Simulation of Vitreous Traction Force and Flow Rate of High Speed Dual-Pneumatic 7500 Cuts Per Minute Vitrectomy Probes.

Purpose: To develop methods to simulate vitreous flow and traction during vitrectomy and qualify these methods using laboratory measurements. Methods: Medium viscosity and phase treatment were adjusted to represent vitreous (Eulerian two-phase flow) or saline solution (single-phase Navier-Stokes flow). Retinal traction was approximated using a one-way fluid-structure interaction simulating cut vitreous volume coupled to a structural simulation of elastic stretching of a cylinder representing vitreous fibers entrained in the flow. Results: Simulated saline solution flow decreased, but vitreous flow increased with increasing cut rate, consistent with experimental trends observed for the 50/50 duty cycle mode. Traction simulations reproduced all trends in variation of traction force with changes in conditions. Simulations reproduced the majority of traction measurements within experimental error. Conclusions: A scientific basis is provided for understanding how flow and traction vary with operational parameters. This model-based analysis serves as a "virtual lab" to determine optimal system settings to maximize flow efficiency while reducing traction. Translational Relevance: The model provides a better understanding regarding how instrument settings can help control a vitrectomy procedure so that it can be made as efficient as possible (maximizing the rate of vitreous removal) while at the same time being made as safe as possible (minimizing retinal traction).

Metric-Based Visual Acuity and Defocus Curve Simulation of Two Multifocal Intraocular Lens Models.

PURPOSE: To predict clinical defocus curve performance of the PanOptix intraocular lens (IOL) model TFNT00, a population-based image quality metric was applied to a pseudophakic eye model. METHODS: Visual acuity (VA) was simulated using a 2-surface reduced eye model. For each virtual eye, the derived corneal surface was combined with scaled IOL surface. Corneal power and aberration, anterior chamber depth, and pupil size were iterated using a Monte-Carlo approach. Image quality of the IOLs was assessed using the total aberration map to compute the amplitude point spread function. A diffraction-normalized light-in-the-bucket metric was calculated for each virtual eye for defocuses from -3.5 D to +1.0 D (step size 0.25 D) and transformed to VAs and defocus curves. Simulated VA for the ReSTOR +3.0 D lens was used to generate a calibration function by linear regression correlation of simulated data with clinical VA data. Simulated TFNT00 VA was then validated by comparing defocus curves to clinical TFNT00 data. RESULTS: From -3.5 D to +1.0 D, the simulated defocus curve was generally consistent with the defocus curve from the TFNT00 clinical trial. The mean absolute difference was 0.022 logMAR (~1 letter) for simulated VA versus clinical trial VA. CONCLUSION: IOL image quality can be assessed using a population-based virtual eye model to simulate VA and predict clinical performance. Computational modeling and simulation can be applied to future IOL development before clinical trials are conducted.

Physiologically based ocular pharmacokinetic modeling using computational methods.

By explicitly representing ocular anatomy, computational fluid dynamic simulation methods model drug mass transport both within and between ocular tissue regions, providing reliable animal-to-human translation of bioavailability. Here, we apply physiologically based models to simulate ocular drug administration. A non-anatomical model is used that applies a simple theorem for calculating ocular bioavailability from a topical dose. A computational fluid dynamic model is also described that incorporates ocular physiology in anatomical models for rabbit, monkey and man. This second method applies material properties and boundary conditions for various tissues enabling simulation of fluid flows, pressures, temperatures, convection, and drug advection following various modes of administration. The method provides a regional distribution with a given tissue not available using standard compartmental models, and enables translation of results from animal experiments into predictions for human ocular pharmacokinetics (PK).

A meta-analysis of Nd:YAG capsulotomy rates for two hydrophobic intraocular lens materials.

PURPOSE: The purpose of this study is to estimate and compare neodymium-doped yttrium aluminum garnet (Nd:YAG) capsulotomy rates for AcrySof ® and Clareon® intraocular lens (IOL) materials using historical data from the medical literature and Alcon-sponsored clinical studies. METHODS: Clinical trials that involved the implantation of AcrySof or Clareon monofocal IOLs in subjects with cataract or presbyopia were extracted from the literature and a company repository of clinical studies. The study duration, number of eyes, and cumulative percent of Nd:YAGs for posterior capsule opacification were extracted. Bayesian random effects meta-analyses were conducted to estimate and compare outcomes for the 2 different IOL materials. RESULTS: A Bayesian random effects, meta-analysis was performed that combined a literature review of published AcrySof Nd:YAG posterior capsulotomy rates and Nd:YAG rates observed in Alcon-sponsored clinical studies of AcrySof and Clareon. Sixteen Alcon studies contained Nd:YAG data suitable for meta-analysis. Three of these Alcon studies contained results for the Clareon material (2 one-year studies, and 1 three-year study). The literature review included 50 papers from 1998 to 2015. In combination, 30,891 eyes were available for analysis and 2040 Nd:YAG procedures were reported in studies with a follow-up duration ranging in length from 4 months to 10 years. The overall probability of performing a Nd:YAG capsulotomy within a year of implant for AcrySof was 1.44% (1.11% to 1.83%) and 0.62% (0.21% to 1.38%) for Clareon. There was small improvement in the probability of Nd:YAG within a year of implant for Clareon lenses of about 0.82% with a 95% credible interval of (0.07% to 1.36%) at 1 year. Results were similar for incidence rates per 100 surgeries in a year: 0.62 (0.21 to 1.40) for Clareon, 1.46 (1.12 to 1.87) for AcrySof, and the difference was 0.84 (0.07 to 1.39) favoring Clareon. At 3 years, the overall probability of performing a Nd:YAG capsulotomy for AcrySof was 4.19% (3.24% to 5.30%) compared with only 1.82% (0.63% to 4.02%) for Clareon. CONCLUSION: A meta-analysis of Clareon multi-piece and single-piece clinical data predicts that the cumulative Clareon Nd:YAG probability will be ≤ AcrySof by 2.37% (0.18% to 3.91%) at 3 years. The results indicate that Clareon is likely to perform as well as, and possibly better than, AcrySof in terms of Nd:YAG capsulotomy rates.

Projected 24-hour post-dose ocular itching scores post-treatment with olopatadine 0.7% versus 0.2.

Olopatadine is an antihistamine and mast cell stabilizer used for treating allergic conjunctivitis. Olopatadine 0.7% has been recently approved for daily dosing in the US, which supersedes the previously approved 0.2% strength. The objective of this analysis was to characterize patients who have better itching relief at 24 h when taking olopatadine 0.7% treatment instead of olopatadine 0.2% (in terms of proportions of responses) and relate this to the severity of baseline itching as an indirect metric of a patient's sensitivity to antihistamines. A differential odds model was developed using data from two conjunctival allergen challenge (CAC) studies to characterize individual-level and population-level response to ocular itching following olopatadine treatment and the data was analyzed retrospectively. This modeling analysis was designed to predict 24 h ocular itching scores and to quantify the differences in 24 h itching relief following treatment with olopatadine 0.2% versus 0.7% in patients with moderate-to-high baseline itching. A one-compartment kinetic-pharmacodynamic Emax model was used to determine the effect of olopatadine. Impact of baseline itching severity, vehicle effect and the drug effect on the overall itching scores post-treatment were explicitly incorporated in the model. The model quantified trends observed in the clinical data with regards to both mean scores and the proportions of patients responding to olopatadine treatment. The model predicts a higher proportion of patients in the olopatadine 0.7% versus 0.2% group will experience relief within 24 h. This prediction was confirmed with retrospective clinical data analysis. The number of allergy patients relieved with olopatadine 0.7% increased with higher baseline itching severity scores, when compared to olopatadine 0.2%.

A model-based approach to investigating the pathophysiological mechanisms of hypertension and response to antihypertensive therapies: extending the Guyton model.

Reproducibly differential responses to different classes of antihypertensive agents are observed among hypertensive patients and may be due to interindividual differences in hypertension pathology. Computational models provide a tool for investigating the impact of underlying disease mechanisms on the response to antihypertensive therapies with different mechanisms of action. We present the development, calibration, validation, and application of an extension of the Guyton/Karaaslan model of blood pressure regulation. The model incorporates a detailed submodel of the renin-angiotensin-aldosterone system (RAAS), allowing therapies that target different parts of this pathway to be distinguished. Literature data on RAAS biomarker and blood pressure responses to different classes of therapies were used to refine the physiological actions of ANG II and aldosterone on renin secretion, renal vascular resistance, and sodium reabsorption. The calibrated model was able to accurately reproduce the RAAS biomarker and blood pressure responses to combinations of dual-RAAS agents, as well as RAAS therapies in combination with diuretics or calcium channel blockers. The final model was used to explore the impact of underlying mechanisms of hypertension on the blood pressure response to different classes of antihypertensive agents. Simulations indicate that the underlying etiology of hypertension can impact the magnitude of response to a given class of therapy, making a patient more sensitive to one class and less sensitive others. Given that hypertension is usually the result of multiple mechanisms, rather than a single factor, these findings yield insight into why combination therapy is often required to adequately control blood pressure.

Aliskiren monotherapy does not cause paradoxical blood pressure rises: meta-analysis of data from 8 clinical trials.

Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics all cause reactive rises in plasma renin concentration, but particularly high levels have been reported with aliskiren. This prompted speculation that blockade of plasma renin activity with aliskiren could be overwhelmed, leading to paradoxical increases in blood pressure. This meta-analysis of data from 4877 patients from 8 randomized, double-blind, placebo- and/or active-controlled trials examined this hypothesis. The analysis focused on the incidence of paradoxical blood pressure increases above predefined thresholds, after > or =4 weeks of treatment with 300 mg of aliskiren, angiotensin receptor blockers (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, 25 mg of hydrochlorothiazide, or placebo. There were no significant differences in the frequency of increases in systolic (>10 mm Hg; P=0.30) or diastolic (>5 mm Hg; P=0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%; P<0.001). None of the 536 patients with plasma renin activity data who received 300 mg of aliskiren exhibited an increase in systolic pressure >10 mm Hg that was associated with an increase in plasma renin activity >0.1 ng/mL per hour. In conclusion, the incidence of blood pressure increases with aliskiren was similar to that during treatment with other antihypertensive drugs. Blood pressure rises on aliskiren treatment were not associated with increases in plasma renin activity. This meta-analysis found no evidence that aliskiren uniquely causes paradoxical rises in blood pressure.

Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi).

Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

Investigations of the use of bioavailability data to adjust occupational exposure limits for active pharmaceutical ingredients.

Occupational exposure limits (OELs) for active pharmaceutical ingredients have traditionally been established using no-observed-adverse-effect levels derived from clinical studies employing po and iv routes of administration and by applying default uncertainty factors or chemical-specific adjustment factors. However, exposure by the inhalation or dermal route is more relevant in terms of occupational safety. In this investigation, to explore new methods for route-to-route extrapolation, the bioavailability of MK-0679, a leukotriene D(4) receptor antagonist, was compared following iv, po, intranasal (in), or intratracheal (it) administration. The relative bioavailability of MK-0679 was iv congruent with it > po congruent with in. Bioavailability correction factors (BCFs) of 2.0 and 0.6 were derived from these data to adjust a hypothetical OEL of 0.1 mg/m(3) for MK-0679 with particle sizes of 10 and 50 mum, respectively. These BCFs were used to adjust the OEL established using po clinical data, to reflect the differences in bioavailability following deposition in different regions of the respiratory tract. To further investigate how bioavailability data could be used in setting OELs, a preliminary pharmacokinetic (PK) model was developed to describe the time course of plasma concentrations using the data from the route comparison study. An inhalation study was then performed to test the validity of using either empirical data or modeling approaches to derive BCFs when setting OELs. These investigations demonstrated how the use of route-specific PK data could reduce some of the uncertainties associated with route-to-route extrapolation and allow for improved precision and quantitative adjustments when establishing OELs. Further investigations are needed to better understand the factors responsible for differences in systemic uptake following deposition in different regions of the respiratory tract and how these can be generalized across different classes of soluble compounds.

An integrated approach for inference and mechanistic modeling for advancing drug development.

An important challenge facing researchers in drug development is how to translate multi-omic measurements into biological insights that will help advance drugs through the clinic. Computational biology strategies are a promising approach for systematically capturing the effect of a given drug on complex molecular networks and on human physiology. This article discusses a two-pronged strategy for inferring biological interactions from large-scale multi-omic measurements and accounting for known biology via mechanistic dynamical simulations of pathways, cells, and organ- and tissue level models. These approaches are already playing a role in driving drug development by providing a rational and systematic computational framework.

Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry.

The physiological and biochemical processes that determine the tissue concentration time courses (pharmacokinetics) of xenobiotics vary, in some cases significantly, with age and gender. While it is known that age- and gender-specific differences have the potential to affect tissue concentrations and, hence, individual risk, the relative importance of the contributing processes and the quantitative impact of these differences for various life stages are not well characterized. The objective of this study was to identify age- and gender-specific differences in physiological and biochemical processes that affect tissue dosimetry and integrate them into a predictive physiologically based pharmacokinetic (PBPK) life-stage model. The life-stage model was exercised for several environmental chemicals with a variety of physicochemical, biochemical, and mode-of-action properties. In general, predictions of average pharmacokinetic dose metrics for a chemical across life stages were within a factor of two, although larger transient variations were predicted, particularly during the neonatal period. The most important age-dependent pharmacokinetic factor appears to be the potential for decreased clearance of a toxic chemical in the perinatal period due to the immaturity of many metabolic enzyme systems, although this same factor may also reduce the production of a reactive metabolite. Given the potential for age-dependent pharmacodynamic factors during early life, there may be chemicals and health outcomes for which decreased clearance over a relatively brief period could have a substantial impact on risk.

Interspecies dose extrapolation for inhaled dimethyl sulfate: a PBPK model-based analysis using nasal cavity N7-methylguanine adducts.

Dimethyl sulfate (DMS) is a volatile sulfuric acid ester used principally as a methylating agent in a wide variety of industrial applications. DMS reacts with organic macromolecules by a SN2 mechanism. The weight of experimental evidence suggests that DMS possesses genotoxic and carcinogenic potential. Inhalation studies have shown that repeated exposure to DMS leads to tumors in the nasal cavity and lower respiratory tract in both rats and mice. Here we present a quantitative assessment for cross-species dose extrapolation for inhaled DMS using a physiologically based pharmacokinetic (PBPK) model. The model is designed to simulate N7-methylguanine (N7 mG) DNA adduct levels in the nasal mucosa following DMS exposure in rats and humans. This model was parameterized and predictions were tested by comparison against experimentally measured N7 mG DNA adduct levels in rat nasal mucosa following inhalation exposure to DMS. The model-based interspecies dose comparison, using N7 mG adduct levels in the nasal respiratory tissue as the appropriate dose metrics, predicts a dose rate seven times higher in rats compared to humans.

Evaluation of the potential impact of age- and gender-specific lung morphology and ventilation rate on the dosimetry of vapors.

In recent years, there have been growing concerns that due to differences, both pharmacokinetic and pharmacodynamic, between children and adults, children could be at greater risk of adverse effects following chemical exposure. The specific goal of this study was to demonstrate an approach for using physiologically based pharmacokinetic (PBPK) modeling to compare inhalation dosimetry in the adult and the child of both males and females. Three categories of gases were considered: rapidly and irreversibly reactive in the respiratory tract (ozone), relatively water-soluble and nonreactive (isopropanol), and relatively water-insoluble and nonreactive (styrene, vinyl chloride, and perchloroethylene). The nonreactive chemicals were also selected because they are metabolized in the respiratory tract. The age-related changes observed for the estimated dose metrics were a function of the physiochemical properties of the inhaled vapor and their interactions in the body. Blood concentrations estimated for all vapors, either poorly metabolized (e.g., PERC), moderately metabolized (e.g., ST), or highly metabolized vapors (e.g., IPA and VC), varied less than a factor of two between infants and adults. These changes, moreover, were confined to the first year after birth, a relatively short window compared to the total lifespan of the individual. In contrast, circulating metabolite concentrations estimated in the blood, as well as amounts metabolized in the liver and lung, appeared to be a strong function of age, due to their dependence on the maturity of the pertinent metabolic enzyme systems.

Physiologically-based kinetic modeling of vapours toxic to the respiratory tract.

The respiratory tract is frequently identified as a site of toxicity for inhaled xenobiotic chemicals. Usually, these observations come from controlled animal studies. For these studies to be of quantitative value to human health risk assessment, species-specific factors governing dosimetry of inhaled substances must be taken into account. Toxicokinetics of vapours in the respiratory tract are defined by absorption, distribution, metabolism, and excretion, as they are in other tissues; however, these concepts take on new dimensions when considering respiratory tract toxicants, especially those that elicit portal of entry effects by directly interacting with the tissue lining the respiratory tract. Species-specific factors related to anatomy, physiology and biochemistry govern inter-species extrapolation of toxicokinetics. This article discusses critical factors of respiratory tract kinetics that should be considered when developing physiological-based toxicokinetic (PBTK) models for inhaled vapours. Important considerations such as impact of regional airflow-delivery, water solubility, reactivity, and rates of local biotransformation on respiratory tract tissue dosimetry are highlighted. These factors can be accounted for only to a limited extent when using default approaches to extrapolate dosimetry of inhaled substances across species. On the other hand, PBTK modeling has the flexibility to accommodate many of the critical determinants of respiratory tract toxicity. PBTK models can also help identify the most critical toxicokinetic data necessary to replace defaults. PBTK approaches have led to more informed estimates of human target tissue dose, and therefore human health risk, especially where these risk assessments have been based on extrapolation of animal dosimetry studies. Experience derived from the development of more intensive case studies have, in turn, enabled simplified approaches to the use of PBTK modeling for respiratory tract toxicants. Whether simplified or highly complex, PBTK modeling approaches are proven to be of great utility to risk assesors interested in applying quantitative information to informed risk assessment evaluations.

Route-specific differences in distribution characteristics of octamethylcyclotetrasiloxane in rats: analysis using PBPK models.

Octamethylcyclotetrasiloxane (D(4)) is used in selected consumer products and has a potential for human exposure from multiple routes. Here we develop a physiologically based pharmacokinetic (PBPK) model to describe the tissue dosimetry, plasma concentration, and clearance in the rat following inhalation and dermal, oral, and iv exposure. An initial multiroute PBPK model, based on a previously published inhalation PBPK model for D(4), provided excellent fits to the observed concentration time course of D(4) metabolites in urine and D(4) exhalation rate following dermal exposures. However, the pharmacokinetics of D(4), following oral and iv exposure, were sensitive to the mode of entry into the blood compartment. A refined model, describing delivery of D(4) from the GI tract to the nonexchangeable/deep blood compartment, provided the best fits to observed plasma D(4), exhaled D(4), and D(4) metabolites excreted in the urine following oral exposure. Pharmacokinetics following iv administration was best described by delivery of D(4) directly into the deep blood compartment, possibly reflecting a kinetically identifiable characteristic of the administration of D(4) as an emulsion for the intravenous route of exposure. This model-based analysis indicates that the pharmacokinetics of D(4) delivered by the inhalation or dermal routes is similar, and is different from the iv or oral delivery routes.

Review and evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry.

In standard risk assessment methods for carcinogenic or noncarcinogenic chemicals, quantitative methods for evaluating interindividual variability are not explicitly considered. These differences are currently considered by the use of statistical confidence limits or default uncertainty factors. This investigation consisted of multiple tasks aimed at making quantitative predictions of interindividual differences in susceptibility by using physiologically based pharmacokinetic (PBPK) models. Initially, a systematic, comprehensive review of the literature was conducted to identify any quantitative information related to gender- or age-specific physiological and biochemical factors that could influence susceptibility to chemical exposure. These data were then organized from a pharmacokinetic perspective by process and by chemical class to identify key factors likely to have a significant impact on susceptibility as it relates to internal target tissue dose. Overall, a large number of age- and gender-specific quantitative differences in pharmacokinetic parameters were identified. The majority of these differences were identified between neonates/children and adults, with fewer differences identified between young adults and the elderly. The next phase of this work consists of using PBPK models to develop examples of approaches through the development of case studies. The goal of the case studies is to continue to develop a methodology that incorporates PBPK modeling to assess the likelihood that a chemical or class of chemicals may present an age- or gender-specific risk. The case studies should also demonstrate practical methods for quantitatively incorporating information on age- and gender-specific pharmacokinetic differences in risk assessments for chemicals.

Physiologically based pharmacokinetic modeling of styrene and styrene oxide respiratory-tract dosimetry in rodents and humans.

Styrene (ST) is widely used to manufacture resins, glass-reinforced plastics, and a number of commercially important polymers (Miller et al., 1994). Chronic ST inhalation studies in rodents have demonstrated unique species specificity in the resulting pulmonary toxicity and carcinogenicity. Increased incidences of pulmonary bronchioloalveolar tumors have been observed in mice, but not in rats. No other tumor type was increased significantly in either species. Clara cells lining the respiratory epithelium metabolize ST to styrene 7,8-oxide (SO), which is cytotoxic and weakly genotoxic. Rodent species show marked differences in the distribution and regional density of Clara cells within the respiratory tract, as well as in their capacity to produce and eliminate SO. A mode of action-based physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of ST and SO in blood, liver, and the respiratory-tract tissues, particularly in terminal bronchioles (target tisue), in order to conduct interspecies extrapolations and determine the extent to which there is a pharmacokinetic basis for the observed species specificity. This PBPK model has a multicompartment description of the respiratory tract and incorporates species-specific quantitative information on respiratory-tract physiology, cellular composition, and metabolic capacity. The model is validated against multiple data sets, including blood, liver, and whole lung tissue concentration of ST and SO following multiple routes of exposure. The trend in neoplastic incidences in mice correlated well with model-estimated SO concentration in the terminal bronchioles. The PBPK model predicts a 10-fold lower SO concentration in the terminal bronchioles in rats compared to mice, which is consistent with the observed species sensitivity to the development of respiratory-tract neoplasms. The model-based analysis suggests that humans would be expected to be 100-fold less sensitive to ST-inducted lung tumors than mice, based on pharmacokinetic differences. Pharmacodynamic factors are also expected to contribute to species sensitivity, potentially augmenting pharmacokinetics-based differences.

Comparing respiratory-tract and hepatic exposure-dose relationships for metabolized inhaled vapors: a pharmacokinetic analysis.

Inhaled vapors that are metabolized locally in the respiratory-tract tissues and systemically in the liver and other organs have different dose-response relationships at the portal of entry compared to systemic target organs. For instance, inhaled chloroform and styrene cause cytotoxicity in the nasal cavity at concentrations much lower that those causing hepatic or renal toxicity. Here, we develop a physiologically based pharmacokinetic (PBPK) model that incorporates a multicompartment, unidirectional flow description of the respiratory tract within a whole-body model in order to estimate both respiratory tract and hepatic metabolism. We then use this model to study the difference in exposure-dose relationship between the respiratory-tract tissues and the liver. The integrated PBPK model confirms that for soluble vapors the exposure-dose curve for metabolism in respiratory-tract tissue will be shifted dramatically to lower concentrations compared to the exposure-dose relationship in systemic organs. This behavior is the result of direct air to tissue equilibration at the portal of entry while other systemic tissues only respond to concentrations in the blood. For cases where metabolism/metabolites of inhaled vapors produce local toxicity, portal of entry effects are expected at lower concentrations and, in general, will be the limiting response for setting reference concentrations (RfCs) for many compounds. The difference in dose-response relationships for metabolism in the respiratory tract versus systemic organs depends on blood/air and blood/tissue partition coefficients and on the degree of systemic extraction of the metabolized vapors.

Dose-response modeling of cytochrome p450 induction in rats by octamethylcyclotetrasiloxane.

Inhalation of octamethylcyclotetrasiloxane (D4) induces CYP2B1/2 protein and causes liver enlargement. We have developed a pharmacodynamic (PD) extension to a physiologically based pharmacokinetic (PBPK) model to characterize these dose-response behaviors. The PD model simulates interactions of D4 with a putative receptor, leading to increased production of cytochrome P450 2B1/2. Induction was modeled with a Hill equation with dissociation constant, Kd, and Hill coefficient, N. Both a 1- and a 5-compartment liver model were evaluated. The PBPK model provided excellent simulations of tissue D4 and hepatic CYP2B1/2 protein concentrations following 6 h/day, 5-day inhalation exposures to 0, 1, 7, 30, 70, 150, 300, 500, 700, or 900 ppm D4. Either the 1- or 5-compartment liver model could accurately simulate increases in CYP2B1/2 protein in the liver. With a 1-compartment liver, Kd and N were 0.67 microM (free liver concentration) and 1.9, respectively. The 5-compartment model used higher N-values (approximately 4.0) and varied Kd between compartments. The fitted 5-compartment model parameters were Kd = 0.67 microM in the midzonal compartment with geometric differences in Kd between compartments of 2.9. On the basis of unbound (free) plasma concentrations, D4 appeared to be a higher potency inducer than phenobarbital (PB). Dose-response curves for increased liver weights had N/mS 1.0 and Kd/mS 3.4 microM, very different values from those for enzyme induction. Exposure concentration leading to a 0.1% increase in CYP2B1/2 protein predicted by the 1- and 5-compartment models were 2.1 ppm and 5.1 ppm, respectively. The 1- and 5-compartment liver models provided very similar fits to the whole liver induction data, excluding the lowest dose, but the 5-compartment liver model had the additional advantage of simultaneously describing the regional induction of CYP2B1/2.