Physiologically based pharmacokinetic modeling as a tool for drug development

Since the pioneering work of Haggard and Teorell in the first half of the 20th century, and of Bischoff and Dedrick in the late 1960s, physiologically based pharmacokinetic (PBPK) modeling has gone through cycles of general acceptance, and of healthy skepticism. Recently, however, the trend in the pharmaceuticals industry has been away from PBPK models. This is understandable when one considers the time and effort necessary to develop, test, and implement a typical PBPK model, and the fact that in the present-day environment for drug development, efficacy and safety must be demonstrated and drugs brought to market more rapidly. Although there are many modeling tools available to the pharmacokineticist today, many of which are preferable to PBPK modeling in most circumstances, there are several situations in which PBPK modeling provides distinct benefits that outweigh the drawbacks of increased time and effort for implementation. In this Commentary, we draw on our experience with this modeling technique in an industry setting to provide guidelines on when PBPK modeling techniques could be applied in an industrial setting to satisfy the needs of regulatory customers. We hope these guidelines will assist researchers in deciding when to apply PBPK modeling techniques. It is our contention that PBPK modeling should be viewed as one of many modeling tools for drug development.     

Physiologically based pharmacokinetic model of docetaxel and interspecies scaling: comparison of simple injection with folate receptor-targeting amphiphilic copolymer-modified liposomes

1.?To compare the disposition of docetaxel (DTX) in male/female rats after intravenous administration of simple injection and folate-poly(PEG-cyanoacrylate-co-cholesteryl cyanoacrylate)-modified liposomes utilising a physiologically based pharmacokinetic (PBPK) modelling method, and extrapolate this model to mice and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters.

2.?Four structural models for single organs were evaluated, and the whole-body PBPK model included artery, vein, lung, brain, heart, spleen, liver, gastrointestinal tract, kidney, muscle and remainder compartment.

3.?Rats following modified liposomes administration were characterised by significant decrease in the partition coefficients for brain, spleen, liver and remainder compartment. The blood-to-plasma partition coefficient also decreased significantly, while a marked rise of partition coefficients for lung, kidney and muscle was revealed. Partition coefficient for heart was approximately 1.3-fold higher in females than males, while the decrease of intestinal clearance was revealed in females compared to males. The final model successfully characterised the time course of DTX in rats, mice and humans.

4.?This PBPK model is beneficial to the prediction of the effects of DTX in different species. It also represented a platform to encompass both formulation- and sex-related effects on DTX disposition and elimination in the future.     

Physiologically based pharmacokinetic prediction of p -phenylbenzoic acid disposition in the pregnant rat

Disposition of p -phenylbenzoic acid (PPBA) in the pregnant Wistar rat (for both mother and fetuses) was predicted by using a physiologically based pharmacokinetic model. This model was constructed from ten organs for the mother and eight organs for fetuses, with fetal blood flow based on anatomical circulation in uteri and skin–amniotic fluid drug exchange. Plasma total clearance, and renal and nonrenal clearances were measured, and transplacental clearance, skin–amniotic fluid clearances and fetal metabolic clearance were taken from previously reported compartment analysis. Tissue-to-plasma partition coefficients (K_p) for the mother were almost the same as that of the interstitial fluid space (0.055–0.28), except for the kidney and liver. In contrast, K_p values for fetuses were small when membrane restricted and diffusion-limited uptakes were assumed in brain, gut, spleen, muscle, fat, and skin for the mother. The physiological model successfully predicted the PPBA concentration–time profiles for both mother and fetuses after intravenous injection into the mother. Further, the model could be applied to predict the results obtained via two other routes of administration. Fetal plasma PPBA concentrations were well predicted after PPBA injection into umbilical vein and fetal muscle. © 1998 John Wiley & Sons, Ltd.     

Physiologically based pharmacokinetic model parameter estimation and sensitivity and variability analyses for acrylonitrile disposition in humans.

A physiologically based pharmacokinetic (PBPK) model of acrylonitrile (ACN) and cyanoethylene oxide (CEO) disposition in humans was developed and is based on human in vitro data and scaling from a rat model (G. L. Kedderis et al., 1996, TOXICOL: Appl. Pharmacol.140, 422-435) for application to risk assessment. All of the major biotransformation and reactivity pathways, including metabolism of ACN to glutathione conjugates and CEO, reaction rates of ACN and CEO with glutathione and tissues, and the metabolism of CEO by hydrolysis and glutathione conjugation, were described in the human PBPK model. Model simulations indicated that predicted blood and brain ACN and CEO concentrations were similar in rats and humans exposed to ACN by inhalation. In contrast, rats consuming ACN in drinking water had higher predicted blood concentrations of ACN than humans exposed to the same concentration in water. Sensitivity and variability analyses were conducted on the model. While many parameters contributed to the estimated variability of the model predictions, the reaction rate of CEO with glutathione, hydrolysis rate for CEO, and blood:brain partition coefficient of CEO were the parameters predicted to make the greatest contributions to variability of blood and brain CEO concentrations in humans. The main contributor to predicted variance in human blood ACN concentrations in people exposed through drinking water was the Vmax for conversion of ACN to CEO. In contrast, the main contributors for variance in people exposed by inhalation were expected to be the rate of blood flow to the liver and alveolar ventilation rate, with the brain:blood partition coefficient also contributing to variability in predicted concentrations of ACN in the brain. Expected variability in blood CEO concentrations (peak or average) in humans exposed by inhalation or drinking water was modest, with a 95th-percentile individual expected to have blood concentrations 1.8-times higher than an average individual.     

Physiologically based pharmacokinetic modelling to predict exposure differences in healthy volunteers and subjects with renal impairment: Ceftazidime case study

Ceftazidime is a widely used β‐lactam antibiotic and almost entirely excreted via glomerular filtration in kidney. The objective of this analysis was to assess the ability of physiologically based pharmacokinetic (PBPK) model to predict ceftazidime exposure in healthy volunteers and subjects with renal impairment. A full PBPK model of ceftazidime was developed using physiochemical properties and clinical data. The total clearance of 115 mL/min and renal clearance of 100 mL/min were obtained from ceftazidime package insert. Healthy and chronic kidney disease (CKD) populations were applied for sampling of virtual subjects. The established PBPK model predicted mean plasma AUC_inf were 138.5 ± 19.6, 230.7 ± 22.2, 369.3 ± 53.1 and 561.8 ± 92.4 h   µg/mL in healthy, mild, moderate and severe renal impairment subjects, respectively, after administration of 1 g ceftazidime intravenous bolus dose. The predicted values were in close agreement with the weighted mean of the five reported clinical studies. The exposure was slightly under predicted in subjects with severely impaired renal function, but still within 1.5‐fold range. The concentration‐time profiles of ceftazidime were also well captured in healthy volunteers and subjects with renal impairment. The developed PBPK model along with systems pharmacokinetics (PK) (renal impaired populations) well predicted the ceftazidime exposure. PBPK models verified with clinical study in healthy volunteers could be potentially applied to predict PK and recommend dose adjustment for CKD patients.     

Physiologically based pharmacokinetic (PBPK) modeling and simulation in neonatal drug development: how clinicians can contribute

Introduction: Legal initiatives to stimulate neonatal drug development should be accompanied by development of valid research tools. Physiologically based (PB)-pharmacokinetic (PK) modeling and simulation are established tools, accepted by regulatory authorities. Consequently, PBPK holds promise to be a strong research tool to support neonatal drug development.

Area covered: The currently available PBPK models still have poor predictive performance in neonates. Using an illustrative approach on distinct PK processes of absorption, distribution, metabolism, excretion, and real-world data in neonates, we provide evidence on the need to further refine available PBPK system parameters through generation and integration of new knowledge. This necessitates cross talk between clinicians and modelers to integrate knowledge (PK datasets, system knowledge, maturational physiology) or test and refine PBPK models.

Expert opinion: Besides refining these models for ‘small molecules’, PBPK model development should also be more widely applied for therapeutic proteins and to determine exposure through breastfeeding. Researchers should also be aware that PBPK modeling in combination with clinical observations can also be used to elucidate age-related changes that are almost impossible to study based on in vivo or in vitro data. This approach has been explored for hepatic biliary excretion, renal tubular activity, and central nervous system exposure.     

A Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans.

A PBPK/PD model was developed for the organophosphate insecticide chlorpyrifos (CPF) (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), and the major metabolites CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP) in rats and humans. This model integrates target tissue dosimetry and dynamic response (i.e., esterase inhibition) describing uptake, metabolism, and disposition of CPF, CPF-oxon, and TCP and the associated cholinesterase (ChE) inhibition kinetics in blood and tissues following acute and chronic oral and dermal exposure. To facilitate model development, single oral-dose pharmacokinetic studies were conducted in rats (0.5-100 mg/kg) and humans (0.5-2 mg/kg), and the kinetics of CPF, CPF-oxon, and TCP were determined, as well as the extent of blood (plasma/RBC) and brain (rats only) ChE inhibition. In blood, the concentration of analytes followed the order TCP > CPF > CPF-oxon; in humans CPF-oxon was not quantifiable. Simulations were compared against experimental data and previously published studies in rats and humans. The model was utilized to quantitatively compare dosimetry and dynamic response between rats and humans over a range of CPF doses. The time course of CPF and TCP in both species was linear over the dose range evaluated, and the model reasonably simulated the dose-dependent inhibition of plasma ChE, RBC acetylcholinesterase (AChE), and brain (rat only) AChE. Model simulations suggest that rats exhibit greater metabolism of CPF to CPF-oxon than humans do, and that the depletion of nontarget B-esterase is associated with a nonlinear, dose-dependent increase in CPF-oxon blood and brain concentration. This CPF PBPK/PD model quantitatively estimates target tissue dosimetry and AChE inhibition and is a strong framework for further organophosphate (OP) model development and for refining a biologically based risk assessment for exposure to CPF under a variety of scenarios.     

Physiologically based pharmacokinetic modeling of 1,4-Dioxane in rats, mice, and humans.

1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver, and kidney damage at sufficiently high exposure levels. Two physiologically based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassay conditions. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.     

Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise.

Dichloromethane (methylene chloride, DCM) is metabolized via two pathways in humans: mixed-function oxidases (MFO) and glutathione-S:-transferase (GST). Most likely, the carcinogenicity for DCM is related to metabolic activation of DCM via the GST pathway. However, as the two pathways are competing, the metabolic capacity for the MFO pathway in vivo is also of interest in risk assessment for DCM. Past estimates of MFO metabolism are based on the in vitro activity of tissue samples. The aim of the present study was to develop a population model for DCM in order to gain more knowledge on the variability of DCM inhalation toxicokinetics in humans, with main emphasis on the MFO metabolic pathway. This was done by merging published in vitro data on DCM metabolism and partitioning with inhalation toxicokinetic data (Astrand et al., 1975, Scand. J. Work.Environ. Health 1, 78-94) from five human volunteers, using the MCMC technique within a population PBPK model. Our results indicate that the metabolic capacity for the MFO pathway in humans is slightly larger than previously estimated from four human liver samples. Furthermore, the interindividual variability of the MFO pathway in vivo is smaller among our five subjects than indicated by the in vitro samples. We also derive a Bayesian estimate of the population distribution of the MFO metabolism (median maximum metabolic rate 28, 95% confidence interval 12-66 micromol/min) that is a compromise between the information from the in vitro data and the toxicokinetic information present in the experimental data.     

Physiologically based pharmacokinetic modeling to predict complex drug–drug interactions: a case study of AZD2327 and its metabolite,competitive and time‐dependent CYP3A inhibitors

4‐{(R)‐(3‐Aminophenyl)[4‐(4‐fluorobenzyl)‐piperazin‐1‐yl]methyl}‐N,N‐diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ ‐opioid receptor. AZD2327 and N‐deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time‐dependent inhibition of CYP3A4. The aim of the current work was to develop a physiologically based pharmacokinetic (PBPK) model to predict quantitatively the magnitude of CYP3A4 mediated drug–drug interaction with midazolam as the substrate. Integrating in silico, in vitro and in vivo PK data, a PBPK model was successfully developed to simulate the clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (C_max) and area under the concentration–time curve (AUC) for midazolam were increased by 1.75 and 2.45‐fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinically relevant drug–drug interactions (DDI). These results are in agreement with those obtained in a clinical trial with a 1.4 and 1.5‐fold increase in C_max and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than a two‐fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways and inhibitors (parent and metabolite) can be predicted using a well‐developed PBPK model. Copyright © 2015 John Wiley & Sons, Ltd.     

Predicting the oral absorption of a poorly soluble,poorly permeable weak base using biorelevant dissolution and transfer model tests coupled with a physiologically based pharmacokinetic model

通过构建瑞舒伐他汀空腹状态下的生理药动学(physiologically based pharmacokinetic model,PBPK)模型,预测其餐后状态下的吸收,并探究其可能的食物效应机制,为服用他汀类药物的高脂血症患者提出合理的饮食建议,提高BCSⅢ类他汀类药物的药物吸收。

根据文献和已有研究获得瑞舒伐他汀建模的理化参数、生物药剂学参数以及药动学参数,利用GastroPlus^TM软件建立瑞舒伐他汀餐后给药的PBPK预测模型,并结合实测的血药浓度数据验证模型,判断是否可以准确预测出瑞舒伐他汀餐后的药物吸收结果,并进行参数敏感性分析。

通过构建瑞舒伐他汀PBPK模型预测其餐后吸收,计算得到模型预测数据与实测数据的平均折叠误差和绝对平均折叠误差<2,结合模型验证的拟合相关系数表明拟合效果较好,同时参数敏感性分析提示高热量饮食、药物的油水分配系数(LogD)和渗透性对瑞舒伐他汀的吸收影响较大。

所建立的模型能够较好地预测瑞舒伐他汀餐后状态下的吸收,基于参数敏感性分析结果,为服用BCSⅢ类他汀类药物的高脂血症患者提出合理的饮食建议,包括适当增加饮食中蛋白质的比重、减少脂肪和水溶性膳食纤维的占比等,可提高BCSⅢ类他汀类药物的肠道吸收。

     

Evaluation of oral and intravenous route pharmacokinetics, plasma protein binding, and uterine tissue dose metrics of bisphenol A: a physiologically based pharmacokinetic approach.

Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastic and epoxy resins, both of which are used in food contact and other applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed to provide a physiological context in which the processes controlling BPA pharmacokinetics (e.g., plasma protein binding, enterohepatic recirculation of the glucuronide [BPAG]) could be incorporated. A uterine tissue compartment was included to allow the correlation of simulated estrogen receptor (ER) binding of BPA with increases in uterine wet weight (UWW) in rats. Intravenous- and oral-route blood kinetics of BPA in rats and oral-route plasma and urinary elimination kinetics in humans were well described by the model. Simulations of rat oral-route BPAG pharmacokinetics were less exact, most likely the result of oversimplification of the GI tract compartment. Comparison of metabolic clearance rates derived from fitting rat i.v. and oral-route data implied that intestinal glucuronidation of BPA is significant. In rats, but not humans, terminal elimination rates were strongly influenced by enterohepatic recirculation. In the absence of BPA binding to plasma proteins, simulations showed high ER occupancy at doses without uterine effects. Restricting free BPA to the measured unbound amount demonstrated the importance of including plasma binding in BPA kinetic models: the modeled relationship between ER occupancy and UWW increases was consistent with expectations for a receptor-mediated response with low ER occupancy at doses with no response and increasing occupancy with larger increases in UWW.     

A Physiologically Based Pharmacokinetic Analysis of Capecitabine,a Triple Prodrug of 5-FU,in Humans: The Mechanism for Tumor-Selective Accumulation of 5-FU

Purpose. To identify the factors governing the dose-limiting toxicity in the gastrointestine (GI) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans. Method. The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measured experimentally in vitro to construct a physiologically based pharmacokinetic model. Sensitivity analysis for each parameter was performed to identify the parameters affecting tissue 5-FU concentrations. Results. The sensitivity analysis demonstrated that (i) the dihydropyrimidine dehydrogenase (DPD) activity in the liver largely determines the 5-FU AUC in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) the metabolic enzyme activity in the GI and the DPD activity in liver are the major determinants influencing exposure to 5-FU in the GI. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges. Conclusions. It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine administration are tumor-specific activation by dThdPase, the nonlinear elimination of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors.     

Development of a physiologically based pharmacokinetic (PBPK) model for methyl iodide in rats,rabbits, and humans

Methyl iodide (MeI) has been proposed as an alternative to methyl bromide as a pre-plant soil fumigant that does not deplete stratospheric ozone. In inhalation toxicity studies performed in animals as part of the registration process, three effects have been identified that warrant consideration in developing toxicity reference values for human risk assessment: nasal lesions (rat), acute neurotoxicity (rat), and fetal loss (rabbit). Uncertainties in the risk assessment can be reduced by using an internal measure of target tissue dose that is linked to the likely mode of action (MOA) for the toxicity of MeI, rather than the external exposure concentration. Physiologically based pharmacokinetic (PBPK) models have been developed for MeI and used to reduce uncertainties in the risk assessment extrapolations (e.g. interspecies, high to low dose, exposure scenario). PBPK model-derived human equivalent concentrations comparable to the animal study NOAELs (no observed adverse effect levels) for the endpoints of interest were developed for a 1-day, 24-hr exposure of bystanders or 8?hr/day exposure of workers. Variability analyses of the PBPK models support application of uncertainty factors (UF) of approximately 2 for intrahuman pharmacokinetic variability for the nasal effects and acute neurotoxicity.     

The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral‐mediated drug–drug interactions on piperaquine antimalarial therapy during pregnancy

Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine–pyrimethamine in sub‐Saharan Africa. Coinfection with HIV is common in many developing countries, however, little is known about the impact of antiretroviral (ARV) mediated drug–drug interaction (DDI) on piperaquine pharmacokinetics during pregnancy. This study applied mechanistic pharmacokinetic modelling to predict pharmacokinetics in non‐pregnant and pregnant patients, which was validated in distinct customised population groups from Thailand, Sudan and Papua New Guinea. In each population group, no significant differences in day 7 concentrations were observed during different gestational weeks (GW) (weeks 10–40), supporting the notion that piperaquine is safe throughout pregnancy with consistent pharmacokinetics, although possible teratogenicity may limit this. Antiretroviral‐mediated DDIs (efavirenz and ritonavir) had moderate effects on piperaquine during different gestational weeks with a predicted AUC_ratio in the range 0.56–0.8 and 1.64–1.79 for efavirenz and ritonavir, respectively, over GW 10–40, with a reduction in circulating human serum albumin significantly reducing the number of subjects attaining the day 7 (post‐dose) therapeutic efficacy concentrations under both efavirenz and ritonavir DDIs. This present model successfully mechanistically predicted the pharmacokinetics of piperaquine in pregnancy to be unchanged with respect to non‐pregnant women, in the light of factors such as malaria/HIV co‐infection. However, antiretroviral‐mediated DDIs could significantly alter piperaquine pharmacokinetics. Further model refinement will include collation of relevant physiological and biochemical alterations common to HIV/malaria patients.     

Role of antioxidants in the O-hydroxyethyl-D-(Ser)8-cyclosporine A (SDZ IMM125)-induced apoptosis in rat hepatocytes

The mechanisms underlying the apoptotic activity of the immunosuppressive drug cyclosporine A and its O-hydroxyethyl-D-(Ser)(8)-derivative SDZ IMM125 in rat hepatocytes are not yet fully understood. It was the purpose of the present study to investigate the role of anti- and pro-oxidants and of caspase-3 and intracellular Ca(2+) in SDZ IMM125-induced apoptosis in rat hepatocytes. SDZ IMM125 induced an increase in chromatin condensation and fragmentation, and the activation of caspase-3. Supplementing the cell cultures with the antioxidants, D,L-alpha-tocopherol-polyethylene-glycol-1000-succinate, ascorbic acid, and the reducing agent, dithiothreitol, significantly inhibited the SDZ IMM125-mediated increase in chromatin condensation and fragmentation, and caspase-3 activity. D,L-alpha-tocopherol-polyethylene-glycol-1000-succinate and dithiothreitol caused significant inhibition on SDZ IMM125-mediated cellular Ca(2+) uptake. The glutathione synthetase inhibitor, buthionine sulfoximine, increased SDZ IMM125-mediated caspase-3 action in parallel to chromatin condensation and fragmentation as well as Ca(2+) influx. Supplementation the culture medium with the intracellular Ca(2+) chelator bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid as well as omission of calcium in the medium reduced SDZ IMM125-induced apoptosis whereas the calcium supplementation of the culture medium elevated SDZ IMM125-induced apoptosis. Calcium antagonists inhibited SDZ IMM125-induced caspase-3 activation. Our data indicate that SDZ IMM125-mediated apoptosis in rat hepatocytes can be inhibited by antioxidants, and that the intracellular redox-state can act as a modulator of cytotoxicity and apoptosis. Further, the results suggest that SDZ IMM125-induced uptake of extracellular calcium is also a redox-sensitive process and that the increased intracellular calcium might directly cause apoptosis by increasing the caspase-3 activity as a central event in the cyclosporine-induced apoptotic mechanism.     

Prediction of human pharmacokinetics of typical compounds by a physiologically based method using chimeric mice with humanized liver

1. In this study, total body clearance (CL_t), volume of distribution at steady state (V_ss) and plasma concentration–time profiles in humans of model compounds were predicted using chimeric mice with humanized livers.

2. On the basis of assumption that unbound intrinsic clearance (CL_Uint) per liver weight in chimeric mice was equal to those in humans, CL_t were predicted by substituting human liver blood flow and liver weights in well-stirred model. V_ss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SF_Kp) in chimeric mice estimated from a difference between the observed and predicted V_ss. These physiological approaches showed high prediction accuracy for CL_t and V_ss values in humans.

3. We compared the predictability of CL_t and V_ss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method.

4. Simulation of human plasma concentration–time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CL_Uint and SF_Kp obtained from chimeric mice.

5. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds.

     

An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

AIMS

To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.

METHODS

Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg⁻¹ of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.

RESULTS

Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h⁻¹ (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)^1.49. AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l⁻¹ h (or AUC3D < 900 mg l⁻¹ h) and in 91% when AUC1D > 600 mg l⁻¹ h (or AUC3D > 900 mg l⁻¹ h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.

CONCLUSIONS

To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg⁻¹ for neonates younger than 70 h, 14, 7, 7 mg kg⁻¹ for neonates between 70 and 108 h and 18, 9, 9 mg kg⁻¹ for neonates between 108 and 180 h.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates.
• Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.

WHAT THIS STUDY ADDS

• A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen.
• Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age.
• A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced.
• Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates.

     

治疗药物监测中基于群体药动学模型设计采样方案的仿真研究

目的建立一种预测在治疗药物监测中需要避免的、只能提供很少信息的"最小信息采样点" 的方法。方法进行了一系列基于一室开放模型的仿真, 并且通过比较不同采样方案中预测参数效果的差异来验证建立的预测最小信息采样点的方法是否合理。我们比较了每种采样方案中各个参数的预测值和真实值( 仿真值) , 通过两者的接近程度来评价该采样方案,预测值和真实值越接近说明通过该方案采样获得的信息量越大, 这个采样方案越合理。结果在预测的最小信息采样点附近的时间点采样, 将会得到准确度和精确度均不佳的参数预测值。此外, 还考查了预测的最小信息采样点和参数之间的关系。计算了一些典型情况下的最小信息采样点, 并通过作图, 了解它们与参数之间的变化关系。在本文研究的例子中, 清除率可预测出一个最小信息采样点而表观分布容积和吸收速率常数各有两个。并且还发现最小信息采样点的预测值随表观分布容积的增大或者清除率和吸收速率常数的减小而增大。结论在实际的治疗药物监测中, 可以根据按照本文所描述的方法预测出的最小信息采样点设计更加合理的采样方案。