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1.  Population Pharmacodynamic Modeling of Hyperglycemic Clamp and Meal Tolerance Tests in Patients with Type 2 Diabetes Mellitus 
The AAPS Journal  2013;15(4):1051-1063.
In this study, glucose and insulin concentration–time profiles in subjects with type 2 diabetes mellitus (T2DM) under meal tolerance test (MTT) and hyperglycemic clamp (HGC) conditions were co-modeled simultaneously. Blood glucose and insulin concentrations were obtained from 20 subjects enrolled in a double-blind, placebo-controlled, randomized, two-way crossover study. Patients were treated with palosuran or placebo twice daily for 4 weeks and then switched to the alternative treatment after a 4-week washout period. The MTT and HGC tests were performed 1 h after drug administration on days 28 and 29 of each treatment period. Population data analysis was performed using NONMEM. The HGC model incorporates insulin-dependent glucose clearance and glucose-induced insulin secretion. This model was extended for the MTT, in which glucose absorption was described using a transit compartment with a mean transit time of 62.5 min. The incretin effect (insulin secretion triggered by oral glucose intake) was also included, but palosuran did not influence insulin secretion or sensitivity. Glucose clearance was 0.164 L/min with intersubject and interoccasion variability of 9.57% and 31.8%. Insulin-dependent glucose clearance for the HGC was about 3-fold greater than for the MTT (0.0111 vs. 0.00425 L/min/[mU/L]). The maximal incretin effect was estimated to enhance insulin secretion 2-fold. The lack of palosuran effect coupled with a population-based analysis provided quantitative insights into the variability of glucose and insulin regulation in patients with T2DM following multiple glucose tolerance tests. Application of these models may also prove useful in antihyperglycemic drug development and assessing glucose–insulin homeostasis.
doi:10.1208/s12248-013-9512-4
PMCID: PMC3787242  PMID: 23904152
hyperglycemic clamp; meal tolerance test; pharmacodynamic modeling; type 2 diabetes mellitus
2.  Pharmacodynamic Model of Parathyroid Hormone Modulation by a Negative Allosteric Modulator of the Calcium-Sensing Receptor 
The AAPS Journal  2011;13(2):265-273.
In this study, a pharmacodynamic model is developed, based on calcium–parathyroid hormone (PTH) homeostasis, which describes the concentration–effect relationship of a negative allosteric modulator of the calcium-sensing receptor (CaR) in rats. Plasma concentrations of drug and PTH were determined from plasma samples obtained via serial jugular vein sampling following single subcutaneous doses of 1, 5, 45, and 150 mg/kg to male Sprague–Dawley rats (n = 5/dose). Drug pharmacokinetics was described by a one-compartment model with first-order absorption and linear elimination. Concentration-time profiles of PTH were characterized using a model in which the compound allosterically modulates Ca+2 binding to the CaR that, in turn, modulates PTH through a precursor-pool indirect response model. Additionally, negative feedback was incorporated to account for tolerance observed at higher dose levels. Model fitting and parameter estimation were conducted using the maximum likelihood algorithm. The proposed model well characterized the data and provided compound specific estimates of the Ki and cooperativity constant (α) of 1.47 ng/mL and 0.406, respectively. In addition, the estimated model parameters for PTH turnover were comparable to that previously reported. The final generalized model is capable of characterizing both PTH–Ca+2 homeostasis and the pharmacokinetics and pharmacodynamics associated with the negative allosteric CaR modulator. As such, the model provides a simple platform for analysis of drugs targeting the PTH–Ca+2 system.
doi:10.1208/s12248-011-9266-9
PMCID: PMC3085713  PMID: 21437757
allosteric; bone; calcium sensing receptor; ionized calcium; osteoporosis; parathyroid hormone; pharmacodynamics; pharmacokinetics
3.  Physiologically Based Pharmacokinetic Model of Amphotericin B Disposition in Rats Following Administration of Deoxycholate Formulation (Fungizone®): Pooled Analysis of Published Data 
The AAPS Journal  2011;13(2):255-264.
The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration–time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability–surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration–time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics.
doi:10.1208/s12248-011-9267-8
PMCID: PMC3085707  PMID: 21431453
amphotericin B; interspecies scaling; physiologically based pharmacokinetic model; tissue distribution
4.  Comparison of Two Pharmacodynamic Transduction Models for the Analysis of Tumor Therapeutic Responses in Model Systems 
The AAPS Journal  2009;12(1):1-10.
Semi-mechanistic pharmacodynamic (PD) models that capture tumor responses to anticancer agents with fidelity can provide valuable insights that could aid in the optimization of dosing regimens and the development of drug delivery strategies. This study evaluated the utility and potential interchangeability of two transduction-type PD models: a cell distribution model (CDM) and a signal distribution model (SDM). The evaluation was performed by simulating dense and sparse tumor response data with one model and analyzing it using the other. Performance was scored by visual inspection and precision of parameter estimation. Capture of tumor response data was also evaluated for a liposomal formulation of paclitaxel in the paclitaxel-resistant murine Colon-26 model. A suitable PK model was developed by simultaneous fitting of literature data for paclitaxel formulations in mice. Analysis of the simulated tumor response data revealed that the SDM was more flexible in describing delayed drug effects upon tumor volume progression. Dense and sparse data simulated using the CDM were fit very well by the SDM, but under some conditions, data simulated using the SDM were fitted poorly by the CDM. Although both models described the dose-dependent therapeutic responses of Colon-26 tumors, the fit by the SDM contained less bias. The CDM and SDM are both useful transduction models that recapitulate, with fidelity, delayed drug effects upon tumor growth. However, they are mechanistically distinct and not interchangeable. Both fit some types of tumor growth data well, but the SDM appeared more robust, particularly where experimental data are sparse.
doi:10.1208/s12248-009-9155-7
PMCID: PMC2811636  PMID: 19902363
cancer; drug delivery; paclitaxel; pharmacodynamics; pharmacokinetics; transduction models
5.  Partial derivative—Based sensitivity analysis of models describing target-mediated drug disposition 
The AAPS Journal  2007;9(2):E181-E189.
Sensitivity analysis is commonly used to characterize the effects of parameter perturbations on model output. One use for the approach is the optimization of an experimental design enabling estimation of model parameters with improved accuracy. The primary objective of this study is to conduct a sensitivity analysis of selected target-mediated pharmacokinetic models, ascertain the effect of parameter variations on model predictions, and identify influential model parameters. One linear model (Model 1, control) and 2 target-mediated models (Models 2 and 3) were evaluated over a range of dose levels. Simulations were conducted with model parameters being perturbed at the higher and lower ends from literature mean values. Profiles of free plasma drug concentrations and their partial derivatives with respect to each parameter vs time were analyzed. Perturbations resulted in altered outputs, the extent of which reflected parmater influence. The model outputs were highly sensitive to perturbations of linear disposition parameters in all 3 models. The equilibrium dissociation constant (KD) was less influential in Model 2 but was influential in the terminal phase in Model 3, highlighting the role ofKD in this region. An equation for Model 3 in support of the result forKD was derived. Changes in the initial receptor concentration [Rtot(0)] paralleled the observed effects of initial plasma volume (Vc) perturbations, with increased influence at higher values. Model 3 was also sensitive to the rates of receptor degradation and internalization. These results suggest that informed sampling may be essential to accurately estimate influential parameters of target-mediated models.
doi:10.1208/aapsj0902020
PMCID: PMC2751407  PMID: 17614360
Nonlinear pharmacokinetics; quasiequilibrium models; equilibrium dissociation constant; receptor internalization

Results 1-5 (5)