function after the administration of multiple oral doses were further performed. Bisoprolol is the beta-blocker with LADME(liberation, absorption, distribution, metabolism, and elimination)-optimized pharmacokinetics. and transmitted securely. Simulated (lines) and observed (points)17 plasma concentration-time profiles of bisoprolol after 5 mg oral administration in healthy men (22 years old, Asian). Human fup (plasma unbound drug) was obtained from the literature46. Thomas S . An official website of the United States government. eCollection 2022 Jun. Model predictions were compared to the experimental data obtained following 7 d of oral administration of bisoprolol to healthy adults and to patients with impaired renal function. Development of a physiologically based model for oseltamivir and simulation of pharmacokinetics in neonates and infants. Google Scholar. There is no age or sex dependency. An intravenous profile is determined only by the distribution and elimination of bisoprolol. If the simulated AUC is comparable to that of the observed but the curve shape still does not match, the effect of stomach transit time and intestinal transit time may be explored using a parameter sensitivity analysis50. All of the tissues except for the liver were supplied from the arterial circulation, and blood exiting of the tissues ows directly into the venous circulation. Moreover, many tissues are generally omitted due to practical limitations. Eur Heart J. Kuentz M, Nick S, Parrott N, Rthlisberger D. A strategy for preclinical formulation development using GastroPlus as pharmacokinetic simulation tool and a statistical screening design applied to a dog study. Bisoprolol and nebivolol are highly selective 1 -adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. LC-ESI-MS method for the determination of bisoprolol in human plasma. To evaluate the performance of the WB-PBPK model in oral absorption prediction, a simulation for a single oral administration was performed. 2021 Jun;10(6):622-632. doi: 10.1002/psp4.12634. The effective diffusion layer thickness was taken as equal to the particle radius34. Thompson CM, Johns DO, Sonawane B, Barton HA, Hattis D, Tardif R, et al. To obtain A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and angina pectoris. J Toxicol Environ Health B Crit Rev 2009; 12: 124. The delayed onset of absorption was found in the observed profile compared to the simulated profile that was generated using typical values of physiological parameters in the WB-PBPK absorption model (Table 1). The kinetics associated with the dissolution and absorption processes are modeled by a system of coupled linear and nonlinear rate equations. To make a WB-PBPK simulation of clinical pharmacokinetics, it is important to predict the distribution and clearance of bisoprolol in different human population groups. J Pharm Sci 2010; 99: 360119. The blood flow rates associatied with the 14 compartments- lung (Lu), liver (Li), spleen (Sp), gut (AC), adipose (Ad), muscle (Mu), heart (He), brain (Br), kidney (Ki), skin (Sk), reproductive organ (RO), red marrow (RM), yellow marrow (YM), rest of body (ROB), are represented by Q, subscripted with the corresponding compartment. Zebeta: 5 mg [DSC], 10 mg [DSC] Generic: 5 mg, 10 mg Pharmacology Mechanism of Action Selective inhibitor of beta 1 -adrenergic receptors; competitively blocks beta 1 -receptors, with little or no effect on beta 2 -receptors at doses 20 mg Pharmacokinetics/Pharmacodynamics Absorption Rapid and almost complete Distribution Effectiveness and Tolerability of Bisoprolol/Perindopril Single-Pill Combination in Patients with Arterial Hypertension and a History of Myocardial Infarction: The PRIDE Observational Study. The grey shaded area represents the 90% confidence interval for the simulated data, and the grey solid, and dotted lines represent individual simulated results that include 100% and 75% of the range of simulated individual data. sharing sensitive information, make sure youre on a federal Physiologically based pharmacokinetics in drug development and regulatory science: a workshop report (Georgetown University, Washington, DC, May 2930, 2002). Recently, these limitations have been solved through in silico estimates, which are based on tissue composition of neutral lipids, phospholipids, and water23,24. Additional absorption mechanisms such as transporter-mediated efflux and influx, and intestinal loss such as gut wall first-pass extraction and chemical degradation should be examined and then included in the original model14,21,49. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles. Thus, a parameter sensitivity analysis was performed to investigate how these three pharmacokinetic parameters were affected by gastrointestinal physiological parameters and biopharmaceutical properties. The pharmacokinetic studies after intravenous administration of bisoprolol at two doses were conducted in 8 Western female subjects (age 253 years)15 and 12 Western male subjects (age 3712 years)16, respectively. Apart from the renal function, age-dependent physiological changes such as tissue blood flow, tissue volume, and hematocrit were also adjusted to represent the reported patient population. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, et al. Eur Heart J 2004; 25: 134162. Furthermore, it can be seen that the all of the observed data lies within the minimal and maximal individual subject simulations from the virtual trial of the 8 healthy subjects and 11 patients. PubMed Central The predicted pharmacokinetic parameters (AUC, Cmax, and Tmax) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The effective diffusion layer thickness was taken as equal to the particle radius34. Therefore, allometric scaling was used to predict hepatic clearance of bisoprolol. Li, Gf., Wang, K., Chen, R. et al. Disclaimer. 1987 Oct;34(4):438-58. doi: 10.2165/00003495-198734040-00002. Bethesda, MD 20894, Web Policies These modifications might require dosage adjustment8,9,10. Adv Ther. Mechanistic approaches to predicting oral drug absorption. Customized in silico population mimics actual population in docetaxel population pharmacokinetic analysis. 1. Here, the venous blood concentration was represented as the tissue concentration divided by tissue-to-plasma partition coefficient (Kp) and then corrected for blood-to-plasma concentration ratio (Rbp). Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Customized in silico population mimics actual population in docetaxel population pharmacokinetic analysis. Taken together, the mass balance differential equation for a generic tissue compartment, except for lung, had the following form20,21,22: Schematic structure of the whole-body PBPK model used to predict in vivo behaviors of bisoprolol in different human populations. In each patient, the same formulation of bisoprolol was administered once or twice . National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC). Jones HM, Dickins M, Youdim K, Gosset JR, Attkins NJ, Hay TL, et al. PMID: 2903820 DOI: 10.2165/00003495-198836030-00002 Abstract Bisoprolol is a beta 1-adrenoceptor antagonist with no partial agonist (intrinsic sympathomimetic) activity or membrane stabilising (local anaesthetic) activity. Kun Wang or Qing-shan Zheng. At the third stage, the refined model was verified at other single oral doses. Physiological parameters and compound-specific properties were randomly sampled from log-normal distributions via a Monte Carlo method39,47,48. Identification of intestinal loss of a drug through physiologically based pharmacokinetic simulation of plasma concentration-time profiles. 2.1 Patient Data. The WB-PBPK model of bisoprolol (Figure 1) was built by GastroPlus version 7.0 (Simulations Plus, Inc, Lancaster, CA, USA) and used for all of the simulations performed in healthy adults and patients with impaired renal function. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). Frontiers | Influence of CYP2D6 and CYP3A5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Bisoprolol in Hypertensive Chinese Patients View Article Impact ORIGINAL RESEARCH article Front. For bisoprolol, perfusion-limited compartments were adopted to model distribution into tissues. 4,17 It is considered a potent drug with a long-half life that can be used once daily to reduce the need for multiple doses of antihypertensive drugs. Sus J, Huguet J, Bosak J, Setnik B, Hauser T, Sicard E. Clin Transl Sci. Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol. and JavaScript. Beta-blockers and heart failure. In this strategy, the first stage was the simulation of the pharmacokinetics in healthy adults after intravenous administration. Gomeni R . Species similarities and differences in pharmacokinetics. The model successfully predicted the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in different normal human populations and patients with impaired renal function. The hepatic clearance (CLliver) was estimated using allometric scaling with a fixed allometric exponent of 0.75 14,28. where BW is bodyweight. Write a review. The inter-individual variability of physiological variables such as organ volume, blood flow, transit times in the various gastrointestinal segments, and pH in all gastrointestinal compartments were assigned to the virtual individuals of the target populations through a Monte Carlo method. Pharmacokinetic and pharmacodynamic data analysis: concept and applications, 4th ed. Note: Br, brain; He, heart; Ki, kidney; Li, liver; Lu, lung; Mu, muscle; RM, red marrow; RO, reproductive organ; ROB, rest of body; Sk, skin; Sp, spleen; YM, yellow marrow. Bisoprolol is a cardioselective 1-adrenergic blocking agent used to treat high blood pressure. Bethesda, MD 20894, Web Policies These modifications might require dosage adjustment8,9,10. -, Eur Heart J. Mathematical modeling of antihypertensive therapy. If comparing the observed and simulated oral profiles indicates there is hysteresis of the initial absorption phase between them, the stomach transit time is higher than the average normal value used in the PBPK model and is required to adjust until the simulated profile captures the observed profile shape well50 and has a lower value of the mean absolute error (MAE) and root mean square error (RMSE). 4 Bisoprolol is generally well tolerated, likely due to its 1-adrenergic . The GastroPlusTM implementation of the PEAR program calculated the human physiologies on the basis of American/Western or Japanese/Asian population databases for males and females aged 1 to 85 years old20. Stomach transit time, which represents gastric emptying time, is a key factor determining the initiation of the absorption phase. The drug reaches the portal vein followed by distribution in the liver and the other PBPK tissues after it transports through the basolateral membrane of enterocytes. The mass balance equations describe the six states of drug substance (unreleased, undissolved, dissolved, degraded, metabolized, and absorbed) in the different regions of the GI tract31,32. Other factors such as chemical degradation, gut wall first-pass extraction, transporter-mediated efflux and influx should be considered further14,21,49. The AUC and Cmax are also markedly affected by permeability. The https:// ensures that you are connecting to the Note: a Western population; b Asian population; , not applicable. Blood pressure lowering efficacy of beta-1 selective beta blockers for primary hypertension. The predicted pharmacokinetic parameters are compared with the observed data in Table 7. The mass balance equations describe the six states of drug substance (unreleased, undissolved, dissolved, degraded, metabolized, and absorbed) in the different regions of the GI tract31,32. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. The mean values of GI tract physiology for pH, transit times, volumes, lengths and radius in human fasted state were taken from published data37,38 and provided by GastroPlusTM(Table 1). 1Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai 201203, China, 2Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China, 3Department of Pharmaceutics of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing 210009, China. AAPS J 2009; 11: 21724. Inter- and intrasubject variability of gastric emptying in healthy volunteers measured by scintigraphy and paracetamol absorption. The predictions of the mean plasma concentration-time profiles using the validated WB-PBPK model, which incorporated the corresponding physiological parameters of the target human populations, was in agreement with the observed mean data in healthy humans and patients with renal dysfunction following multiple oral doses, indicating that the model is sufficient to capture the mean pharmacokinetic profiles of bisoprolol in both healthy and patient populations after multiple oral administration. Virtual subjects of all of the stochastic variables were generated for each simulation. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. An official website of the United States government. For the 20 mg oral dose, the urine excretion curve was also well simulated. The change of creatinine clearance, which reliably reflects the extent of renal impairment, was obtained from the literature10, and changes in the age-related physiological parameters (Table 3) were based on GastroPlusTM demographic and physiological databases. Qha is the blood flow rate to the liver via hepatic artery (ha). The logP, pKa, solubility and effective permeability were obtained using the ADMET PredictorTM module of GastroPlus, which has been consistently ranked as the most accurate predictive software in quantitative structure-pharmacokinetic relationship models (QSPKR models) of biopharmaceutical properties42,43,44. Stomach transit time is strongly influenced by both volume and composition of gastric contents. The prediction of drug metabolism, tissue distribution, and bioavailability of 50 structurally diverse compounds in rat using mechanism-based absorption, distribution, and metabolism prediction tools. Google Scholar. The WB-PBPK prediction strategy in the current work was modified by Jones et al21. Pharmacokinetic and pharmacodynamic data analysis: concept and applications. Xenobiotica 2007; 37: 1295310. The half-life (t1/2) was computed by the following equation: t1/2=In2(Vss/CL). Given that the filtration clearance contributes up to 70% of renal clearance, the 'GFR ratio approach'29,30 was used. Received 2012 Feb 8; Accepted 2012 Jul 1. bisoprolol, whole-body physiologically based pharmacokinetic model, drug absorption, drug distribution, renal function impairment. Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. where Vt, Ct, Qt,, Kp, and CLint,u represent the volume, concentration, blood flow rate, tissue-to-plasma partition coefficient, and unbound intrinsic clearance of the tissue, respectively; Cb,a represents the arterial blood concentration; Rbp represents the blood-to-plasma concentration ratio and fup represents the fraction unbound in plasma. PubMed Pharmacokinetics of bisoprolol fumarate. The equations used for fraction drug unbound in tissues (fuT) were derived from the literature22. The AUC and Cmax are also markedly affected by permeability. This type of model provides a mechanistic approach for studying drug disposition and allows for the incorporation of disease-related changes in physiology and the assessment of these effects on drug disposition13,14. Please enable it to take advantage of the complete set of features! Overall, these published tissue composition equations provided accurate estimates of Vss in humans (Table 5). Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed for the prediction of bisoprolol pharmacokinetics in virtual healthy subjects and patients with renal impairment. Reddy MB, Connor A, Brennan BJ, Morcos PN, Zhou A, McLawhon P, et al. Bookshelf Dressman JB, Amidon GL, Reppas C, Shah VP. Modelling and PBPK simulation in drug discovery. If the observed value is greater than the predicted value, fold-error=observed/predicted; If observed value is less than the predicted value, fold-error=predicted/observed; To examine the agreement between the predicted concentrations and the corresponding measured concentrations, the mean absolute error (MAE) and the root mean square error (RMSE), which represent accuracy and precision, were calculated using the following formulas35,58: The WB-PBPK model for bisoprolol was constructed according to the scheme presented in Figure 1. ) was estimated using allometric scaling was used were adopted to model distribution tissues. Efficacy of beta-1 selective beta blockers for primary hypertension pharmacokinetics in neonates and infants discovery and development at Pfizer at! Of coupled linear and nonlinear rate equations of interspecies scaling and in vitro extrapolation in.! Same formulation of bisoprolol ranged from 1.25 to 10 mg of PBPK modelling in drug and! 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