Simplified Physiologically Based Pharmacokinetic Models Research Articles

Updated in Silico Prediction Methods for Fractions Absorbed and Key Input Parameters of 355 Disparate Chemicals for Physiologically Based Pharmacokinetic Models for Time-Dependent Plasma Concentrations after Virtual Oral Doses in Humans.

Human metabolic profiles for substances such as toxic food-derived compounds are usually allometrically extrapolated from traditionally determined in vivo rat concentration profiles. To evaluate internal exposures in humans without any reference to experimental data, physiologically based pharmacokinetic (PBPK) modeling could be used if the model input parameters could be estimated in silico. This approach would simplify the use of PBPK models for forward dosimetry after oral doses. In this study, the in silico estimation of input parameters for PBPK models (i.e., fraction absorbed × intestinal availability, absorption rate constants, and volumes of the systemic circulation) was updated for an panel of 355 chemicals (212 previously analyzed and 143 additional substances) using a light gradient boosting machine learning algorithms (LightGBM) based on between 11 and 29 in silico-calculated chemical descriptors. Simplified human PBPK models were then used to calculate virtual maximum plasma concentrations (Cmax) and areas under the concentration-time curve (AUC) based on two sets of input parameters, i.e., traditionally derived values from in vivo data and those calculated in silico using the current updated systems. Both sets of Cmax and AUC data were well correlated (r = 0.87 and r = 0.73, respectively; p < 0.01, n = 355). Therefore, input parameters for human PBPK models for a diverse range of compounds could be successfully estimated using chemical descriptors and in silico tools. This approach to pharmacokinetic modeling has potential for application in computational toxicology and in the clinical setting for assessing the potential risk of general chemicals.

Plasma Concentration Profiles for Hepatotoxic Pyrrolizidine Alkaloid Senkirkine in Humans Extrapolated from Rat Data Sets Using a Simplified Physiologically Based Pharmacokinetic Model.

The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available. The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed. The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans. Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model. After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells. Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.

Forward and reverse dosimetry for aniline and 2,6-dimethylaniline in humans extrapolated from humanized-liver mouse data using simplified physiologically based pharmacokinetic models.

Although human urinary aniline and 2,6-dimethylaniline were unexpectedly detected in biomonitoring data, little is known about the daily intake doses of aniline and 2,6-dimethylaniline in the living environment or their relation to tolerable daily intake (TDI) values in humans. In the current study, to evaluate the daily oral intake of aniline and 2,6-dimethylaniline in humans, forward and reverse dosimetry was carried out using simplified in silico physiologically based pharmacokinetic (PBPK) modeling established using in vivo experimental pharmacokinetic data. These data were from humanized-liver mice after single oral doses of 100 mg/kg aniline (previously determined) and 116 mg/kg 2,6-dimethylanine (currently investigated). The in vivo elimination rates of 2,6-dimethylaniline from plasma in humanized-liver mice were generally slow compared with those of aniline. Faster in vitro metabolic elimination rates of aniline mediated by liver 9000 × g supernatant fractions from rats than those from humans may suggest the existence of higher first-pass effects in rats than in humanized-liver mice. In silico aniline and 2,6-dimethylaniline concentration curves in human urine after virtual oral administrations were estimated by human PBPK models created with data from humanized-liver mice. Reverse dosimetry analysis using human PBPK models estimated the daily intake of aniline, based on reported human urinary concentrations in biomonitoring data, to be roughly similar to the aniline TDI level. These results suggest that forward and reverse dosimetry using simplified human PBPK models founded on data from humanized-liver mice can be used to evaluate possible higher than expected exposures of aniline and 2,6-dimethylaniline in humans.

Machine Learning Prediction of the Three Main Input Parameters of a Simplified Physiologically Based Pharmacokinetic Model Subsequently Used to Generate Time-Dependent Plasma Concentration Data in Humans after Oral Doses of 212 Disparate Chemicals.

Physiologically based pharmacokinetic (PBPK) modeling has the potential to play significant roles in estimating internal chemical exposures. The three major PBPK model input parameters (i.e., absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances) were generated in silico for 212 chemicals using machine learning algorithms. These input parameters were calculated based on sets of between 17 and 65 chemical properties that were generated by in silico prediction tools before being processed by machine learning algorithms. The resulting simplified PBPK models were used to estimate plasma concentrations after virtual oral administrations in humans. The estimated absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearance values for the 212 test compounds determined traditionally (i.e., based on fitting to measured concentration profiles) and newly estimated had correlation coefficients of 0.65, 0.68, and 0.77 (p < 0.01, n = 212), respectively. When human plasma concentrations were modeled using traditionally determined input parameters and again using in silico estimated input parameters, the two sets of maximum plasma concentrations (r = 0.85, p < 0.01, n = 212) and areas under the curve (r = 0.80, p < 0.01, n = 212) were correlated. Virtual chemical exposure levels in liver and kidney were also estimated using these simplified PBPK models along with human plasma levels. These results indicate that the PBPK model input parameters for humans of a diverse set of compounds can be reliability estimated using chemical descriptors calculated using in silico tools.

Updated in silico prediction methods for fractions absorbed and absorption rate constants of 372 disparate chemicals for use in physiologically based pharmacokinetic models for estimating internal concentrations in rats.

Physiologically based pharmacokinetic (PBPK) modeling has the potential to estimate internal chemical exposures. Algorithms for predicting the input parameters for PBPK modeling, such as absorption rate constants (ka), were previously reported for 323 chemicals in rats. In this study, a currently updated system for estimating the fraction absorbed × intestinal availability of compounds, along with a modified estimation system that generates ka values, is reported, based on the previously analyzed 323 primary compounds, 10 secondary compounds, and 39 additional substances. The in silico estimation of input parameters for PBPK models (i.e., fraction absorbed × intestinal availability and ka) was adapted for an updated panel of 372 chemicals using machine learning algorithms based on between 16 and 18 in silico-calculated chemical properties. Simplified human PBPK models were then used to calculate virtual areas under the plasma concentration-time curve (AUC) based on two sets of input parameters, i.e., traditionally derived values from in vivo data and those calculated in silico using the current updated machine learning systems. The AUC data sets were well correlated; the current correlation coefficient increased from 0.61 to 0.82 (p < 0.01, n = 372). Therefore, the above-described computational methods constitute a new alternative approach that could contribute to chemical safety evaluations.

Pharmacokinetics of loxoprofen in a self-administered overdose in a Japanese patient admitted to hospital

BackgroundLoxoprofen is a propionic acid derivative and is the most widely prescribed non-steroidal anti-inflammatory drug in Japan. Loxoprofen is generally considered to be relatively nontoxic.Case presentationA 33-year-old man (body weight, 55 kg) who intentionally took an overdose of 100 tablets of loxoprofen (6000 mg) as a suicide attempt was emergently admitted to Kyoto Medical Center. On arrival, the patient was suffering disorders of consciousness. His plasma concentrations of loxoprofen and its reduced trans-alcohol metabolite were 52 and 24 μg/mL, 3.7 and 2.3 μg/mL, 0.81 and 0.54 μg/mL, and 0.015 and 0.011 μg/mL, respectively, at 4, 26, 50, and 121 h after the oral overdose. The observed apparent terminal elimination half-life of loxoprofen during days 1 and 2 of hospitalization was in the range 6–12 h, which is several times longer than the reported normal value. This finding implied nonlinearity of loxoprofen pharmacokinetics over the current 100-fold dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic (PBPK) model founded on data from a normal dose of 60 mg. The reasons for the delayed eliminations from plasma of loxoprofen and its trans-alcohol metabolite in this case are uncertain, but slight renal impairment (low eGFR values) developed on the second and third hospital days and could be a causal factor.ConclusionsBecause the patient’s level of consciousness had gradually improved, he was discharged on the fourth day of hospitalization. The virtual plasma exposures of loxoprofen and its reduced trans-alcohol metabolite estimated using the current simplified PBPK model were lower than the measured values in the overdose case. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide in cases of loxoprofen overdose.

In Silico Prediction of Input Parameters for Simplified Physiologically Based Pharmacokinetic Models for Estimating Plasma, Liver, and Kidney Exposures in Rats after Oral Doses of 246 Disparate Chemicals.

Recently developed computational models can estimate plasma, hepatic, and renal concentrations of industrial chemicals in rats. Typically, the input parameter values (i.e., the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance) for simplified physiologically based pharmacokinetic (PBPK) model systems are calculated to give the best fit to measured or reported in vivo blood substance concentration values in animals. The purpose of the present study was to estimate in silico these three input pharmacokinetic parameters using a machine learning algorithm applied to a broad range of chemical properties obtained from several cheminformatics software tools. These in silico estimated parameters were then incorporated into PBPK models for predicting internal exposures in rats. Following this approach, simplified PBPK models were set up for 246 drugs, food components, and industrial chemicals with a broad range of chemical structures. We had previously generated PBPK models for 158 of these substances, whereas 88 for which concentration series data were available in the literature were newly modeled. The values for the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance could be generated in silico by equations containing between 14 and 26 physicochemical properties. After virtual oral dosing, the output concentration values of the 246 compounds in plasma, liver, and kidney from rat PBPK models using traditionally determined and in silico estimated input parameters were well correlated (r ≥ 0.83). In summary, by using PBPK models consisting of chemical receptor (gut), metabolizing (liver), excreting (kidney), and central (main) compartments with in silico-derived input parameters, the forward dosimetry of new chemicals could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of hematotoxic, hepatotoxic, or nephrotoxic potential as a part of risk assessment.

Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential.

Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2-dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100-250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. The predicted time-dependent hepatic concentrations after virtual administrations in humanized-liver mice were partly confirmed with single measured hepatic concentrations of bromobenzene and 1,4-dibromobenzene 2 h after oral doses of 150-250 mg/kg to humanized-liver mice. Moreover, leaked human albumin mRNA, a marker of the extent of human hepatic injuries, in humanized-liver mouse plasma was detected after oral administration of bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene. These results suggest that dosimetry approaches for determining tissue and/or blood exposures of hepatic toxicants bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene in humanized-liver mice were useful after virtual oral doses using simplified PBPK models. Using simplified PBPK models and plasma data from humanized-liver mice has potential to predict and evaluate the hepatic toxicity of bromobenzenes and related compounds in humanized-liver mice and in humans.

Metabolic Profiles of Tetrabromobisphenol A in Humans Extrapolated from Humanized-Liver Mouse Data Using a Simplified Physiologically Based Pharmacokinetic Model.

Tetrabromobisphenol A, a brominated flame retardant, is increasingly prevalent worldwide and presents a potential health risk. Adjusted animal biomonitoring equivalents of tetrabromobisphenol A after orally administered doses in humanized-liver mice were scaled up to humans using known species allometric scaling factors to set up simplified physiologically based pharmacokinetic (PBPK) models. Absorbed tetrabromobisphenol A was slightly, moderately, and extensively metabolized in vivo to its glucuronide in rats, control mice, and humanized-liver mice tested, respectively. In silico estimated hepatic exposures of tetrabromobisphenol A and its glucuronide generated using the rat PBPK model-generated plasma concentration profiles were consistent with the reported values. The extent of hepatic injury in humanized-liver mice caused by tetrabromobisphenol A was evaluated by detecting human albumin mRNA in mouse plasma after oral administration of a high dose of tetrabromobisphenol A (1000 mg/kg). Reverse dosimetry analyses were carried out using two human PBPK models (set up based on the humanized-liver-mouse model and by optimizing the input parameters for reported human plasma concentrations of tetrabromobisphenol A glucuronide) to estimate the tetrabromobisphenol A daily intake based on reported human serum concentrations of total tetrabromobisphenol A from biomonitoring data. Within the predictability of the forward and reverse dosimetry estimations, the calculated daily intake was found to be far below established health benchmark levels (i.e., the suggested daily reported reference dose) with a wide (4 orders of magnitude) safety margin. These results suggest that the simplified PBPK models can be successfully applied to forward and reverse dosimetry estimations of tissue and/or blood exposures of tetrabromobisphenol A in humans after oral doses.

Human urinary concentrations of monoisononyl phthalate estimated using physiologically based pharmacokinetic modeling and experimental pharmacokinetics in humanized-liver mice orally administered with diisononyl phthalate

Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-14C]DINP mixture was synthesized and orally administered (50 mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined.Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice. Biphasic plasma concentration–time curves of MINP and its glucuronide were seen in control mice. In contrast, no such biphasic relationship was seen in humanized-liver mice, in which MINP and oxidized MINP were extensively excreted in the urine within 48 h.Animal biomonitoring equivalents of MINP and oxidized MINP from humanized-liver mice studies were scaled to human equivalents using known species allometric scaling factors with a simple physiologically based pharmacokinetic (PBPK) model.Estimated urinary oxidized MINP concentrations in humans were roughly consistent with reported concentrations of MINP (with a different side chain). The simplified PBPK model could estimate human urinary concentrations of MINP after ingestion of DINP and was capable of both forward and reverse dosimetry.

Association of pharmacokinetic profiles of lenalidomide in human plasma simulated using pharmacokinetic data in humanized-liver mice with liver toxicity detected by human serum albumin RNA.

Lenalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species. Screening for thalidomide analogs devoid of teratogenicity/toxicity-attributable to drug metabolism and disposition, but having immunomodulatory properties-is a strategic pathway towards development of new anticancer drugs. Plasma concentrations of lenalidomide were investigated in immunodeficient control and humanized-liver mice following oral administration of lenalidomide (50 mg/kg). Plasma concentrations of lenalidomide (1-2 hr after administration) were slightly but significantly higher in humanized-liver mice than in control mice (p < 0.05). Human albumin mRNA, a liver-specific toxicity marker, was found in the blood of humanized-liver mice 24 hr after lenalidomide administration. Simulations of human plasma concentrations of lenalidomide were achieved with simplified physiologically-based pharmacokinetic models in control and humanized-liver mice or by the direct fitting analysis of reported human data, in accordance with reported lenalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of lenalidomide, a compound resulting from introducing one aromatic amino group into thalidomide and removing one keto group, resulted in less species variation in in vivo pharmacokinetics in control and humanized-liver mice and that immunodeficient humanized-liver mice can serve as experimental model animals for human liver injury in drug development at high doses, with human albumin RNA analysis in plasma.

Association with polymorphic marmoset cytochrome P450 2C19 of in vivo hepatic clearances of chirally separated R-omeprazole and S-warfarin using individual marmoset physiologically based pharmacokinetic models

1. Simulated clearances of R-warfarin and efavirenz were recently reported for individual cynomolgus monkeys genotyped for cytochrome P450 2C19 and 2C9, respectively. To expand and verify this modeling procedure, simulations of R/S-omeprazole and R/S-warfarin clearances after oral administrations in individual marmosets were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling consisting of gut, liver and central compartments.2. Pharmacokinetics of R/S-omeprazole were chirally determined using the previously reported plasma microsamples in this study. The areas under the plasma concentration/time curves (AUC) of R-omeprazole and S-warfarin, but not S-omeprazole and R-warfarin, after oral administrations in the P450 2C19 homozygous mutant group were significantly higher than those in the wild-type group. These modeled hepatic intrinsic clearances were also significantly associated with the marmoset P450 2C19 genotypes. Other parameter values, e.g. absorption rate constants or systemic circulation volumes, were not likely determining factors.3. The reported individual AUC values measured in 4–6 marmosets after oral R-omeprazole and S-warfarin administrations were significantly correlated with the AUC values predicted using the PBPK models after virtual administrations.4. This study indicates that clearances of R-omeprazole, S-warfarin and related medicines associated with polymorphic P450 2C19 in individual marmosets can be simulated using simplified individual PBPK models.

Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice

1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity – attributable to metabolites formed by cytochrome P450 enzymes – but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs.2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice. Following oral administration of pomalidomide (100 mg/kg), plasma concentrations of 7-hydroxypomalidomide and 5-hydroxypomalidomide glucuronide were slightly higher in humanized-liver mice than in control mice.3. Simulations of human plasma concentrations of pomalidomide were achieved with simplified physiologically-based pharmacokinetic models in both groups of mice in accordance with reported pomalidomide concentrations after low dose administration in humans.4. The results indicate that pharmacokinetic profiles of pomalidomide were roughly similar between control mice and humanized-liver mice and that control and humanized-liver mice mediated pomalidomide 5-hydroxylation in vivo. Introducing one aromatic amino group into thalidomide resulted in less species differences in in vivo pharmacokinetics in control and humanized-liver mice.

Human plasma concentrations of cytochrome P450 probe cocktails extrapolated from pharmacokinetics in mice transplanted with human hepatocytes and from pharmacokinetics in common marmosets using physiologically based pharmacokinetic modeling

1. The pharmacokinetic data of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys, dogs and minipigs using simplified physiologically based pharmacokinetic (PBPK) modeling. In this study, the modeling methodology was further adapted to estimate human plasma concentrations of P450 probes based on data from mice transplanted with human hepatocytes or based on data from marmosets.2. Using known species allometric scaling factors, the observed plasma concentrations of caffeine, warfarin, omeprazole, metoprolol, and midazolam in chimeric TK-NOG mice with humanized liver were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in marmosets were also scaled to reported equivalents in humans using in vitro metabolic clearance data.3. Human plasma concentration profiles of the five P450 probes estimated by simplified human PBPK models based on the observed pharmacokinetics in mice with humanized liver and on the reported pharmacokinetics in marmosets were consistent with previously published pharmacokinetic data in Caucasians.4. These results suggest that mice with humanized liver and/or marmosets could be suitable pharmacokinetic models for humans during research into new drugs, especially when used in combination with simple PBPK models.

Human plasma concentrations of five cytochrome P450 probes extrapolated from pharmacokinetics in dogs and minipigs using physiologically based pharmacokinetic modeling

The pharmacokinetics of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys using simplified physiologically based pharmacokinetic (PBPK) modeling. In the current study, despite some species difference in drug clearances, this modeling methodology was adapted to estimate human plasma concentrations of P450 probes based on data from commonly used medium-sized experimental animals, namely dogs and minipigs.Using known species allometric scaling factors and in vitro metabolic clearance data, the observed plasma concentrations of slowly eliminated caffeine and warfarin and rapidly eliminated omeprazole, metoprolol and midazolam in two young dogs were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in minipigs was also scaled to human monitoring equivalents.The human plasma concentration profiles of the five P450 probes estimated by the simplified human PBPK models based on observed/reported pharmacokinetics in dogs/minipigs were consistent with previously published pharmacokinetic data in humans.These results suggest that dogs and minipigs, in addition to monkeys, could be suitable models for humans during research into new drugs, especially when used in combination with simple PBPK models.

Human plasma concentrations of cytochrome P450 probes extrapolated from pharmacokinetics in cynomolgus monkeys using physiologically based pharmacokinetic modeling

1. Cynomolgus monkeys are widely used in preclinical studies as non-human primate species. Pharmacokinetics of human cytochrome P450 probes determined in cynomolgus monkeys after single oral or intravenous administrations were extrapolated to give human plasma concentrations.2. Plasma concentrations of slowly eliminated caffeine and R-/S-warfarin and rapidly eliminated omeprazole and midazolam previously observed in cynomolgus monkeys were scaled to human oral biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Results of the simplified human PBPK models were consistent with reported experimental PK data in humans or with values simulated by a fully constructed population-based simulator (Simcyp).3. Oral administrations of metoprolol and dextromethorphan (human P450 2D probes) in monkeys reportedly yielded plasma concentrations similar to their quantitative detection limits. Consequently, ratios of in vitro hepatic intrinsic clearances of metoprolol and dextromethorphan determined in monkeys and humans were used with simplified PBPK models to extrapolate intravenous PK in monkeys to oral PK in humans.4. These results suggest that cynomolgus monkeys, despite their rapid clearance of some human P450 substrates, could be a suitable model for humans, especially when used in conjunction with simple PBPK models.

Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models

The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice.

Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverseeffect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for 1,4-dioxane in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a developed PBPK model in rats. The model consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for 1,4-dioxane. Evaluation of the rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after daily oral treatment with 1,4-dioxane (500 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of 1,4-dioxane in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. 1,4-Dioxane was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for 1,4-dioxane is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.