Publications by authors named "Jenny Y Chien"

22 Publications

  • Page 1 of 1

Development and Verification of a Body Weight-Directed Disease Trial Model for Glucose Homeostasis.

J Clin Pharmacol 2021 02 7;61(2):234-243. Epub 2020 Sep 7.

Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Therefore, the objective of our research was to establish a body weight-directed disease trial model for glucose homeostasis. To that end, we conducted a model-based meta-analysis using time course data of body weight loss (following lifestyle change or surgical procedure) and corresponding improvement of insulin sensitivity expressed as the Matsuda index. Changes in body weight were best described by a sigmoidal E model, whereas changes in the Matsuda index were best described by a linear model with a slope of 3.49. Once developed and verified, the model-based meta-analysis was linked to a disease-drug trial model for T2DM previously developed by our group to characterize and predict the impact of weight loss on clinically relevant glucose homeostasis biomarkers. The joint model was then used to conduct clinical trial simulations, which showed that weight loss can greatly improve clinically relevant glucose homeostasis biomarkers in T2DM patients.
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http://dx.doi.org/10.1002/jcph.1728DOI Listing
February 2021

Development and Qualification of a Drug-Disease Modeling Platform to Characterize Clinically Relevant Endpoints in Type 2 Diabetes Trials.

Clin Pharmacol Ther 2018 10 1;104(4):699-708. Epub 2018 Feb 1.

Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, University of Florida, Lake Nona (Orlando), Florida, USA.

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized by persistently elevated blood glucose concentration (hyperglycemia). We developed a mechanistic drug-disease modeling platform based on data from more than 4,000 T2DM subjects in seven phase II/III clinical trials. The model integrates longitudinal changes in clinically relevant biomarkers of glycemic control with information on baseline disease state, demographics, disease progression, and different therapeutic interventions, either when given alone or as add-on combination therapy. The model was able to simultaneously characterize changes in fasting plasma glucose, fasting serum insulin, and glycated hemoglobin A1c following administration of sulfonylurea, metformin, and thiazolidinedione as well as disease progression in clinical trials ranging from 16-104 weeks of treatment. The mechanistic components of this generalized mechanism-based platform, based on knowledge of pharmacology, insulin-glucose homeostatic feedback, and diabetes pathophysiology, allows its application to be further expanded to other antidiabetic drug classes and combination therapies.
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http://dx.doi.org/10.1002/cpt.998DOI Listing
October 2018

Simulation-Based Evaluation of Dose-Titration Algorithms for Rapid-Acting Insulin in Subjects with Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antihyperglycemic Medications.

Diabetes Technol Ther 2017 08 12;19(8):483-490. Epub 2017 Jul 12.

2 Merck & Co, Inc. , Kenilworth, Pennsylvania.

Background: The purpose of this prospective, model-based simulation approach was to evaluate the impact of various rapid-acting mealtime insulin dose-titration algorithms on glycemic control (hemoglobin A1c [HbA1c]).

Methods: Seven stepwise, glucose-driven insulin dose-titration algorithms were evaluated with a model-based simulation approach by using insulin lispro. Pre-meal blood glucose readings were used to adjust insulin lispro doses. Two control dosing algorithms were included for comparison: no insulin lispro (basal insulin+metformin only) or insulin lispro with fixed doses without titration.

Results: Of the seven dosing algorithms assessed, daily adjustment of insulin lispro dose, when glucose targets were met at pre-breakfast, pre-lunch, and pre-dinner, sequentially, demonstrated greater HbA1c reduction at 24 weeks, compared with the other dosing algorithms. Hypoglycemic rates were comparable among the dosing algorithms except for higher rates with the insulin lispro fixed-dose scenario (no titration), as expected. The inferior HbA1c response for the "basal plus metformin only" arm supports the additional glycemic benefit with prandial insulin lispro.

Conclusions: Our model-based simulations support a simplified dosing algorithm that does not include carbohydrate counting, but that includes glucose targets for daily dose adjustment to maintain glycemic control with a low risk of hypoglycemia.
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http://dx.doi.org/10.1089/dia.2016.0361DOI Listing
August 2017

A Comprehensive Review of Novel Drug-Disease Models in Diabetes Drug Development.

Clin Pharmacokinet 2016 07;55(7):769-788

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida at Lake Nona (Orlando), 6550 Sanger Road, Room 467, Orlando, FL, 32827, USA.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, which affects millions of people worldwide. The disease is characterized by chronically elevated blood glucose concentrations (hyperglycaemia), which result in comorbidities and multi-organ dysfunction. This is due to a gradual loss of glycaemic control as a result of increasing insulin resistance, as well as decreasing β-cell function. The objective of T2DM drug interventions is, therefore, to reduce fasting and postprandial blood glucose concentrations to normal, healthy levels without hypoglycaemia. Several classes of novel antihyperglycaemic drugs with various mechanisms of action have been developed over the past decades or are currently under clinical development. The development of these drugs is routinely supported by the application of pharmacokinetic/pharmacodynamic modelling and simulation approaches. They integrate information on the drug's pharmacokinetics, clinically relevant biomarker information and disease progression into a single, unifying approach, which can be used to inform clinical study design, dose selection and drug labelling. The objective of this review is to provide a comprehensive overview of the quantitative approaches that have been reported since the 2008 review by Landersdorfer and Jusko in an increasing order of complexity, starting with glucose homeostasis models. Each of the presented approaches is discussed with respect to its strengths and limitations, and respective knowledge gaps are highlighted as potential opportunities for future drug-disease model development in the area of T2DM.
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http://dx.doi.org/10.1007/s40262-015-0359-yDOI Listing
July 2016

Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials.

Clin Pharmacokinet 2016 May;55(5):625-34

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.

Background And Objective: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects.

Methods: The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models.

Results: Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% [coefficient of variation (CV)]. There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h [inter-individual variability (CV) 33.8%]. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree.

Conclusion: The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection.
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http://dx.doi.org/10.1007/s40262-015-0338-3DOI Listing
May 2016

The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes.

Cell Metab 2013 Sep;18(3):333-40

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders.
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http://dx.doi.org/10.1016/j.cmet.2013.08.005DOI Listing
September 2013

Optimization of drug-drug interaction study design: comparison of minimal physiologically based pharmacokinetic models on prediction of CYP3A inhibition by ketoconazole.

Drug Metab Dispos 2013 Jul 12;41(7):1329-38. Epub 2013 Apr 12.

Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285, USA.

Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f(m)) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.
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http://dx.doi.org/10.1124/dmd.112.050732DOI Listing
July 2013

Drug delivery trends in clinical trials and translational medicine: growth in biologic molecule development and impact on rheumatoid arthritis, Crohn's disease, and colitis.

J Pharm Sci 2012 Aug 9;101(8):2668-74. Epub 2012 May 9.

Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.

There are 94,709 clinical trials across 179 countries. Approximately half (47,467) are related to the three categories within the scope of the free online resource "Drug Delivery Trends in Clinical Trials and Translational Medicine," which are (1) drug delivery technology and systems, (2) biological molecule platforms, and (3) pharmacokinetic and pharmacodynamic interactions. In this commentary, trends in biological molecule platforms and their impacts are discussed. The sales of top 15 biologic drugs have reached over $63 billion in 2010. In the past 10 years, major pharmaceutical companies have acquired biological molecule platforms and have become integrated biopharmaceutical companies, highlighting the role of biotechnology in driving new therapeutic product development. The top three products--Remicade, Enbrel, and Humira--indicated for arthritis and colitis and targeted to tumor necrosis factor-alpha (TNF-α), each generated over $6 billion in annual sales. In addition to TNF-α, biologic candidates targeted to other inflammatory molecules are in clinical development, partly driven by commercial interests and medical need. Although clinical experience indicates that all the anti-TNF-α molecular platforms are effective for rheumatoid arthritis, Crohn's disease, and colitis, whether the new agents can provide additional relief or cures remains to be seen.
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http://dx.doi.org/10.1002/jps.23154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826476PMC
August 2012

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance.

J Pharm Sci 2011 Oct 3;100(10):4090-110. Epub 2011 May 3.

Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.

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.
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http://dx.doi.org/10.1002/jps.22552DOI Listing
October 2011

PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach.

J Pharm Sci 2011 Oct 3;100(10):4127-57. Epub 2011 May 3.

Leader Consultant, 4009 Sylvia Daoust, Québec city, Québec, Canada, G1X 0A6.

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.
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http://dx.doi.org/10.1002/jps.22550DOI Listing
October 2011

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets.

J Pharm Sci 2011 Oct 26;100(10):4050-73. Epub 2011 Apr 26.

Leader Consultant, 4009 Sylvia Daoust, Québec city, Québec, Canada, G1X 0A6.

This study is part of the Pharmaceutical Research and Manufacturers of America (PhRMA) initiative on predictive models of efficacy, safety, and compound properties. The overall goal of this part was to assess the predictability of human pharmacokinetics (PK) from preclinical data and to provide comparisons of available prediction methods from the literature, as appropriate, using a representative blinded dataset of drug candidates. The key objectives were to (i) appropriately assemble and blind a diverse dataset of in vitro, preclinical in vivo, and clinical data for multiple drug candidates, (ii) evaluate the dataset with empirical and physiological methodologies from the literature used to predict human PK properties and plasma concentration-time profiles, (iii) compare the predicted properties with the observed clinical data to assess the prediction accuracy using routine statistical techniques and to evaluate prediction method(s) based on the degree of accuracy of each prediction method, and (iv) compile and summarize results for publication. Another objective was to provide a mechanistic understanding as to why one methodology provided better predictions than another, after analyzing the poor predictions. A total of 108 clinical lead compounds were collected from 12 PhRMA member companies. This dataset contains intravenous (n = 19) and oral pharmacokinetic data (n = 107) in humans as well as the corresponding preclinical in vitro, in vivo, and physicochemical data. All data were blinded to protect the anonymity of both the data and the company submitting the data. This manuscript, which is the first of a series of manuscripts, summarizes the PhRMA initiative and the 108 compound dataset. More details on the predictability of each method are reported in companion manuscripts.
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http://dx.doi.org/10.1002/jps.22554DOI Listing
October 2011

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 4: prediction of plasma concentration-time profiles in human from in vivo preclinical data by using the Wajima approach.

J Pharm Sci 2011 Oct 7;100(10):4111-26. Epub 2011 Apr 7.

Metabolism and Pharmacokinetics, Bristol-Myer's Squibb Company, Princeton, New Jersey 08543.

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.
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http://dx.doi.org/10.1002/jps.22551DOI Listing
October 2011

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution.

J Pharm Sci 2011 Oct 30;100(10):4074-89. Epub 2011 Mar 30.

Modeling and Simulation, DMPK, AstraZeneca Ltd., Macclesfield, Cheshire SK10 3JL, UK.

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.
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http://dx.doi.org/10.1002/jps.22553DOI Listing
October 2011

Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug-drug interaction trials.

Br J Clin Pharmacol 2010 Oct;70(4):523-36

Lilly Research Laboratories,Department of Drug Disposition, Lilly Research Laboratories, SunninghillRoad,Windlesham, Surrey, UK.

Aims: To develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50mg dose. Additional objectives were to develop a semi-mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6-mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates.

Results: The mean population estimates of the first order absorption rate constant (k(a) ), apparent clearance (CL/F) and apparent volume of distribution at steady state (V(ss) /F) were 0.15h(-1) , 111 lh(-1) and 2950 l, respectively. Further, using the proposed semi-mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 lh(-1) with between-subject variability of 84%. d-optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the second d-optimal sample was earlier at 14 and 19h, respectively, compared with 24h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates.

Conclusions: A two compartment population pharmacokinetic model best described desipramine disposition. The semi-mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug-drug interaction (DDI) studies. Based on this meta-analysis of seven trials, a sample size of 21 subjects in cross-over design is appropriate for assessing CYP2D6 interaction with novel compounds.
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http://dx.doi.org/10.1111/j.1365-2125.2010.03731.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950987PMC
October 2010

Drug delivery trends in clinical trials and translational medicine: evaluation of pharmacokinetic properties in special populations.

J Pharm Sci 2011 Jan;100(1):53-8

Eli Lilly & Company, Lilly Research Laboratories, Indianapolis, Indiana, USA.

In spite of the recent advances in technology to optimize the absorption, distribution, metabolism and elimination (ADME) properties of new and promising medicinal products to reduce clinical failures, the investigation of drug disposition in the pediatric and elderly populations continues to be under evaluated. With the increasing prevalence of aging populations world-wide, there is a growing concern from health care providers, regulators and the general public that drug delivery is still less than optimal for the vulnerable patient populations likely to be more sensitive to adverse effects of the new investigational drugs. This review of the ClinicalTrials.gov database revealed a rapidly increasing number of clinical trials and a trend towards wider inclusion criteria of the elderly population in clinical trials over the past 10 years. However, when we summarized trials by drug delivery, biological platforms, and disease categories, less than 10% of these trials included pharmacokinetic evaluation in elderly subjects greater than 65 years of age, and less than 4% included pharmacokinetic evaluation in children less than 17 years of age. Across the various disease areas, the percentage of trials that included pharmacokinetic evaluation in the children and elderly has remained low and is consistently less than the studies that included the younger 18 to 65 age group. Therefore, it is not known whether the right information is being generated from the growing number of clinical trials to guide optimal dosing recommendations in special patient populations.
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http://dx.doi.org/10.1002/jps.22253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867146PMC
January 2011

A new probabilistic rule for drug-dug interaction prediction.

J Pharmacokinet Pharmacodyn 2009 Feb 21;36(1):1-18. Epub 2009 Jan 21.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.

An innovative probabilistic rule is proposed to predict the clinical significance or clinical insignificance of DDI. This rule is coupled with a hierarchical Bayesian model approach to summarize substrate/inhibitor's PK models from multiple published resources. This approach incorporates between-subject and between-study variances into DDI prediction. Hence, it can predict both population-average and subject-specific AUCR. The clinically significant DDI, weak DDI, and clinically insignificant inhibitions are decided by the probabilities of predicted AUCR falling into three intervals, (-infinity, 1.25), (1.25, 2), and (2, infinity). The main advantage of this probabilistic rule to predict clinical significance of DDI over the deterministic rule is that the probabilistic rule considers the sample variability, and the decision is independent of sampling variation; while deterministic rule based decision will vary from sample to sample. The probabilistic rule proposed in this paper is best suited for the situation when in vivo PK studies and models are available for both the inhibitor and substrate. An early decision on clinically significant or clinically insignificant inhibition can avoid additional DDI studies. Ketoconazole and midazolam are used as an interaction pair to illustrate our idea. AUCR predictions incorporating between-subject variability always have greater variances than population-average AUCR predictions. A clinically insignificant AUCR at population-average level is not necessarily true when considering between-subject variability. Additional simulation studies suggest that predicted AUCRs highly depend on the interaction constant K(i) and dose combinations.
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http://dx.doi.org/10.1007/s10928-008-9107-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737820PMC
February 2009

Drug delivery trends in clinical trials and translational medicine: Updated analysis of ClinicalTrials.gov database.

J Pharm Sci 2009 Jun;98(6):1928-34

Department of Pharmaceutics, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

While the number of clinical trials has continued to grow by about 20% in the past six months, no corresponding growth in product approval by the food and drug administration is seen or anticipated in the near future. Late-stage clinical failures due to lack of efficacy or toxicity continues to be a challenge. The optimization of absorption, distribution, metabolism and elimination (ADME) has improved drug candidate selection and reduced early clinical failure. The current challenge is how to avoid late stage clinical failures. Expanded knowledge of drug target distribution, pharmacokinetics and validated biomarkers will allow implementation of appropriate drug delivery and clinical trial designs to reduce drug exposure to off-target organs such as the liver and kidney and could reduce potential untoward effects. In essence, integration of drug delivery and targeting to reduce exposure in off-target tissues in the preclinical and clinical program may hold the key to increasing the odds of success in drug development. In this update, we briefly review data on clinical trials pertinent to drug delivery in the current regulatory environment. It also provides our analysis on the emerging trends in second generation antibody therapeutics in drug delivery and targeting.
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http://dx.doi.org/10.1002/jps.21649DOI Listing
June 2009

Drug delivery trends in clinical trials and translational medicine.

J Pharm Sci 2008 Jul;97(7):2543-7

Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana, USA.

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http://dx.doi.org/10.1002/jps.21426DOI Listing
July 2008

Stochastic prediction of CYP3A-mediated inhibition of midazolam clearance by ketoconazole.

Drug Metab Dispos 2006 Jul 12;34(7):1208-19. Epub 2006 Apr 12.

Department of Drug Disposition, Lilly Research Laboratories, Indianapolis, IN 46285, USA.

Conventional methods to forecast CYP3A-mediated drug-drug interactions have not employed stochastic approaches that integrate pharmacokinetic (PK) variability and relevant covariates to predict inhibition in terms of probability and uncertainty. Empirical approaches to predict the extent of inhibition may not account for nonlinear or non-steady-state conditions, such as first-pass effects or accumulation of inhibitor concentration with multiple dosing. A physiologically based PK model was developed to predict the inhibition of CYP3A by ketoconazole (KTZ), using midazolam (MDZ) as the substrate. The model integrated PK models of MDZ and KTZ, in vitro inhibition kinetics of KTZ, and the variability and uncertainty associated with these parameters. This model predicted the time- and dose-dependent inhibitory effect of KTZ on MDZ oral clearance. The predictive performance of the model was validated using the results of five published KTZ-MDZ studies. The model improves the accuracy of predicting the inhibitory effect of increasing KTZ dosing on MDZ PK by incorporating a saturable KTZ efflux from the site of enzyme inhibition in the liver. The results of simulations using the model supported the KTZ dose of 400 mg once daily as the optimal regimen to achieve maximum inhibition by KTZ. Sensitivity analyses revealed that the most influential variable on the prediction of inhibition was the fractional clearance of MDZ mediated by CYP3A. The model may be used prospectively to improve the quantitative prediction of CYP3A inhibition and aid the optimization of study designs for CYP3A-mediated drug-drug interaction studies in drug development.
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http://dx.doi.org/10.1124/dmd.105.008730DOI Listing
July 2006

Predictions of the in vivo clearance of drugs from rate of loss using human liver microsomes for phase I and phase II biotransformations.

Pharm Res 2006 Apr 24;23(4):654-62. Epub 2006 Mar 24.

Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.

Purpose: The utility of in vitro metabolism to accurately predict the clearance of hepatically metabolized drugs was evaluated. Three major goals were: (1) to optimize substrate concentration for the accurate prediction of clearance by comparing to Km value, (2) to prove that clearance of drugs by both oxidation and glucuronidation may be predicted by this method, and (3) to determine the effects of nonspecific microsomal binding and plasma protein binding.

Methods: The apparent Km values for five compounds along with scaled intrinsic clearances and predicted hepatic clearances for eight compounds were determined using a substrate loss method. Nonspecific binding to both plasma and microsomal matrices were also examined in the clearance calculations.

Results: The Km values were well within the 2-fold variability expected for between laboratory comparisons. Using both phase I and/or phase II glucuronidation incubation conditions, the predictions of in vivo clearance using the substrate loss method were shown to correlate with published human clearance values. Of particular interest, for highly bound drugs (>95% plasma protein bound), the addition of a plasma protein binding term increased the accuracy of the prediction of in vivo clearance.

Conclusions: The substrate loss method may be used to accurately predict hepatic clearance of drugs.
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http://dx.doi.org/10.1007/s11095-006-9663-4DOI Listing
April 2006

Pharmacokinetics/Pharmacodynamics and the stages of drug development: role of modeling and simulation.

AAPS J 2005 Oct 7;7(3):E544-59. Epub 2005 Oct 7.

Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285, USA.

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation (M&S) are well-recognized powerful tools that enable effective implementation of the learn-and-confirm paradigm in drug development. The impact of PK/PD M&S on decision making and drug development risk management is dependent on the question being asked and on the availability and quality of data accessible at a particular stage of drug development. For instance, M&S methodologies can be used to capture uncertainty and use the expected variability in PK/PD data generated in preclinical species for projection of the plausible range of clinical dose; clinical trial simulation can be used to forecast the probability of achieving a target response in patients based on information obtained in early phases of development. Framing the right question and capturing the key assumptions are critical components of the "learn-and-confirm" paradigm in the drug development process and are essential to delivering high-value PK/PD M&S results. Selected works of PK/PD modeling and simulation from preclinical to phase III are presented as case examples in this article.
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http://dx.doi.org/10.1208/aapsj070355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751257PMC
October 2005

CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease.

Hepatology 2003 Aug;38(2):428-35

Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.

Previous studies suggest that hepatic cytochrome P450 2E1 (CYP2E1) activity is increased in individuals with chronic alcoholism, nonalcoholic steatohepatitis (NASH), and morbid obesity, and may contribute to liver disease. We studied 16 morbidly obese subjects with varying degrees of hepatic steatosis and 16 normal-weight controls. Obese subjects were evaluated at baseline, 6 weeks, and 1 year after gastroplasty, a procedure that leads to weight loss. Hepatic CYP2E1 activity was assessed by determination of the clearance of chlorzoxazone (CLZ), an in vivo CYP2E1-selective probe. Liver biopsy tissue was obtained during surgery for histopathology. Both the total and unbound oral CLZ clearance (Cl(u)/F) was elevated approximately threefold in morbidly obese subjects compared with controls (P <.001). The Cl(u)/F was significantly higher among subjects with steatosis involving >50% of hepatocytes, compared with those with steatosis in < or =50% of hepatocytes (P =.02). At postoperative week 6 and year 1, the median body mass index (BMI) of subjects who underwent gastroplasty decreased by 11% and 33%, total oral CLZ clearance declined by 16% (P <.01) and 46% (P <.05), and Cl(u)/F decreased by 18% (P <.05) and 35% (P =.16), respectively. Moreover, those subjects with a year 1 BMI <30 kg/m(2) exhibited a median Cl(u)/F that was 63% lower (P =.02) than the respective clearance for all other subjects. In conclusion, hepatic CYP2E1 activity is up-regulated in morbidly obese subjects. A positive association between the degree of steatosis and CYP2E1 activity preoperatively and between the extent of obesity and CYP2E1 activity postoperatively, suggests that CYP2E1 induction is related to or caused by hepatic pathology that results from morbid obesity.
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http://dx.doi.org/10.1053/jhep.2003.50342DOI Listing
August 2003