Nonclinical assays with JNJ‐54861911, a β‐secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4‐way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ‐54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high‐precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first‐in‐human single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo‐corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9‐18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure–response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ‐54861911 peak plasma concentrations (Cmax) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax, 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ‐54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.

OBJECTIVES:Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ-54861911, were assessed after single and multiple dosing in healthy participants.METHODS:Two randomized, placebo-controlled, double-blind studies were performed using single and multiple ascending JNJ-54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples, up to 36 hours after last dose, were collected to assess the pharmacokinetic and pharmacodynamic (Aβ, sAPPα,β,total levels) profiles of JNJ-54861911.RESULTS:JNJ-54861911 was well-tolerated, adverse events were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles. Plasma- and CSF-Aβ and CSF-sAPPβ were reduced in a dose-dependent manner. Aβ reductions (up to 95%) outlasted exposure to JNJ-54861911. APOE ε4 carrier status and baseline Aβ levels did not influence Aβ/sAPPβ reductions.CONCLUSION:JNJ-54861911, a potent brain-penetrant BACE1 inhibitor, achieved high and stable Aβ reductions after single and multiple dosing in healthy participants.

Reduction of Aβ production by inhibition of Beta-amyloid cleaving enzyme (BACE) BACE1 has been proposed as a promising treatment in Alzheimer’s disease (AD), especially when treating early in the disease process. Subjects with prodromal AD (pAD, CDR 0.5) and subjects asymptomatic at risk for developing Alzheimer’s dementia (ARAD, CDR 0) can be identified by positive biomarker patterns and are referenced here as early Alzheimer’s disease subjects. JNJ-54861911 has been described as a potent oral BACE inhibitor1. We report the results from the first clinical trial in biomarker-identified subjects with early AD, which show strong and dose-dependent reductions of Aβ in plasma and CSF. After a screening funnel, including general health, cognition, brain MRI and CSF biomarkers, pAD and ARAD aged 50 to 90 were identified. Eligible subjects were randomized (1:1:1;) to receive Placebo, 10mg or 50mg JNJ-54861911 once daily for a 4-week treatment period, tolerability, plasma and CSF pharmacokinetics (PK) and pharmacodynamics (PD) (including Aβ1-37, 1-38, 1-40 and 1-42, as well as sAPPα and sAPPβ) were assessed. To account for inter-subject variability of baseline Aβ and sAPP levels, reductions were expressed as percentage change from predose levels. 424 subjects were screened and for 112 of these subjects biomarker information was collected. 30% of subjects with CDR 0 and 70% of subjects with CDR 0.5 were biomarker-positive, identifying 45 eligible subjects in total. Overall, treatment was safe and well tolerated. The 4 week treatment resulted in strong Aβ reductions in plasma (10mg: 83%; 50mg: 93%) and CSF (10mg: 67%; 50mg: 90%). The changes observed in CSF for all 4 Aβ peptides were consistent (Fig 1). sAPPβ peptides decreased while sAPPα increased up to 2-fold and no change was observed in total sAPP.

Metabotropic glutamate receptor-2 positive allosteric modulator, JNJ-40411813 (ADX71149), was characterised for clinical effects in healthy volunteers in two phase-1 studies. In study 1, healthy men received 50-, 100-, 150- or 225 mg and women received 100 mg JNJ-40411813 (n=6, each cohort) or placebo (n=2, each cohort) twice daily for seven days; smoking men (n=30) received placebo twice daily on days 1-7, 100 mg JNJ-40411813 (n=20) or placebo (n=10) on days 8-14. In study 2, healthy men received intravenous 0.005 mg/kg S(+) ketamine over 60 min at 3 (n=24; cohort 1), 12 h (n=8; cohort 3), and 24 h (n=8; cohort 2) after a single oral dose of 500 mg JNJ-40411813 or placebo. The pharmacokinetics and effects of JNJ-40411813 on cognition and subjective awareness were evaluated. Plasma JNJ-40411813 exposure was dose-dependent, t max ranged from 3-4 h and t 1/2 19.4-34.2 h across the dose levels. JNJ-40411813 significantly (p=0.02) reduced continuity of attention score (150 mg dose) and ameliorated smoking withdrawal-induced changes in power of attention and quality of episodic memory versus placebo. A modest reduction in alertness was observed at 150-225 mg doses, JNJ-40411813 (500 mg) reduced S(+) ketamine-induced negative symptoms by approximately 43% and 30% in cohorts 1 and 3, respectively. JNJ-40411813 was generally well-tolerated.

In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood-brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (Kp,uu,brain), intracellular accumulation (Kp,uu,cell), and binding and distribution in the brain (Vu,brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties.

The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.

V. Sinha, I. Loryan, P. De Boer, X. Langlois, C. Mackie, A. Van Peer, W. Drinkenburg, A. Vermeulen, D. Heald, M. Hammarlund-Udenaes Janssen Research and Development, Clinical Pharmacology, Beerse, Belgium Uppsala University, Translational PKPD Group Department of Pharmaceutical Biosciences, Uppsala, Sweden Janssen Research and Development, Experimental Medicine, Beerse, Belgium Janssen Research and Development, Neurosciences, Beerse, Belgium Janssen Research and Development, Pharmaceutical Development and Manufacturing Sciences, Beerse, Belgium Janssen Research and Development, Model Based Drug Development, Beerse, Belgium Janssen Research and Development, Clinical Pharmacology, Titusville, USA

SUMMARY A novel CNS drug candidate demonstrated useful first-in-human safety properties but was challenged by a short half-life and high Cmax-Cmin plasma level variations. A sustained released formulation was assessed. Drug absorption in the distal bowel and ascending colon was found to be equivalent to that in the proximal small intestine. A swellable matrix tablet based on HPMC was generated and optimized such that drug release over a 6 or 12 h time frame could be achieve in vitro. Clinical assessments of these formulation suggested useful biopharmaceutical properties with prolonged absorption. INTRODUCTION In cases of drugs with short plasma half-lives or narrow therapeutic windows, the ability to sustain drug release subsequent to oral dosing could not only optimize the therapeutic index of the drug but also improve patient compliance. A number of dosage form concepts have been designed to address these needs including matrixforming tablets in which drug release is controlled by diffusion and erosion. These systems can often provide for the release characteristic required, are simple to manufacture and scale, are often very cost-effective and make use of well characterized, generally regarded as safe (GRAS) excipients. These systems can retard drug release delaying it to more distal portions of the GI tract meaning that one prerequisite for a useful system is that the drug gives good permeability in the distal small bowel and colon. Compound A is a BCS Class I drug candidate which has been successfully tested in man both as a solution and simple (immediate release) tablet. Biological half-life data suggested that a sustained release formulation might add value. In order to assess the feasibility of a controlled release dosage form, a study was completed wherein drug uptake was assessed when drug was administered in the distal small intestine or ascending colon. HPMC-based matrix tablet were then designed and prototypes generated using in vitro drug release. Selected matrix tablets were then assessed in a clinical trial to evaluate human pharmacokinetics. EXPERIMENTAL METHODS Compound A was obtained from Janssen Pharmaceutica, Beerse, Belgium and was characterized with a purity >98%. Matrix formulation were generated using HPMC at two different molecular weights (6500 and 100000), HPC and drug dried waxy maize starch. Tablets were designed to contain 40 mg eq of Compound A with a total tablet weight of approximately 350 mg. Four dissolution paradigms were applied to test the concepts generate all of which involved a USP II apparatus, thermostated to 37 o C and with a paddle speed of 75 rpm and a total media volume of 900 mL. The four media tested included (one phase) 0.01 N HCl, 0.05 M pH 6.8 phosphate buffer, (two phase) (1 h) 0,01 N HCl then (23 h) pH 6.8 phosphate buffer and (1 h) 0.01 N HCl (250 mL) and (23 h) Fessif (1000 mL). Regional intestinal absorption studies were completed in man using the Enterion® capsule in which the drug was administered as a solution in aqueous 2hydroxypropyl-cyclodextrin to either the distal small intestine or ascending colon and compared to an oral solution delivered po. Subsequently, matrix tablets based on a fast and slow release pattern were also assessed in man compared with a simple immediate release (IR) tablet. The matrix tablets contained 40 mg eq of Compound A and the IR tablets 10 mg eq (two IR tablets were dosed in the clinical evaluation). All studies were GCP-compliant with full informed consent and conducted under relevant national and international law and guidelines. The clinical investigations were completed as open label trials using 12 and 24 healthy subjects (male, Caucasians between age 18 and 55 years and within 20% of their ideal body weight) for the regional absorption and matrix tablet studies, repsectively. Each subject received a test formulation as described (either fasted or after a high fat breakfast). Blood was sampled at 0, 1, 2, 3, 4, 5, 6, 8 and 24 h after dosing and analysed using a fully validated HPLC analytical method. Pharmacokinetic parameters including Tmax, Cmax and AUC24h were determined by standard model-independent methods using actual times of blood sampling. RESULTS AND DISCUSSION Drug absorption was assessed using the Enterion® capsule 1 which was loaded with a solution of Compound A in a cyclodextrin vehicle with the drug administered either to the distal small intestine (at doses of 2 and 10 mg) or in the ascending colon (at a dose of 10 mg). This was compared to an oral dose of the 10 mg cyclodextrin solution. The AUC of the drug administered to the distal small bowel and ascending colon was similar to that of the orally dosed medication. The Cmax was reduced by approximately 30% when the oral solution was compared to the colon however Cmax were comparable when oral and distal small bowel dosing were assessed. These data suggested that a controlled release dosage form may be feasible. Controlled release tablet was considered with the following properties including a total dose of 40 mg and a drug release window of between 6 and 12 h. A significant design concern related to the sensitivity of solubility on pH which decreased rapidly with increasing pH. Based on drug release from a swellable matrix, this may negatively impact the release mechanism as the tablet transitions from the stomach to the intestine. To proactively address this, solubility differences as a function of pH were attenuated by adding 2-hydroxypropyl-cyclodextrin to the matrix such that diffusion would continue to drive drug release over the life time of the matrix. 2 The excipient space of the tablet therefore included the active API, HP CD and three polymers including HPMC at various molecular weights/viscosity grads, HPC and drum dried waxy maize starch. Screening experiments found that the optimal amount of the matrix-forming polymers was ~30% with little change in drug release as this percent changes from 20 to 40%. In the case of HP CD, concentrations between 20 and 50% yielded similar release profiles however excluding the cyclodextrin generated systems that poorly released drug at pH 6.8 and which were also highly dependent on ionic strength of the release media. Two prototype, matrix-based tablets were therefore designed based on high and low viscosity HPMC. A “fast” releasing matrix was prepared based on HPMC 6500 mPa.s and a slow releasing tablet based on 100000 mPa.s material. Four dissolution assessments were completed with the two matrix tablets as is illustrated in Figures 1 and 2. Figure 1. Drug Release Dynamics for a “Fast” system in Four Media including 0.01N HCl (green), 0,05 M pH 6.8 Phosphate Buffer (blue), 1h 0.01 N HCl + 23 h 0.05 M, pH 6.8 Phosphate Buffer (red) and 1 h 0.01 N HCl + 23 h Fessif (black, dotted line).. Figure 2. Drug Release Dynamics for a “Slow” system in Four Media including 0.01N HCl (green), 0,05 M pH 6.8 Phosphate Buffer (blue), 1h 0.01 N HCl + 23 h 0.05 M, pH 6.8 Phosphate Buffer (red) and 1 h 0.01 N HCl + 23 h Fessif (black, dotted line). These tablets were then examined in a clinical assessment under fasted conditions and compared to the simple IR tablets. Two IR tablets (10 mg eq. of Compound A per tablet) versus 40 mg eq in the controlled release tablets were evaluated (Table I). Table I. Pharmacokinetic Parameters in Man (Fasted) Associated with Compound A Dosing as Either an Immediate Release Tablet, a Slow Matrix and a Fast Matrix Tablet

To predict human pharmacokinetics such as the clearance and the plasma concentration profile of a new compound, many animal-based methods have been used in the past. They are typically based on animal information on the compound of interest. This translational step is crucial in pharmaceutical development since it is used to estimate the human pharmacokinetic (PK) parameters and the starting dose for the first-in-human study. Among the currently used methods, allometric scaling is probably one of the oldest and simplest, because it uses essentially body weight and brain weight to correct for species in the prediction of the human PK measures. The assumption that body weight can be used as a surrogate for an animal species is key in the current methods. It also assumes that there is a general biological process that holds in mammal species such as mice, rats, rabbits, monkeys, dogs, and man. Brain weight, lifespan, and a number of other corrections are often successfully used to fine-tune the relationship between clearance and body weight. This research project investigates the variability that goes along with current practice and suggests a meta-analytical approach to control for the variability of human unbound clearance. The new approach also establishes a model linking the animal data to human data using historical data in a way that has not been done before.

ABSTRACTPurposeA case example is presented in which the physiologically based modeling approach has been used to model the absorption of a lipophilic BCS Class II compound predominantly metabolized by CYP3A4, and to assess the interplay of absorption related parameters with the drug–drug interaction (DDI) potential.MethodsThe PBPK model was built in the rat using Gastroplus® to study the absorption characteristics of the compound. Subsequently relevant model parameters were used to predict the non‐linear human PK observed during first‐in‐human study after optimizing the absorption model for colonic absorption, bile micelle solubilization and unbound fraction in gut enterocytes (fugut) using SIMCYP® simulator. The model fitted absorption parameters were then used to assess the drug–drug interaction (DDI) potential of the test compound when administered along with multiple doses of a potent CYP 3A4 inhibitor, ketoconazole. The impact of fugut in the extent of DDI was assessed using parameter sensitivity analysis.Results and ConclusionsAfter optimizing the preclinical model and taking into consideration bile micelle solubilization and colonic absorption, the non‐linear pharmacokinetics of the test compound was satisfactorily predicted in man. Sensitivity analysis performed with the absorption parameter fugut indicated that it could be an important parameter in predicting oral absorption. In addition, DDI simulations using SIMCYP® suggest that Cmax and AUC ratios may also be sensitive to the fugut input in the model. Since fugut cannot be measured experimentally, sensitivity analysis may help in assessing the importance of fugut in human PK and DDI prediction using SIMCYP®. Copyright © 2012 John Wiley & Sons, Ltd.

Background: It is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better patient compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (C max ), area under the plasma concentration-time curve (AUC) and a suitable half-life (t 1/2 ). The C max and t 1/2 following oral drug administration are functions of the oral clearance (CL/F) and apparent volume of distribution during the terminal phase by the oral route (V z /F), each of which may be predicted and combined to estimate C max and t 1/2 . Allometric scaling is a widely used methodology in the pharmaceutical industry to predict human pharmacokinetic parameters such as clearance and volume of distribution. In our previous published work, we have evaluated the use of allometry for prediction of CL/F and AUC. In this paper we describe the evaluation of different allometric scaling approaches for the prediction of C max , V z /F and t 1/2 after oral drug administration in man. Methods: Twenty-nine compounds developed at Janssen Research and Development (a division of Janssen Pharmaceutica NV), covering a wide range of physicochemical and pharmacokinetic properties, were selected. The C max following oral dosing of a compound was predicted using (i) simple allometry alone; (ii) simple allometry along with correction factors such as plasma protein binding (PPB), maximum life-span potential or brain weight (reverse rule of exponents, unbound C max approach); and (iii) an indirect approach using allometrically predicted CL/F and V z /F and absorption rate constant (k a ). The k a was estimated from (i) in vivo pharmacokinetic experiments in preclinical species; and (ii) predicted effective permeability in man (P eff ), using a Caco-2 permeability assay. The V z /F was predicted using allometric scaling with or without PPB correction. The t 1/2 was estimated from the allometrically predicted parameters CL/F and V z /F. Predictions were deemed adequate when errors were within a 2-fold range. Results: C max and t 1/2 could be predicted within a 2-fold error range for 59% and 66% of the tested compounds, respectively, using allometrically predicted CL/F and V z /F. The best predictions for C max were obtained when k a values were calculated from the Caco-2 permeability assay. The V z /F was predicted within a 2-fold error range for 72% of compounds when PPB correction was applied as the correction factor for scaling. Conclusions: We conclude that (i) C max and t 1/2 are best predicted by indirect scaling approaches (using allometrically predicted CL/F and V z /F and accounting for k a derived from permeability assay); and (ii) the PPB is an important correction factor for the prediction of V z /F by using allometric scaling. Furthermore, additional work is warranted to understand the mechanisms governing the processes underlying determination of C max so that the empirical approaches can be fine-tuned further.

The objective of this study was to evaluate the performance of various empirical, semimechanistic and mechanistic methodologies with and without protein binding corrections for the prediction of human volume of distribution at steady state (Vss). PhRMA member companies contributed a set of blinded data from preclinical and clinical studies, and 18 drugs with intravenous clinical pharmacokinetics (PK) data were available for the analysis. In vivo and in vitro preclinical data were used to predict Vss by 24 different methods. Various statistical and outlier techniques were employed to assess the predictability of each method. There was not simply one method that predicts Vss accurately for all compounds. Across methods, the maximum success rate in predicting human Vss was 100%, 94%, and 78% of the compounds with predictions falling within tenfold, threefold, and twofold error, respectively, of the observed Vss. Generally, the methods that made use of in vivo preclinical data were more predictive than those methods that relied solely on in vitro data. However, for many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. It is recommended to initially use the in vitro tissue composition‐based equations to predict Vss in preclinical species and humans, putting the assumptions and compound properties into context. As in vivo data become available, these predictions should be reassessed and rationalized to indicate the level of confidence (uncertainty) in the human Vss prediction. The top three methods that perform strongly at integrating in vivo data in this way were the Øie–Tozer, the rat –dog–human proportionality equation, and the lumped‐PBPK approach. Overall, the scientific benefit of this study was to obtain greater characterization of predictions of human Vss from several methods available in the literature. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4074–4089, 2011

The objective of this study was to evaluate the performance of the Wajima allometry (Css‐MRT) approach published in the literature, which is used to predict the human plasma concentration–time profiles from a scaling of preclinical species data. A diverse and blinded dataset of 108 compounds from PhRMA member companies was used in this evaluation. The human intravenous (i.v.) and oral (p.o.) pharmacokinetics (PK) data were available for 18 and 107 drugs, respectively. Three different scenarios were adopted for prediction of human PK profiles. In the first scenario, human clearance (CL) and steady‐state volume of distribution (Vss) were predicted by unbound fraction corrected intercept method (FCIM) and Øie–Tozer (OT) approaches, respectively. Quantitative structure activity relationship (QSAR)–based approaches (TSrat‐dog) based on compound descriptors together with rat and dog data were utilized in the second scenario. Finally, in the third scenario, CL and Vss were predicted using the FCIM and Jansson approaches, respectively. For the prediction of oral pharmacokinetics, the human bioavailability and absorption rate constant were assumed as the average of preclinical species. Various statistical techniques were used for assessing the accuracy of the simulation scenarios. The human CL and Vss were predicted within a threefold error range for about 75% of the i.v. drugs. However, the accuracy in predicting key p.o. PK parameters appeared to be lower with only 58% of simulations falling within threefold of observed parameters. The overall ability of the Css‐MRT approach to predict the curve shape of the profile was in general poor and ranged between low to medium level of confidence for most of the predictions based on the selected criteria. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4111–4126, 2011

The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUCp.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of binding assumptions were much less accurate. The results for prediction of AUCp.o. were consistent with i.v. CL. However, the greatest challenge to successful prediction of human p.o. CL is the estimate of F in human. Overall, the results of this initiative confirmed predictive performance of common methodologies used to predict human CL.

The objective of this study is to assess the effectiveness of physiologically based pharmacokinetic (PBPK) models for simulating human plasma concentration–time profiles for the unique drug dataset of blinded data that has been assembled as part of a Pharmaceutical Research and Manufacturers of America initiative. Combinations of absorption, distribution, and clearance models were tested with a PBPK approach that has been developed from published equations. An assessment of the quality of the model predictions was made on the basis of the shape of the plasma time courses and related parameters. Up to 69% of the simulations of plasma time courses made in human demonstrated a medium to high degree of accuracy for intravenous pharmacokinetics, whereas this number decreased to 23% after oral administration based on the selected criteria. The simulations resulted in a general underestimation of drug exposure (Cmax and AUC0‐t). The explanations for this underestimation are diverse. Therefore, in general it may be due to underprediction of absorption parameters and/or overprediction of distribution or oral first‐pass. The implications of compound properties are demonstrated. The PBPK approach based on in vitro‐input data was as accurate as the approach based on in vivo data. Overall, the scientific benefit of this modeling study was to obtain more extensive characterization of predictions of human PK from PBPK methods. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4127–4157, 2011