A physiologically based pharmacokinetic model for nicotine and cotinine in man.

Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided; chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotine's physiological effects is discussed.     

A physiologically based pharmacokinetic model for nicotine and cotinine in man

Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided;chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotine's physiological effects is discussed.     

Good relationship between saliva cotinine kinetics and plasma cotinine kinetics after smoking one cigarette

This study investigated the relationship between plasma and saliva cotinine kinetics after smoking one cigarette and the relationship between cotinine kinetics and estimated nicotine intake, which was calculated as mouth level exposure (MLE) of nicotine, from smoking two test cigarettes with different nicotine yields. This study was conducted in 16 healthy adult Japanese smokers, who did not have null nor reduced-activity alleles of CYP2A6, with a quasi-randomized crossover design of smoking a low-tar cigarette or a high-tar cigarette. Saliva cotinine showed similar concentration profiles to plasma cotinine, and all of the calculated pharmacokinetic parameters of cotinine showed the same values in plasma and saliva. The C_max and AUC of cotinine showed almost the same dose-responsiveness to the estimated MLE of nicotine between plasma and saliva, but the t_max and t_1/2 of cotinine were not affected by the estimated MLE of nicotine in either plasma or saliva. The results show that saliva cotinine kinetics reflects plasma cotinine kinetics, and measurement of saliva cotinine concentration gives the same information as plasma cotinine on the nicotine intake. Thus, saliva cotinine would be a good and less-invasive exposure marker of cigarette smoke, reflecting the plasma cotinine concentration and kinetics.     

Interspecies prediction of pharmacokinetics and tissue distribution of doxorubicin by physiologically-based pharmacokinetic modeling

The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK) model to describe and predict whole-body disposition of doxorubicin following intravenous administration. The PBPK model was established using previously published data in mice and included 10 tissue compartments: lungs, heart, brain, muscle, kidneys, pancreas, intestine, liver, spleen, adipose tissue, and plasma. Individual tissues were described by either perfusion-limited or permeability-limited models. All parameters were simultaneously estimated and the final model was able to describe murine data with good precision. The model was used for predicting doxorubicin disposition in rats, rabbits, dogs, and humans using interspecies scaling approaches and was qualified using plasma and tissue observed data. Reasonable prediction of the plasma pharmacokinetics and tissue distribution was achieved across all species. In conclusion, the PBPK model developed based on a rich dataset obtained from mice, was able to reasonably predict the disposition of doxorubicin in other preclinical species and humans. Applicability of the model for special populations, such as patients with hepatic impairment, was also demonstrated. The proposed model will be a valuable tool for optimization of exposure profiles of doxorubicin in human patients.     

Physiologically Based Pharmacokinetic Modeling of Drug Disposition in Rat and Human: A Fuzzy Arithmetic Approach

PURPOSE: Probabilistic methods are insufficient for dealing with the vagueness inherent in human judgment of minimal data available during early drug development. We sought to use fuzzy set theory as a basis for quantifying and propagating vague judgment in a physiologically based pharmacokinetic (PBPK) model for diazepam disposition. MATERIALS AND METHODS: First, using diazepam distribution data in rat tissues and fuzzy regression, we estimated fuzzy rat tissue-to-plasma partition coefficients (Kp's). We scaled the coefficients prior to human PBPK modeling. Next, we constructed the fuzzy set of hepatic intrinsic clearance (CLint) by integrating CLint values measured in vitro from human hepatocytes. Finally, we used these parameters, and other physiological and biochemical information, to predict human diazepam disposition. We compared the simulated plasma kinetics with published concentration-time profiles. RESULTS: We successfully identified rat Kp's by fuzzy regression. The predicted rat tissue concentration-time contours enveloped the animal tissue distribution data. For the human PBPK model, the mean in vivo plasma concentrations were contained in the simulated concentration-time envelopes. CONCLUSIONS: We present a novel computational approach for handling information paucity in PBPK models using fuzzy arithmetic. Our methodology can model the vagueness associated with human perception and interpretation of minimal drug discovery data.     

Sexual dimorphism of nicotine metabolism and distribution in the rat. Studies in vivo and in vitro

Interpretation of sex differences in nicotine metabolism and disposition in rats required studies both in vivo and in vitro to provide both metabolic and pharmacokinetic data. In each of four rat strains studied in vitro, males metabolized nicotine faster than did females. In Sprague-Dawley rats, studies of nicotine kinetics after a single iv dose of [14C]nicotine revealed a larger nicotine volume of distribution in females than in males. A prolonged plasma nicotine half-life in females balanced the larger volume of distribution, so that no sex difference appeared in plasma clearance of nicotine. Nevertheless, sex differences in nicotine metabolism are indicated inasmuch as 1) females had lower plasma cotinine concentrations than did males; 2) urinary recoveries of nicotine were higher in female than in male rats; 3) total urinary output of nicotine metabolites was higher in male than female rats, consistent with the enhanced N- and C-oxidation of nicotine by male rats observed in vitro. In female rats the reduced rate of nicotine metabolism, as well as a larger volume of distribution of nicotine, explains in part the reported increased lethality of female compared with male rats.     

Disposition kinetics of nicotine and cotinine enantiomers in rabbits and beagle dogs

The disposition kinetics of nicotine and cotinine enantiomers was determined in rabbits. The clearance of (R)-nicotine was similar to that of (S)-nicotine, but clearance of (R)-cotinine was twice that of (S)-cotinine. Fractional conversions of both enantiomers of nicotine to cotinine were approximately 50%. These results suggest that in rabbits the biotransformation pathways of cotinine, but not nicotine, are influenced by stereochemistry. The disposition kinetics of nicotine enantiomers in beagle dogs was also studied. In dogs, the clearance of (R)-nicotine was slightly greater than the clearance of (S)-nicotine. Methods for the synthesis of (R)-nicotine and (R)-cotinine of high enantiomeric purity and a gas chromatographic method for determination of nicotine enantiomeric purity are described.     

Nicotine metabolism in isolated perfused lung and liver of phenobarbital- and benzoflavone-treated rats

The kinetics of nicotine elimination was investigated in isolated perfused lung and liver of phenobarbital (PB)- and 5,6-benzoflavone (BF)-pretreated rats. The estimated kinetic parameters demonstrated a high nicotine elimination rate in rat lung approaching the capacity of liver when both organs were in an uninduced state. The concentration-time profiles of cotinine as the main metabolite were almost identical for isolated lung and liver. In both organs the cotinine plasma concentrations reached a plateau level after 60 min of perfusion. Pretreatment of rats with 5,6-benzoflavone did not affect the rate of nicotine elimination and cotinine formation either in the lung or in the liver. Phenobarbital treatment, however, induced nicotine clearance in lung approximately 2-fold. This effect is quantitatively lower than the PB-related 8-fold induction of hepatic nicotine elimination observed in a previous study. The present results also indicate that the turnover of cotinine is markedly enhanced after PB induction. The elimination half-lives and clearance values for cotinine as the substrate were approximately 10-fold increased in rat liver after PB pretreatment. Thus, an important contribution of extrahepatic tissues to nicotine metabolism in rats has to be assumed. Moreover, since cotinine elimination is significantly increased after PB induction it is questionable whether cotinine plasma concentrations can further be used as suitable parameter for nicotine consumption.This study was supported by a grant from the German Council on Smoking and Health (Forschungsrat Rauchen und Gesundheit), Hamburg, FRG     

Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1

Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i.e., T-DM1) in rats was characterized using platform PBPK model for antibody. Both the PBPK models were combined via degradation and deconjugation processes. The degradation of conjugated antibody was assumed to be similar to a normal antibody, and the deconjugation of DM1 from T-DM1 in rats was estimated using plasma PK data. The rat PBPK model was translated to humans to predict clinical PK of T-DM1. The translation involved the use of human antibody PBPK model to characterize the PK of conjugated trastuzumab, use of allometric scaling to predict human clearance of DM1 catabolites, and use of monkey PK data to predict deconjugation of DM1 in the clinic. PBPK model-predicted clinical PK profiles were compared with clinically observed data. The PK of total trastuzumab and T-DM1 were predicted reasonably well, and slight systemic deviations were observed for the PK of DM1-containing catabolites. The ADC PBPK model presented here can serve as a platform to develop models for other ADCs.     

Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model.

The aim of this study was to predict the disposition of midazolam in individual surgical patients by physiologically based pharmacokinetic (PBPK) modeling and explore the causes of interindividual variability. Tissue-plasma partition coefficients (k(p)) were scaled from rat to human values by a physiologically realistic four-compartment model for each tissue, incorporating the measured unbound fraction (f(u)) of midazolam in the plasma of each patient. Body composition (lean body mass versus adipose tissue) was then estimated in each patient, and the volume of distribution at steady state (V(dss)) of midazolam was calculated. Total clearance (CL) was calculated from unbound intrinsic CL, f(u), and estimated hepatic blood flow. Curves of midazolam plasma concentration versus time were finally predicted by means of a perfusion-limited PBPK model and compared with measured data. In a first study on 14 young patients undergoing surgery with modest blood loss, V(dss) was predicted with an only 3.4% mean error (range -24-+39%) and a correlation between predicted and measured values of 0.818 (p < 0.001). Scaling of k(p) values by the four-compartment model gave better predictions of V(dss) than scaling using unbound k(p). In the PBPK modeling, the mean +/- standard deviation (SD) prediction error for all data was 9.7 +/- 33%. In a second study with 10 elderly patients undergoing orthopedic surgery, hemodilution and blood loss led to a higher f(u) of midazolam. The PBPK modeling correctly predicted a marked increase in V(dss), a smaller increase in CL, and a prolonged terminal half-life of midazolam, as compared with findings in the first study. Interindividual variation in the disposition of midazolam could thus in part be related to the physiological characteristics of the patients and the f(u) of the drug in their plasma.     

Constant-rate infusion of nicotine and cotinine. I. A physiological pharmacokinetic analysis of the cotinine disposition, and effects on clearance and distribution in the rat

The tissue partition of cotinine was measured by a GC-MS method following a 6-day constant-rate input of nicotine and cotinine to male rats by means of an osmotic minipump. The tissue-to-blood partition coefficients of cotinine were calculated for adipose (0.08), brain (0.48), heart muscle (0.51), following the cotinine infusion. When nicotine was infused the tissue partitioning of cotinine increased by a factor of 2.3-4.9, depending on the tissue sampled. Another group of animals were killed at timed intervals from 10 min to 30 hr, after having received a single intravenous bolus dose of 0.5 mg cotinine, and the washout of cotinine was traced in blood and tissues. A physiological model was used to simulate the disposition of cotinine. Generally, the model-predicted concentrations were consistent with those found experimentally. The fractional uptake of cotinine into various tissues was simulated. Blood, intestinal, and skeletal muscle tissues embodied more than 70% of the total body load of the drug. Clearance (Cl), volume of distribution (Vd), and the biological half-life (t1/2) were calculated both from the infusion study and by fitting a monoexponential model to the iv blood data of the rat. Significant differences were found in the apparent clearance calculated from the single iv bolus dose compared to the constant rate infusion. The volume of distribution was, however, consistent from both studies. The impact of a change in clearance was also simulated.     

Physiologically based pharmacokinetics of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats

The disposition kinetics of Cyclosporine A (CyA) in rat, based on measurement in arterial blood, appeared dose-linear over a wide i.v. dose range (1.2-30 mg/kg). Physiologically based pharmacokinetic (PBPK) analysis, however, demonstrated that this was an apparent observation resulting from counterbalancing nonlinear factors, such as saturable blood and tissue distribution, as well as clearance (CLb). A PBPK model was successfully developed taking into account these multiple nonlinear factors. Tissue distribution was distinctly different among various organs, being best described by either a linear model (muscle, fat; Model 1), one involving instantaneous saturation (lung, heart, bone, skin, thymus; Model 2), noninstantaneous saturation (kidney, spleen, liver, gut; Model 3), or one with saturable efflux (brain; Model 4). Overall, the whole body volume of distribution at steady state for unbound CyA (Vuss) decreased with increasing dose, due at least in part to saturation of tissue-cellular cyclophilin binding. Clearance, essentially hepatic, and described by the well-stirred model, was also adequately characterized by Michaelis-Menten kinetics, Km 0.60 microgram/ml. In model-based simulations, both volume of distribution at steady state (Vss,b) and CLb varied in a similar manner with dose, such that terminal t1/2 remained apparently unchanged; these dose responses were attenuated by saturable blood binding. CyA concentration measured in arterial blood was not always directly proportional to the true exposure, i.e., unbound or target tissue concentrations. The PBPK model not only described comprehensively such complicated PK relationships but also permitted assessment of the sensitivity of individual parameters to variation in local nonlinear kinetics. Using this approach, dose-dependent CyA uptake into brain was shown to be sensitive to both active and passive transport processes, and not merely the affinity of the active (efflux) transporter at the level of the blood-brain barrier.     

Physiologically based pharmacokinetic study on a cyclosporin derivative,SDZ IMM 125

The immunosuppressant, SDZ IMM 125 (IMM), is a derivative of cyclosporin A (CyA). The disposition kinetics of IMM in plasma, blood cells, and various tissues of the rat was characterized by a physiologically based pharmacokinetic (PBPK) model; the model was then applied to predict the disposition kinetics in dog and human. Accumulation of IMM in blood cell is high (equilibrium blood cell/plasma ratio=8), although the kinetics of drug transference between plasma and blood cell is moderately slow, taking approximately 10 min to reach equilibrium, implying a membranelimited distribution into blood cells. A local PBPK model, assuming blood-flow limited distribution and tissue/blood partition coefficient (K _P) data, failed to adequately describe the observed kinetics of distribution, which were slower than predicted. A membrane transport limitation is therefore needed to model dynamic tissue distribution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, and glomerular filtration) of IMM were assessed at steady statein vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, which described closely the IMM concentration-time profiles in arterial blood as well as 14 organs/tissues of the rat after intravenous administration. The model was then scaled up to larger mammals by modifying physiological parameters, tissue distribution and elimination clearances;in vivo enzymatic activity was considered in the scale-up of metabolic clearance. The simulations agreed well with the experimental measurements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric relationship. In addition, the nonlinear increase in maximum blood concentration andAUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitatively link preclinical and clinical data.     

The pharmacokinetics of cotinine in plasma and saliva from non-smoking healthy volunteers

Summary Cotinine is a major metabolite of nicotine in man. Its disposition kinetics has been followed in plasma and saliva from nine nonsmokers, 23 to 56 years of age. Cotinine 5, 10 and 20 mg was given intravenously and orally to each subject, and plasma, saliva and urine samples were collected for 96 h.The kinetics of cotinine was best described by a multi-compartment model with three distinct phases both in plasma and saliva. Regardless of the mode of administration, there was no indication of dose-dependent kinetics. Mean total plasma clearance was 63.8 ml·h^–1·kg^–1 and mean renal clearance was 4.7 ml·h^–1·kg^–1, i.e. only 10% of the dose was excreted unchanged in the urine. The volume of distribution, as calculated from the plasma curves, was slightly greater than the body weight, 1.1 l·kg^–1. The concentration of cotinine was 20 to 40% higher in unstimulated mixed saliva than in plasma during the absorption, distribution and elimination phases. As the clearance and distribution values in saliva were directly proportional to the corresponding values in plasma, similar terminal half-life values were obtained in the two body fluids, 15.5 and 16.8 h for plasma and saliva, respectively.Thus the kinetics of cotinine is linear after intravenous and after oral dosing, and salivary concentrations give the same information about cotinine disposition in the body as do plasma concentrations.     

Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats

A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion‐limited process whereas hepatic clearance and gastrointestinal absorption were described as first‐order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h^?1 kg^?1) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg^?1 i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg ^?1 i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (K_a 0.75 h^?1), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg^?1. Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg^?1) or lower doses (0.2 or 1.24 mg kg^?1) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg^?1 as well as oral doses ranging from 0.2 to 100 mg kg^?1. Published in 2009 by John Wiley & Sons, Ltd.     

Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human

The objectives of the following investigation were (1) development of a physiologically based pharmacokinetic (PBPK) model capable of characterizing the plasma and tissue pharmacokinetics (PK) of nonspecific or antigen specific monoclonal antibodies (mAbs) in wild type, FcRn knockout, tumor bearing and non tumor bearing mice and (2) evaluation of the scale up potential of the model by characterizing the mouse, rat, monkey and human plasma PK of mAbs, simultaneously. A PBPK model containing 15 tissues, a carcass and a tumor compartment was developed by modifying/augmenting previously published PBPK models. Each tissue compartment was subdivided into plasma, blood cell, endothelial, interstitial and cellular sub-compartments. Each tissue was connected through blood and lymph flow to the systemic circulation. Lymph flow was set to a value 500 times lower than plasma flow and vascular reflection coefficients for each tissue were adjusted according to their vascular pore size. In each tissue endothelial space, mAb entered via pinocytosis and the interaction of FcRn with mAb was described by on and off rates. FcRn bound mAb was recycled and unbound mAb was eliminated by a first order process (K(deg)). The PBPK model was simultaneously fit to the following datasets to estimate four system parameters: (1) plasma and tissue PK of nonspecific mAb in wild type mouse with or without simultaneous intravenous immunoglobulin (IVIG) administration, (2) plasma and tissue PK of nonspecific mAb in FcRn knockout mouse, (3) plasma and tissue PK of nonspecific mAb in tumor bearing mouse, (4) plasma and tissue PK of tumor antigen specific mAb in tumor bearing mouse, and (5) plasma PK of mAb in rat, monkey and human. The model was able to characterize all the datasets reasonably well with a common set of parameters. The estimated value of the four system parameters i.e. FcRn concentration (FcRn), rate of pinocytosis per unit endosomal space (CL(up)), K(deg) and the proportionality constant (C_LNLF) between the rate at which antibody transfers from the lymph node compartment to the blood compartment and the plasma flow of the given species, were found to be 4.98E-05 M (CV% = 11.1), 3.66E-02 l/h/l (%CV = 3.48), 42.9 1/h (%CV = 15.7) and 9.1 (CV% > 50). Thus, a platform PBPK model has been developed that can not only simultaneously characterize mAb disposition data obtained from various previously published mouse PBPK models but is also capable of characterizing mAb disposition in various preclinical species and human.     

Pharmacokinetic modeling of manganese in the rat IV: Assessing factors that contribute to brain accumulation during inhalation exposure

A recently published physiologically based pharmacokinetic (PBPK) model successfully accounted for steady-state tissue manganese (Mn) concentration seen with normal dietary intakes and for biphasic, whole-body time-course profiles observed with tracer (54Mn) dosing. In this present study, PBPK modeling was used to evaluate Mn kinetics and brain concentrations in rats exposed to Mn both in their diet and by inhalation. Three published studies were used: (1) rats fed on diets ranging from 2 to 100 ppm, (2) rats on 125 ppm in diet and exposed via inhalation at 0.0 to 3.00 mg Mn/m3 each day for 14 d, and (3) rats to 0.1 or 0.5 mg Mn/m3 for 6 h/d, 5 d/wk over a 90-d period. The original model structure with well-mixed and "deep" compartments for each tissue could not describe rapid increases in tissue concentrations and rapid declines seen in high concentration inhalation studies. A second structure was developed that included (1) saturable, high-affinity binding of Mn in all tissues and (2) asymmetric diffusion from blood into brain (i.e., transport into and out of specific brain regions such as the striatum was described with different diffusion constants). This second model was consistent with liver and striatum experimental data. Preferential increases in some brain regions were predicted for exposures above 0.2 mg/m3 and had a rapid (i.e., 1 or 2 wk) return to steady-state levels. Multi-dose-route PBPK models for Mn based on this alternative model structure can be readily scaled to evaluate tissue Mn kinetics in other species and for human populations. Once validated across test animals, these PBPK models will be useful in tissue-dose based risk assessment with manganese.     

Predicting the effects of 8C2, a monoclonal anti-topotecan antibody, on plasma and tissue disposition of topotecan

We are investigating an inverse targeting strategy to reduce the dose limiting systemic toxicities resultant from intraperitoneal administration of topotecan, a model chemotherapeutic drug. This approach utilizes systemic co-administration of anti-topotecan antibodies to alter the plasma and tissue disposition kinetics of topotecan. To better predict the effects of 8C2, a high affinity anti-topotecan monoclonal antibody, on the pharmacokinetics of topotecan, two mathematical models have been developed and evaluated. Model 1 is a hybrid physiologically based pharmacokinetic (PBPK) model that was created by merging a PBPK model for topotecan with a simple two compartment model of 8C2 pharmacokinetics. Model 2 is a comprehensive PBPK model developed by merging a PBPK model for IgG with a PBPK model for topotecan. To help validate the simulation results from both the models, a tissue distribution experiment was conducted, in which topotecan and 8C2 were co-administered in mice. Experimental and simulated data were compared by calculating the median percent prediction error (%PE) for all tissues. For both models, the median %PE values for all the tissues were less than 100 %, indicating that the predicted values were, on average, less than twofold the observed plasma and tissue topotecan concentrations values. In general model 2 was found to be more predictive of the data set than model 1, as the overall median %PE value for model 2 (%PE = 63) was less than model 1 (%PE = 73).     

Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans

The objective of this study was to use in synergy physiologically based and empirical approaches to estimate the drug-specific input parameters of PBPK models of disposition to simulate the plasma concentration-time profile of epiroprim in human. The estimated input parameters were the tissue:plasma partition coefficients (Pt:p) for distribution and the blood clearance (CL) for the in vivo conditions. Epiroprim represents a challenge for such methods, because it shows large interspecies differences in its pharmacokinetic properties. Two approaches were used to predict the human Pt:p values: the tissue composition model (TCM) and the "Arundel approach" based on the volume of distribution at steady state (Vdss) determined in vivo in the rat. CL in human was predicted by (1) conventional allometric scaling of in vivo animal clearances (CAS), (2) physiologically based direct scaling up of in vitro hepatocyte data (DSU), and (3) allometric scaling of animal intrinsic in vivo blood CL normalized by the ratios of animal:human intrinsic clearances determined in vitro with hepatocytes (NAS). The performance of prediction was assessed by comparing separately the above pharmacokinetic parameters (Vdss estimated from the Pt:p values and blood CL) with the corresponding in vivo data obtained from the plasma kinetic profiles. These input parameters were used in PBPK models, and the resulting plasma concentration-time profiles of epiroprim were compared with those observed in rat and human. Previously to the construction of the human PBPK model, a model for the rat was also developed to gain more confidence on the model structure and assumptions. Overall, using the TCM and the NAS for the parameterization of the distribution and clearance, respectively, the PBPK model gave the more accurate predictions of epiroprim's disposition in human. This study represents therefore an attractive approach, which may potentially help the clinical candidate selection.