Thoughtflow: Standards and Tools for Provenance Capture and Workflow Definition to Support Model-Informed Drug Discovery and Development.

Pharmacometric analyses are complex and multifactorial. It is essential to check, track, and document the vast amounts of data and metadata that are generated during these analyses (and the relationships between them) in order to comply with regulations, support quality control, auditing, and reporting. It is, however, challenging, tedious, error-prone, and time-consuming, and diverts pharmacometricians from the more useful business of doing science. Automating this process would save time, reduce transcriptional errors, support the retention and transfer of knowledge, encourage good practice, and help ensure that pharmacometric analyses appropriately impact decisions. The ability to document, communicate, and reconstruct a complete pharmacometric analysis using an open standard would have considerable benefits. In this article, the Innovative Medicines Initiative (IMI) Drug Disease Model Resources (DDMoRe) consortium proposes a set of standards to facilitate the capture, storage, and reporting of knowledge (including assumptions and decisions) in the context of model-informed drug discovery and development (MID3), as well as to support reproducibility: "Thoughtflow." A prototype software implementation is provided.

Model-Based Approach for Optimizing Study Design and Clinical Drug Performances of Extended-Release Formulations of Methylphenidate for the Treatment of ADHD.

Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: 1) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; 2) provide PK endpoint metrics for comparing ER formulations; 3) define criteria for optimizing development of ER formulations using a convolution-based model linking in vitro release, in vivo release, and hour-by-hour behavioral ratings of ADHD symptoms; and 4) define an optimized trial design for assessing the activity of MPH in pediatric populations. The convolution-based model accurately described the complex PK profiles of a variety of ER MPH products, providing a natural framework for establishing an in vitro/in vivo correlation and for defining criteria for assessing comparative bioequivalence of MPH ER products.

Use of Longitudinal Dose-Response Modeling to Support the Efficacy and Tolerability of Alitretinoin in Severe Refractory Chronic Hand Eczema (CHE).

Longitudinal dose-response analyses of alitretinoin (an investigational agent in the US) were conducted to supplement results from phase III studies in severe, refractory chronic hand eczema, with objectives to address several outstanding development issues (e.g., optimal dose, possible factors affecting efficacy and/or tolerability). Models were fitted to the physicians' global assessment score and triglycerides over time. Five hundred trials were simulated to evaluate the relevance of findings. Analyses clarified that the optimal dose of alitretinoin was 30 mg once daily, where response rates were ∼10% over placebo at 12 weeks and increased by 5-7% over placebo for every 4 weeks thereafter, for up to 24 weeks. Elderly subjects had higher magnitudes of efficacy and an increased probability of high triglycerides. Results from analyses sufficiently addressed the development issues, thereby adding to the weight of evidence supporting the efficacy and safety of alitretinoin in the treatment of severe, refractory chronic hand eczema.

A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-released formulation of risperidone.

RBP-7000 is a sustained-release (once-monthly injection for subcutaneous administration) formulation of risperidone using the ATRIGEL® Delivery System, developed for treatment of schizophrenia to address compliance issues associated with oral administration. The objective of this analysis was to report the results of a population pharmacokinetic analysis and to describe the relationship between risperidone and 9-hydroxyrisperidone levels with dopamine (DA) D2-receptor occupancy, prolactin levels, and adverse events using data collected in 45 clinically stable schizophrenic patients receiving RBP-7000 in single ascending doses (risperidone) of 60, 90, and 120 mg. The population PK model accounted for an initial peak, a delayed and slow delivery, the disposition of risperidone, and the conversion of risperidone to 9-hydroxyrisperidone. BMI was a covariate affecting absorption of risperidone and ultimately formation of 9-hydroxyrisperidone. A logistic analysis indicated a correlation between the increase in Active Moiety (risperidone + 9-OH-risperidone) exposure (Cmax ) and the probability of observing GI disorders. An Emax population PK/prolactin model best described the relationship between the circulating Active Moiety and the serum prolactin levels. Gender was a significant covariate associated with Emax . These data provided a comprehensive characterization of the relationship between circulating Active Moiety and the efficacy/safety profile of RBP-7000 in clinically stable schizophrenic patients.

Joint modeling of efficacy, dropout, and tolerability in flexible-dose trials: a case study in depression.

Many difficulties may arise during the modeling of the time course of Hamilton Rating Scale for Depression (HAM D)scores in clinical trials for the evaluation of antidepressant drugs: (i) flexible designs, used to increase the chance of selecting more efficacious doses, (ii) dropout events, and (iii) adverse effects related to the experimental compound.It is crucial to take into account all these factors when designing an appropriate model of the HAM D time course and to obtain a realistic description of the dropout process. In this work, we propose an integrated approach to the modeling of a double-blind, flexible-dose, placebo-controlled, phase II depression trial that comprises response,tolerability, and dropout. We investigate three different dropout mechanisms in terms of informativeness. Goodness of fit is quantitatively assessed with respect to response (HAM D score) and dropout data. We show that dropout is a complex phenomenon that may be influenced by HAM D evolution, dose changes, and occurrence of drug-related adverse effects.

A novel metric to assess the clinical utility of a drug in the presence of efficacy and dropout information.

The fact that there are high dropout rates in clinical trials of antipsychotic medications raises critical questions regarding the most appropriate method of designing new trials, analyzing efficacy data, and evaluating the clinical utility (CU) of novel treatments. In this article, we consider the use of a model-based approach to define an integrated CU criterion for better characterizing the clinical response to a treatment, for optimizing proof-of-concept trials, and for providing differentiating criteria for novel medications when complete information is not available.

From trial and error to trial simulation III: a framework for interim analysis in efficacy trials with antidepressant drugs.

Clinical trials with antidepressant drugs often fail to detect drug effect, even with drugs that are known to be efficacious. In a previous publication, we showed that a model-based approach is required to address some of the existing challenges in the design of clinical trial protocols. Here, we illustrate how the implementation of an interim analysis (IA) may help to identify studies that are headed for failure, early in the trial before completion of treatment. In contrast to traditional IA procedures, an adaptive Bayesian approach is proposed to optimize the timing of analysis and decision criteria for futility and efficacy, taking into account enrollment rate and treatment response at intermediate visits in the trial. Validation procedures involving re-enrollment of patients confirmed the performance of the method. Our findings reveal that optimization of the timing and decision criteria at the interim stage is critical for the accuracy of the conclusions about treatment efficacy or futility.

A new population-enrichment strategy to improve efficiency of placebo-controlled clinical trials of antidepressant drugs.

The rate-limiting factor in the discovery of novel antidepressants is the inefficient methodology of traditional multicenter randomized clinical trials (RCTs). We applied a model-based approach to a large clinical database (five RCTs in major depressive disorder (MDD), involving 1,837 patients from 124 recruitment centers) with two objectives: (i) to learn about the role of center-specific placebo response in RCT failure and (ii) to apply what is learned to improve the efficiency of RCTs by enhancing the detection of treatment effect (TE). Sensitivity analysis indicated that center-specific placebo response was the most relevant predictor of RCT failure. To reduce the statistical "noise" generated by centers with nonplausible, excessively high/low placebo responses, we developed an enrichment-window strategy. Clinical trial simulation was used to assess the enrichment strategy applied before the standard statistical analysis, resulting in an overall reduction in failure of RCTs from ~50 to ~10%.

Adaptive-optimal design in PET occupancy studies.

Positron emission tomography (PET) is an imaging technique that is used to investigate ligand-receptor binding in the living brain and to determine the time course of plasma concentration/receptor occupancy (RO). The purpose of this work was to demonstrate the added value of an adaptive-optimal design for PET scan timings and dose selection over traditional study designs involving fixed or educated selections of timings and doses. A k(on)-k(off) model relating plasma concentration to PET data was applied to generate the simulated data. Optimization was performed on scanning timings and doses using the D-optimality criterion. Optimal designs as applied to scanning timings provided unbiased estimates and improved the accuracy of results relative to those of fixed and educated designs. Optimization of both timings and dose provided improvements in accuracy and precision when the initial dose selection was noninformative regarding the time course of RO. These results indicate that adaptive-optimal designs can provide an efficient experimental design for RO studies using PET, by minimizing the number of subjects required and maximizing information related to the plasma concentration-RO relationship.

Model-based approach and signal detection theory to evaluate the performance of recruitment centers in clinical trials with antidepressant drugs.

The objective of this study was to characterize the performance of each recruitment center in multicenter clinical trials and to provide criteria to discriminate between informative and noninformative centers using the signal detection approach. Data were derived from the GlaxoSmithKline Clinical Trial database on paroxetine and bupropion, totaling 4,016 subjects with major depressive disorders (MDDs) across nine trials. The probability of observing clinically relevant difference of active treatment from placebo was estimated in each center as a function of the placebo Hamilton Depression Rating Scale (HAMD-17) scores at baseline and at week 8. The center's performance was defined using the posterior probability (PP) of detecting a signal of a treatment effect. Only 60% of the centers were classified as informative. In these centers, the signal of treatment effect increased by approximately 80%. The signal detection approach appears to be a useful methodology to rank the performance of recruitment centers and to classify each center as informative or not in respect of detection of clinically relevant signals of efficacy. A further analysis indicated that a minimal sample of four subjects is required in order to predict the typical placebo response in each center.

Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients.

The (123)I-IBZM SPECT measured D(2) receptor occupancy (D(2)RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D(2) receptor occupancy (D( 2)RO) and plasma concentration (C(P)) in stabilized schizophrenic patients on clinically relevant doses using (123)I-IBZM SPECT; 2) To investigate the time course of AP-induced D(2)RO and corresponding C(P). Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D( 2)RO and C(P) were measured over time following a sparse-sampling experimental design, and individual PK and D(2)RO-time profiles were estimated using a population approach. Observed striatal D(2)RO and C(P) ranges were 28-75% and 9.4-60.5 ng/mL for risperidone, 22-84% and 8.6-89.5 ng/mL for olanzapine, 5-53% and 41.6-818.2 ng/mL for clozapine and 0-64% and 37.9-719.6 ng/mL for quetiapine. A PK-D(2)RO relationship was found for the four APs. D(2)RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D(2)RO and C(P) at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D(2)RO below 65%. D(2)RO patterns over time differ between AP. These results should be considered for accurate interpretation of D(2)RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.

Population pharmacokinetics of mycophenolic acid in kidney transplant pediatric and adolescent patients.

Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.

Pharmacokinetic-pharmacodynamic modelling of recombinant human erythropoietin in athletes.

The aim of this study was to develop a pharmacokinetic model that takes into account the negative feedback loop of endogenous erythropoietin production observed after repeated recombinant human erythropoietin administration. A pharmacodynamic data analysis was performed using the changes in i) reticulocyte count, ii) serum levels of soluble transferrin receptors, and iii) soluble transferrin receptors/serum proteins ratio as an index of the therapeutic effect of the hormone. Nine athletes were included in the study; they received repeated subcutaneous administrations (50 IU x kg(-1) per day) of recombinant human erythropoietin. The mean half-life of the terminal part of the curve was 35.5 h, and the total clearance was 17 ml x h(-1) x kg(-1). The total clearance was about two times higher in athletes than in untrained subjects (5.5 - 7.5 ml x h(-1) x kg(-1)) and the half-life period of plasma erythropoietin after subcutaneous administration was five times longer compared to intravenous administration (4 to 7 h). Thus, after subcutaneous administration, the terminal part of the curve should correspond to the absorption phase, instead of to the elimination phase (flip-flop phenomenon). The pharmacodynamic relationship based on a sigmoid Emax model can be reasonably used to relate the changes observed in the markers to recombinant human erythropoietin administration. Recombinant human erythropoietin induces a delayed increase in reticulocytosis and in soluble transferrin receptor levels. In comparison with baseline, the increase of these markers became significant from the third and the tenth day after the initial administration of the hormone, respectively. These results were in accordance with the equilibration delay computed from the pharmacokinetic-pharmacodynamic data modelling (half-life of 25.7 h and 10 days, respectively). The recombinant hormone was well tolerated during this study.

An application of nonlinear mixed-effects modeling to pharmacokinetic data exhibiting nonlinear and time-dependent behavior.

A population pharmacokinetic (PK) analysis was performed on plasma concentrations of GW468816 observed in dogs after 10, 25, and 50 mg/kg/day repeated intravenous administration. A two-compartment model was fitted to the concentration-time data using the NONMEM program. Dose and time dependency of PK parameters was investigated. Selection of the best model was performed using a stepwise approach. A Michaelis-Menten elimination process was used to describe the PK dose dependency, whereas an interoccasion variability on V(m) (the maximum elimination rate of the Michaelis-Menten elimination process) was initially used to describe the time dependency of the PKs, and the final model included an exponential function to account for time variance on V(m). The K(m) value of the final model was 29.6 microg/mL, whereas V(m) was estimated to vary with time from 4.97 microg/h/kg at day 1 to a maximum mean value of 9.64 microg/h/kg at day 14. This approach can be applied to either rich or sparse data leading to estimates of individual parameters by using Bayesian feedback. The overall information obtained can be used to interpret toxicological and pharmacological endpoints and integrated with further in vitro-in vivo studies to supply a comprehensive PK behavior before the first time in human studies.

Pharmacokinetic-pharmacodynamic modelling of recombinant human erythropoietin in athletes : a population approach.

OBJECTIVE: To develop a pharmacokinetic model able to take into account the negative feedback loop of endogenous erythropoietin production observed after repeated administration of recombinant human erythropoietin (rHuEPO), and to propose a pharmacokinetic-pharmacodynamic model capable of assessing and quantifying the relationship between changes in: (i) serum soluble transferrin receptor (sTfR) levels, (ii) reticulocyte haematocrit (RetHct), and (iii) percentage macrocytes (%Macro) secondary to repeated administration of rHuEPO. SUBJECTS AND METHODS: Eighteen trained athletes (three females and 15 males) participated in this study. They received subcutaneous injections of rHuEPO-α 50 U/kg bodyweight for 26 days (days 1, 3, 5, 9, 10, 12, 15, 17, 19, 22, 24 and 26) with iron supplementation. Venous blood samples were collected before, during and after rHuEPO treatment for determination of serum erythropoietin concentrations, haematological parameters (RetHct, %Macro) and sTfR levels. Population pharmacokinetic-pharmacodynamic calculations were performed using NONMEM® software. RESULTS: The serum erythropoietin concentration-time profile was compatible with a one-compartment open model and first-order input rate. The mean half-lives calculated from the first and the terminal log-linear parts of the curves were 5.2 and 35.8 hours, respectively. After subcutaneous administration of rHuEPO, the terminal part of the curve should correspond to the absorption rather than the elimination phase ('flip-flop' phenomenon). The total clearance divided by bio-availability was 4.33 L/h. The pharmacodynamic relationship based on a sigmoid E(max) model can be reasonably used to relate changes observed in haematological and biochemical markers after rHuEPO administration to changes in serum erythropoietin concentrations. rHuEPO induces a delayed increase in sTfR levels, RetHct and %Macro. The half-life (t1/2) k(0) (equilibration delay) values were 10.2 days for sTfR, 2 days for RetHct and 10.2 days for %Macro. The pharmaco-kinetic-pharmacodynamic approach developed in this study allowed below-base-line decreases in RetHct levels (i.e. from days 10-26 after the end of rHuEPO treatment) to be taken into account. A negative-feedback loop of red blood cell production further to high haemoglobin and haematocrit values could explain this decrease. CONCLUSIONS: The approach described here may provide an additional tool in the war against drug abuse by athletes; indeed, the model could be useful for simulating pharmacokinetic-pharmacodynamic relationships according to different rHuEPO dosage schedules.

Population pharmacokinetic-pharmacodynamic model of craving in an enforced smoking cessation population: indirect response and probabilistic modeling.

PURPOSE: A population pharmacokinetic-pharmacodynamic model accounting for placebo effect was used to relate nicotine concentration and enforced smoking cessation craving score measured by the Tiffany rating scale short form. METHODS: Twenty-four smokers were enrolled in a placebo-controlled, randomized, double-blind, three periods, crossover trial. The study objective was to describe the nicotine-induced changes on craving scores. Two modeling strategies based on a mechanistic (indirect response models with drug-related inhibition on the k(in) synthesis rate and with a drug-related stimulation of the k(out) removal rate were evaluated) and a probabilistic (logistic regression) approach were used. RESULTS: Placebo response model properly fitted the circadian changes on craving scores. The analysis revealed that the indirect response model with inhibition on k(in) was the preferred model for the smoking data whereas the preferred model for the Nicotine Replacement Therapy data was the one with stimulation on k(out). The logistic analysis showed that the nicotine concentration was a significant predictor of reduction in craving during the free-smoking period. CONCLUSIONS: Nicotine dosage regimen can influence the nicotine mechanism of action: an instantaneous delivery at an individually selected time seems to inhibit the onset of craving while constant delivery at a pre-defined time seems to attenuate the craving.

Computer-assisted drug development (CADD): an emerging technology for designing first-time-in-man and proof-of-concept studies from preclinical experiments.

Computer-assisted drug development (CADD) is an emerging technology for accelerating drug development based on the integration of mathematical modelling and simulation. This methodology provides a knowledge-based decisional tool on alternative development strategies based on the evaluation of potential risks on drug safety, and the definition of experimental design of new trials with expected power and probability of success. An example of CADD implementation is presented to design the first-time-in-man (FTIM) and the proof-of-concept (PoC) study of a new CNS compound. The final objective of the example presented is not necessarily to supply a success story of a correct prediction of human data from animal studies but to define a credible strategy suitable to design FTIM and PoC studies using preclinical data without the support of any human in vivo information. Rhesus monkey and human PK were initially estimated using allometric scaling on data collected in dogs, cynomolgus monkeys and rats. A PK/PD model was derived from a study conducted in rodent and validated by comparing the model predicted response to the one observed in a PET experiment conducted in rhesus monkey. The final PK/PD model, incorporating potential variability and uncertainty on scaled human prediction together with a receptor affinity adjustment derived from in vitro binding studies, was used to design the first-time-in-man and the proof-of-concept study.

Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer.

The objective of the present study was to determine the pharmacokinetic profile of vinorelbine in patients 65 years or older with metastatic cancer in progression. Twelve patients were enrolled in this study. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20-30 mg/m2 through a central venous catheter. Chemotherapy was repeated weekly. A total of 46 courses of vinorelbine was studied. Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Toxicity evaluation was carried out before each course of chemotherapy. Plasma vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorometric detection. A Bayesian estimation of individual pharmacokinetic parameters was carried out using the nonlinear mixed-effect modeling approach as implemented in the NONMEM computer program. An open three-compartment pharmacokinetic model with a zero order input rate was used to describe the kinetics of vinorelbine. Area under the plasma-concentration time curve (AUC) normalized to a 30 mg/m2 administered dose averaged 0.89 mg/liter x h (coefficient of variation = 23.7%). The total plasma clearance averaged 0.93 liter/h/kg (0.61-1.83 liter/h/kg; coefficient of variation = 38.6%). The elimination half-life was 38.1 +/- 5.8 h. A high correlation was found between patient age and total clearance (r = -0.8; P < 0.001). The main hematological toxicity observed was anemia in 11 patients. Neutropenia occurred in 50% of patients. Significant correlations were found between AUC and the decrease in the hemoglobin level (r = 0.60) and between AUC and the decrease in the neutrophil count (r = 0.66). Thrombocytopenia was observed in only one patient. In conclusion, the age-related decrease in clearance found in this study supports the design of a Phase I study of vinorelbine in patients older than 65 years or perhaps 70 years.

Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer.

PURPOSE: The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients with advanced colorectal cancer using circadian change kinetics. METHODS: Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m(2)) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m(2)) and then continuous infusion (600 mg/m(2)) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component (over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters (65 patients) were investigated using patient's sex, body area, age, body weight, height, liver enzymes and serum creatinine as covariables. RESULTS: Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean clearance (CL(mean)) and initial volume of distribution (V), were as follows: the male subgroup showed a CL(mean) value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of 20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. CONCLUSION: In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients.