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Xi Wang,1 Debra C DuBois,1,2 Siddharth Sukumaran,2 Vivaswath Ayyar,1 William J Jusko,2,3 Richard R Almon1–3 1Department of Biological Sciences, 2Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; 3New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, USA Abstract: Both obesity and chronic inflammation are often associated with insulin resistance and type 2 diabetes. The Zucker diabetic fatty (ZDF) rat (fa/fa) is an obese animal model frequently used in type 2 diabetes research. The current study determines whether chronic administration (from 5 weeks of age through 24 weeks of age) of salsalate, a salicylate with anti-inflammatory properties, would be effective in mitigating diabetes disease progression in ZDF rats. Although a trend existed for lower blood glucose in the salsalate-treated group, significant differences were obscured by high animal-level variability. However, even in the non-drug-treated group, not all ZDF rats became diabetic as expected. Therefore, animals were parsed into two groups, regardless of drug treatment: normoglycemic ZDF rats, which maintained blood glucose profiles identical to nondiabetic Zucker lean rats (ZLRs), and hyperglycemic ZDF rats, which exhibited progressive elevation in blood glucose. To ascertain the differences between ZDF rats that became hyperglycemic and those that did not, relevant physiological indices and expression levels of adiponectin, tumor necrosis factor-α, interleukin-6, and glucocorticoid-induced leucine zipper messenger RNAs in adipose tissue were measured at sacrifice. Plasma C-reactive protein concentrations and expression levels of cytokine and glucocorticoid-induced leucine zipper messenger RNAs suggested more prevalent chronic inflammation in hyperglycemic animals. Early elevation of the insulin-sensitizing adipokine, adiponectin, was present in both ZDF groups, with the rate of its age-related decline faster in hyperglycemic animals. The most marked difference between the two groups of ZDF animals was in insulin output. Although the two ZDF populations had very similar elevated plasma insulin concentrations for the first 10 weeks, after that time, plasma insulin decreased markedly in the animals that became hyperglycemic, whereas it remained high in the normoglycemic ZDF rats. Thus, hyperglycemic ZDF animals exhibit both insulin resistance and progressive beta cell failure, whereas normoglycemic ZDF rats exhibit a lesser degree of insulin resistance that does not progress to beta cell failure. In these respects, the normoglycemic ZDF rats appear to revert back to a phenotype that strongly resembles that of nondiabetic Zucker fatty rats from which they were derived. Keywords: type 2 diabetes, ZDF rats, animal models

Xi Wang,1 Debra C DuBois,1,2 Yanguang Cao,2 William J Jusko,2,3 Richard R Almon1–31Department of Biological Sciences, University at Buffalo, Buffalo, NY, USA; 2Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA; 3New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, USAAbstract: This study investigates the antidiabetic effects of salsalate on disease progression of diabetes in non-obese diabetic Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes. Salsalate was formulated in rat chow (1,000 ppm) and used to feed rats from 5 to 21 weeks of age. At 5 weeks of age, GK and Wistar (WIS) control rats were subdivided into four groups, each composed of six rats: GK rats with standard diet (GK-C); GK rats with salsalate-containing diet (GK-S); WIS rats with standard diet (WIS-C); and WIS rats with salsalate-containing diet (WIS-S). The GK-C rats (167.2±11.6 mg/dL) showed higher blood glucose concentrations than WIS-C rats (133.7±4.9 mg/dL, P

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.

A model-based approach was implemented for the development of the proliferator-activated receptor gamma (PPARgamma) agonist rivoglitazone. Population pharmacokinetic and pharmacodynamic models were developed using data collected from 2 phase I and 2 phase II studies in healthy volunteers and participants with type 2 diabetes mellitus. A 2-compartment model with first-order absorption and elimination and an absorption time lag best described rivoglitazone pharmacokinetics. Modified indirect-response models were used to characterize changes in fasting plasma glucose, HbA(1c), and hemodilution as a function of rivoglitazone plasma concentrations. In addition, differences in hemodilution among participants correlated with the incidence of edema. Current use of oral antidiabetic medication was a significant covariate for the fasting plasma glucose-HbA(1c) exposure-response model. Using a learn-and-confirm process, models developed prior to the second phase II study were able to make valid predictions for exposures and response variables in that study. In future studies, seamless designs can be supported by models such as those developed here. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a major health risk in many countries, and the incidence rates are increasing. Diverse therapeutic agents are applied to treat this condition. Since 1960, numerous mathematical models have been developed to describe the glucose-insulin system, analyse data from diagnostic tests and quantify drug effects. This review summarizes the present state-of-the-art in diabetes modelling, with a focus on models describing drug effects, and identifies major strengths and limitations of the published models. For diagnostic purposes, the minimal model has remained the most popular choice for several decades, and numerous extensions have been developed. Use of the minimal model is limited for applications other than diagnostic tests. More mechanistic models that include glucose-insulin feedback in both directions have been applied. The use of biophase distribution models for the description of drug effects is not always appropriate. More recently, the effects of various antidiabetic agents on glucose and insulin have been modelled with indirect response models. Such models provide good curve fits and mechanistic descriptions of the effects of antidiabetic drugs on glucose-insulin homeostasis. These and other types of models were used to describe secondary drug effects on glucose and insulin, and effects on ancillary biomarkers. Modelling of disease progression in diabetes can utilize indirect response models as a disturbance of homeostasis. Future needs are to include glucose-insulin feedback more often, develop mechanistic models for new drug groups, consider dual drug effects on complementary subsystems, and incorporate elements of disease progression. [ABSTRACT FROM AUTHOR]

The influence of diet and genetics was investigated in a healthy white person who had distinctly low methylprednisolone clearance. Pharmacokinetic and pharmacodynamic parameter values were similar on 2 occasions during the consumption of a low-carbohydrate diet and a Weight Watchers diet, indicating that the decreased clearance was unlikely attributable to a change in diet composition. Although the subject was found to be homozygous for CYP3A5*3, genetic findings were not significant for a number of other CYP3A4 and CYP3A5 allelic variants. Because of the high prevalence of CYP3A5*3/*3 in whites and because 5 of 7 white control subjects are also homozygous for CYP3A5*3, this genotype cannot fully explain the reduced metabolism of the drug. Other genetic or contributing factors might have been involved. New polymerase chain reaction-based genotyping methods for functionally defective CYP3A5*6, *8, *9, and *10 alleles were developed in this study. These assays will be useful for CYP3A5 genotype analysis in future clinical studies. [ABSTRACT FROM AUTHOR]

This study investigated the potential differences in methylprednisolone pharmacodynamics between healthy subjects with different histamine N-methyltransferase (HNMT) C314T genotypes. Six individuals with C/C genotype and 4 with C/T genotype were administered a single intravenous dose of methylprednisolone 0.6 mg/kg ideal body weight in a randomized 2-period manner. Methylprednisolone plasma concentrations were fitted with a 1-compartment model. Cortisol and whole blood histamine suppression were assessed by indirect response models, with circadian baseline cortisol analyzed by Fourier analysis. The area between the baseline and effect curve and the area under the effect versus time curve suppression ratio were used to characterize plasma histamine suppression. Methylprednisolone pharmacokinetics and plasma and whole blood histamine suppression were similar between the 2 genotype groups. Median nadir of cortisol and the 50% inhibitory concentration for cortisol were significantly higher in subjects with C/T genotype than those with C/C genotype (P=.031 and .033, respectively, Wilcoxon rank sum test). Subjects who are heterozygous for the T314 variant allele thus appeared less sensitive to the suppressive effects of methylprednisolone on cortisol secretion. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus is an autoimmune disease primarily affecting women. Currently, systemic lupus erythematosus therapy is suboptimal due to adverse effects of immunosuppressants, particularly corticosteroids. This study determines the single effects of prednisolone, dehydroepiandrosterone, bromocriptine, tamoxifen, mycophenolic acid, 2-chloro-2'-deoxyadenosine, azathioprine, and chloroquine on lectin-stimulated proliferation of human T lymphocytes, as well as determining whether there are interactions in the joint effects of prednisolone and these agents. The T lymphocytes from the whole blood of 10 middle-aged women were stimulated by phytohemagglutinin and cultured with varying drug concentrations. The Hill function was used to evaluate single-drug response data. Isobolograms were constructed to qualitatively analyze interactions. Parametric analysis based on competitive and noncompetitive interaction models was further applied to quantify the joint interactions and predict steroid-sparing potential. The surface interaction parameter (psi) estimated from parametric analysis was in concordance with isobolographic inspection for all interactions studied. All interactions favored the noncompetitive model. Results suggest that dehydroepiandrosterone is additive in its effect with prednisolone, whereas tamoxifen interacts synergistically, both providing steroid-sparing effects. Novel immuno-suppressants such as mycophenolic acid may still provide added pharmacologic benefit during therapy despite a slight antagonistic interaction with prednisolone. These studies help rationalize actual or potential use of other drugs with prednisolone in the treatment of systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were obtained from 4 clinical studies carried out in healthy volunteers. Epoetin alfa (rHuEpo) was administered as 5 single IV doses ranging from 10 to 500 IU/kg, as 8 single SC doses ranging from 300 to 2400 IU/kg, and as 2 multiple SC dosage regimens (150 IU/kg/3 times a week [tiw] and 600 IU/kg/wk). A dual-absorption rate model (fast zero-order and slow first-order inputs) with nonlinear disposition characterized the PK of SC rHuEpo. A high K(m) value was obtained indicating that clearance was mildly nonlinear. Absorption was slow (t(max) approximately 24 hours), and the bioavailability of SC rHuEpo increased with dose (ranging from 46%-100%). A catenary cell production and loss model with a feedback down regulation component was used to fit the reticulocyte data yielding estimates of the stimulatory capacity (S(max)), sensitivity (SC(50)), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. An SC(50) of 27 to 61 IU/L was estimated indicating that low physiological plasma rHuEpo concentrations were sufficient to produce pharmacological effects. No marked sex-dependent differences in clinical responses to rHuEpo therapy were found despite baseline differences. Realistic pharmacokinetic and physiological models accounted for clinical responses from a wide array of dosing conditions with rHuEpo. The rationale for greater efficacy of SC administration of rHuEpo compared to IV was ascertained. [ABSTRACT FROM AUTHOR]

The integrity of current corticosteroid dose equivalency tables, as assessed by mechanistic models for cell trafficking and cortisol dynamics, was investigated in this study. Single, presumably equivalent, doses of intravenous hydrocortisone, methylprednisolone, dexamethasone, and oral prednisolone were given to 5 white men, according to total body weight, in a 5-way crossover, placebo-controlled study. Pharmacodynamic (PD) response-time profiles for T helper cells, T suppressor cells, neutrophils, and adrenal suppression were evaluated by extended indirect response models. For adrenal suppression, prednisolone appears to be less potent than methylprednisolone or dexamethasone. A good correlation was found between the estimated in vivo EC50 values and relative receptor affinity (equilibrium dissociation constants normalized to dexamethasone). Area under the effect curves of all PD responses was calculated using a linear-trapezoidal method. Although T helper cell trafficking and adrenal suppression achieved significant differences by repeated-measures ANOVA (p = 0.014 and 0.022), post hoc analysis using the Bonferroni method revealed no difference between treatments. Although limited by the use of single doses and a relatively small sample size, this study applies mechanistic models for several biomarkers showing that currently used dosing tables reflect reasonable dose equivalency relationships for four corticosteroids. [ABSTRACT FROM AUTHOR]

Sirolimus (RAPA) and cyclosporine (CsA) are immunosuppressive compounds that are being used concomitantly in renal transplant patients. Both drugs are dosed orally, have common intestinal and hepatic metabolism and intestinal transport mechanisms, and thus offer potential for pharmacokinetic drug interactions. A single-dose, open-label, four-period, four-treatment, randomized crossover study was completed in 15 male and 6 female volunteers. Each subject received a 10-mg oral dose of RAPA alone (Rapamune Oral Solution), a 300-mg oral dose of CsA alone (3 x 100-mg Neoral Soft Gelatin Capsules), RAPA and CsA jointly, and CsA followed by RAPA delayed by 4 hours. Blood samples were collected for either 144 hours (RAPA) or 48 hours (CsA) and analyzed by either liquid chromatography/tandem mass spectrometry (RAPA) or radioimmunoassay (CsA). RAPA bioavailability was markedly increased by CsA when given jointly, with Cmax,tmax, and AUC being increased 116%, 92%, and 230%, respectively. However, when RAPA was administered 4 hours after CsA, increases in RAPA Cmax, tmax, and AUC were only 37%, 58%, and 80%, respectively. CsA did not affect t1/2 or mean residence time (MRT) by either mode of combined administration. RAPA did not significantly affect CsA bioavailability after either joint or delayed combined administrations. It was concluded that CsA markedly increases the bioavailability of RAPA, which may be attributed to a large intestinal and hepatic first-pass effect, rather than altered elimination. RAPA did not affect the bioavailability of CsA. [ABSTRACT FROM AUTHOR]

A proposed model of thrombopoietin (TPO) regulation is that of a constitutive production of TPO with circulating levels being predominately regulated by changes in platelet and megackaryocyte mass. Using a pharmacodynamic (PD) approach, the authors examined the validity of this model for patients with acute myeloid leukemia (AML) undergoing dose-intensive postinduction chemotherapy (HDT). TPO and platelet values were assayed weekly in AML patients undergoing HDT. A parsimonious dynamic model was then applied to these experimental data. The results (1) support the proposed model of TPO regulation, (2) model and quantify the effects of HDT on the megakaryocyte compartment, (3) characterize variables not amenable to direct measurement, and (4) have clinical utility as this model predicted that TPO given after HDT would not have a significant effect on platelet recovery, a finding borne out in clinical trials. This model provides information relevant to the interpretation of clinical trials of hematopoietic growth factors. [ABSTRACT FROM AUTHOR]

This study sought to determine effects of multiple dosing of prasterone (DHEA, dehydroepiandrosterone) on the pharmacokinetics of prednisolone and endogenous cortisol secretion. These drugs are likely to be coadministered to patients with systemic lupus erythematosus. Fourteen normal women (ages 30.1 +/- 5.4 years) received single-dose oral prednisone (20 mg) before and after 200 mg/day of oral prasterone for one menstrual cycle (approximately 28 days). Identical assessments, timed to onset of menses, were conducted pretreatment (baseline) and at days 28 and 29 of prasterone treatment and included serum total and free prednisolone, prednisone, DHEA, DHEA-S (dehydroepiandrosterone sulfate), ACTH-stimulated cortisol, and sex hormones and 24-hour urine free cortisol. Pharmacokinetic parameters of prednisolone as assessed by Cmax, t 1/2, AUC, or serum protein binding were not affected by prasterone. The ACTH-stimulated plasma cortisol concentrations were mildly reduced, but 24-hour urinefree cortisol excretion was unchanged during prasterone administration. Serum androstenedione and testosterone increased, while no changes in serum estradiol or estrone occurred. The administration of 200 mg oral prasterone produced serum concentrations of DHEA and DHEA-S significantly greater than endogenous levels. Chronic dosing with 200 mg/day of prasterone did not alter either prednisolone pharmacokinetics or inhibition of cortisol secretion by prednisolone. [ABSTRACT FROM AUTHOR]

Prednisolone pharmacokinetics (PK) and pharmacodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32-hour sampling in each phase. Women were studied during the luteal phase of their menstrual cycle. Total and free plasma prednisolone concentrations were assayed by HPLC and ultrafiltration, and pharmacokinetic data were analyzed by compartmental fitting using WinNonlin. Plasma cortisol concentrations were assayed by HPLC; T-helper, T-suppressor lymphocyte, and neutrophil cell counts were determined by FACS and hemocytometry, and these pharmacodynamic data were evaluated by basic and extended indirect response models using ADAPT II. Total body weight-normalized free prednisolone oral clearance and apparent volume of distribution were higher in men compared with women, regardless of race (by 22% in whites and 40% in blacks for oral clearance, p < 0.01; by32% in whites and 38% in blacks for apparent volume of distribution, p < 0.01). The 50% inhibitory concentration (IC50) values for T-suppressor cell-trafficking inhibition were higher in whites than in blacks, regardless of sex (by 125% in men and 208% in women, p < 0.01). The IC50 or SC50 values for effects of prednisolone on cortisol secretion and T-helper lymphocyte or neutrophil trafficking were not statistically different between men and women, blacks and whites. The findings of this study suggest that there are some prednisolone PK/PD differences related to sex and race. However, these differences do not suggest the need for dosage adjustments, and additional experiments with repeat dosing are needed to fully evaluate the clinical implication of these findings. [ABSTRACT FROM AUTHOR]

A mechanism-based pharmacokinetic/pharmacodynamic model was used to assess lansoprazole effects on gastric pH. The irreversible inactivation of the H+/K+-ATPase enzyme by lansoprazole controls the secretion rate of H+ ions and gastric pH values. The basal circadian rhythm of gastric acid production was taken into account as well as the effects of food intake. A model was applied to multiple-dose data from a crossover study of four dosage regimens of lansoprazole in two groups of normal male subjects. Model parameters were estimated by nonlinear regression and were compared to historical values reported in the literature. The predicted mean gastric ion concentration was 23.2 mM (pH 1.6) with the peak time at 12.6 hours (8:30 p.m.), and the half-time for H+ removal from the stomach averaged 1.7 hours. The estimated half-life of gastric food removal was 0.8 hours. The rate constant for normal H+/K+-ATPase degradation was 0.045 h(-1). The pharmacodynamic parameter describing lansoprazole action on gastric acid secretion was the second-order enzyme inactivation constant, which averaged 0.16 microg(-1) x L x h(-1). The parameters obtained for both the baseline and drug treatment data were consistent with the literature and physiologically relevant with the exception of effective food volume, which was large presumably due to buffer effects. The model successfully incorporated the physiological regulation of gastric acid production, the effects of food on gastric acid, and the effects of multiple-dosing regimens of lansoprazole on gastric acid production to give reasonable profiles of gastric pH. [ABSTRACT FROM AUTHOR]

The independent as well as interactive effects of chronic (greater than 6 months) oral contraceptive (OC) use and cigarette smoking on single- dose (4 mg/kg) theophylline disposition were assessed in 49 young, healthy women. Significant elevations (40%) in theophylline plasma clearance were found in women who smoked. OC use resulted in decreases in clearance of a similar magnitude (28%). These factors do not appear to interact with respect to theophylline disposition. The combination of main effects tended to cancel one another (clearance of 49.1 ml h-1 kg-1 ideal body weight for OC non-user, non-smoker, vs 49.7 ml h-1 kg-1 for OC user-smoker). Single dose exposure to OC in non-users did not significantly alter theophylline pharmacokinetics for the group as a whole. However, in the subgroup of smoking subjects, significant decreases in clearance were evident (P less than 0.05). Analogous results were found for half-life. Volume of distribution was slightly diminished in smokers, but was unaffected in OC users. Areas under the serum concentration-time (AUC) profiles of norgestrel and ethinyloestradiol were examined in 27 women as indices of OC exposure. The smallest values of theophylline clearance were found in the subjects with largest AUC of both OC steroids. Appropriate statistical analyses of data which are influenced by multiple factors are discussed. Special concern is needed when the factor partitioning process yields subgroups of unequal sizes. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (T k0 , duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population T k0 was 3.14 h yielding an average zero-order absorption rate (k 0 ) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on T k0 ). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD., (© 2024, The American College of Clinical Pharmacology.)

The pharmacokinetics (PK) of methylprednisolone (MPL) exhibited tissue-specific saturable binding and reversible conversion with its metabolite, methylprednisone (MPN). Blood and 11 tissues were collected in male rats after intravenous (i.v.) bolus doses of 50 mg/kg MPL and 20 mg/kg MPN and upon i.v. infusion of MPL and MPN at 0.3, 3, and 10 mg/h per kg. The concentrations of MPL and MPN were simultaneously measured. A comprehensive physiologically based pharmacokinetic (PBPK) model was applied to describe the plasma and tissue profiles and estimate PK parameters of the MPL/MPN interconversion system. Both dosed and formed MPL and MPN were in rapid equilibrium or achieved steady-state rapidly in plasma and tissues. MPL tissue partitioning was nonlinear, with highest capacity in liver (322.9 ng/ml) followed by kidney, heart, intestine, skin, spleen, bone, brain, muscle, and lowest in adipose (2.74 ng/ml) and displaying high penetration in lung. The tissue partition coefficient of MPN was linear but widely variable (0.15∼5.38) across most tissues, with nonlinear binding in liver and kidney. The conversion of MPL to MPN occurred in kidney, lung, and intestine with total clearance of 429 ml/h, and the back conversion occurred in liver and kidney at 1342 ml/h. The irreversible elimination clearance of MPL was 789 ml/h from liver and that of MPN was 2758 ml/h with liver accounting for 44%, lung 35%, and kidney 21%. The reversible metabolism elevated MPL exposure in rats by 13%. This highly complex PBPK model provided unique and comprehensive insights into the disposition of a major corticosteroid. SIGNIFICANCE STATEMENT: Our dual physiologically based pharmacokinetic (PBPK) study and model of methylprednisolone/methylprednisone (MPL/MPN) with multiple complexities reasonably characterized and parameterized their disposition, and provided greater insights into the interpretation of their pharmacodynamics in rats. Drug knowledge gained in this study may be translatable to higher-order species to appreciate the clinical utility of MPL. The complex model itself is instructive for advanced PBPK analysis of drugs with reversible metabolism and/or nonlinear tissue partitioning features., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

The classical organ clearance models have been proposed to relate the plasma clearance CL p to probable mechanism(s) of hepatic clearance. However, the classical models assume the intrinsic capability of drug elimination (CL u,int ) that is physically segregated from the vascular blood but directly acts upon the unbound drug concentration in the blood (f ub C avg ), and do not handle the transit-time delay between the inlet/outlet concentrations in their closed-form clearance equations. Therefore, we propose unified model structures that can address the internal blood concentration patterns of clearance organs in a more mechanistic/physiological manner, based on the fractional distribution parameter f d operative in PBPK. The basic partial/ordinary differential equations for four classical models are revisited/modified to yield a more complete set of extended clearance models, i.e., the Rattle, Sieve, Tube, and Jar models, which are the counterparts of the dispersion, series-compartment, parallel-tube, and well-stirred models. We demonstrate the feasibility of applying the resulting extended models to isolated perfused rat liver data for 11 compounds and an example dataset for in vitro-in vivo extrapolation of the intrinsic to the systemic clearances. Based on their feasibilities to handle such real data, these models may serve as an improved basis for applying clearance models in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is often chemotherapy-resistant, and novel drug combinations would fill an unmet clinical need. Previously we reported synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells, but underlying protein-level interaction mechanisms remained unclear. We employed a reliable, sensitive, comprehensive, quantitative, high-throughput IonStar proteomic workflow to investigate the time course of gemcitabine and trabectedin effects, alone and combined, upon pancreatic cancer cells. MiaPaCa-2 cells were incubated with vehicle (controls), gemcitabine, trabectedin, and their combinations over 72 hours. Samples were collected at intervals and analyzed using the label-free IonStar liquid chromatography-mass spectrometry (LC-MS/MS) workflow to provide temporal quantification of protein expression for 4,829 proteins in four experimental groups. To characterize diverse signal transduction pathways, a comprehensive systems pharmacodynamic (SPD) model was developed. The analysis is presented in two parts. Here, Part I describes drug responses in cancer cell growth and migration pathways included in the full model: receptor tyrosine kinase- (RTK), integrin-, G-protein coupled receptor- (GPCR), and calcium-signaling pathways. The developed model revealed multiple underlying mechanisms of drug actions, provides insight into the basis of drug interaction synergism, and offers a scientific rationale for potential drug combination strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Despite decades of research efforts, pancreatic adenocarcinoma (PDAC) continues to present a formidable clinical challenge, demanding innovative therapeutic approaches. In a prior study, we reported the synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells. To investigate potential mechanisms underlying this synergistic pharmacodynamic interaction, liquid chromatography-mass spectrometry-based proteomic analysis was performed, and a systems pharmacodynamics model (SPD) was developed to capture pancreatic cancer cell responses to gemcitabine and trabectedin, alone and combined, at the proteome level. Companion report Part I describes the proteomic workflow and drug effects on the upstream portion of the SPD model related to cell growth and migration, specifically the RTK-, integrin-, GPCR-, and calcium-signaling pathways. This report presents Part II of the SPD model. Here we describe drug effects on pathways associated with cell cycle, DNA damage response (DDR), and apoptosis, and provide insights into underlying mechanisms. Drug combination effects on protein changes in the cell cycle- and apoptosis pathways contribute to the synergistic effects observed between gemcitabine and trabectedin. The SPD model was subsequently incorporated into our previously-established cell cycle model, forming a comprehensive, multi-scale quantification platform for evaluating drug effects across multiple scales, spanning the proteomic-, cellular-, and subcellular levels. This approach provides a quantitative mechanistic framework for evaluating drug-drug interactions in combination chemotherapy, and could potentially serve as a tool to predict combinatorial efficacy and assist in target selection., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Minimal physiologically based pharmacokinetic (mPBPK) models are physiologically relevant, require less information than full PBPK models, and offer flexibility in pharmacokinetics (PK). The well-stirred hepatic model (WSM) is commonly used in PBPK, whereas the more plausible dispersion model (DM) poses computational complexities. The series-compartment model (SCM) mimics the DM but is easier to operate. This work implements the SCM and mPBPK models for assessing fractional tissue distribution, oral absorption, and hepatic clearance using literature-reported blood and liver concentration-time data in rats for compounds mainly cleared by the liver. Further handled were various complexities, including nonlinear hepatic binding and metabolism, differing absorption kinetics, and sites of administration. The SCM containing one to five ( n ) liver subcompartments yields similar fittings and provides comparable estimates for hepatic extraction ratio ( ER ), prehepatic availability ( F g ), and first-order absorption rate constants ( k a ). However, they produce decreased intrinsic clearances ( CL int ) and liver-to-plasma partition coefficients ( K ph ) with increasing n as expected. Model simulations demonstrated changes in intravenous and oral PK profiles with alterations in K ph and k a and with hepatic metabolic zonation. The permeability (PAMPA P ) of the various compounds well explained the fitted fractional distribution ( f d ) parameters. The SCM and mPBPK models offer advantages in distinguishing systemic, extrahepatic, and hepatic clearances. The SCM allows for incorporation of liver zonation and is useful in assessing changes in internal concentration gradients potentially masked by similar blood PK profiles. Improved assessment of intraorgan drug concentrations may offer insights into active moieties driving metabolism, biliary excretion, pharmacodynamics, and hepatic toxicity. SIGNIFICANCE STATEMENT: The minimal physiologically based pharmacokinetic model and the series-compartment model are useful in assessing oral absorption and hepatic clearance. They add flexibility in accounting for various drug- or system-specific complexities, including fractional distribution, nonlinear binding and saturable hepatic metabolism, and hepatic zonation. These models can offer improved insights into the intraorgan concentrations that reflect physiologically active moieties often driving disposition, pharmacodynamics, and toxicity., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Dexamethasone (DEX) given at a dose of 6 mg once-daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID-19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti-inflammatory effects in COVID-19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed-effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID-19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL-6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL-6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti-inflammatory compounds as well as drug combinations in the treatment of cytokine storms., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Minimal physiologically-based pharmacokinetic (mPBPK) models are an alternative to full physiologically-based pharmacokinetic (PBPK) models as they offer reduced complexity while maintaining the physiological interpretation of key model components. Full PBPK models have been developed for pregnancy, but a mPBPK model eases the ability to perform a "top-down" meta-analysis melding all available pharmacokinetic (PK) data in the mother and fetus. Our hybrid mPBPK model consists of mPBPK models for the mother and fetus with connection by the placenta. This model was applied to describe the rich PK data of antenatal corticosteroid betamethasone (BET) jointly with the limited data for dexamethasone (DEX) in the mother and fetus. Physiologic model parameters were obtained from the literature while drug-dependent parameters were estimated by the simultaneous fitting of all available data for DEX and BET. Maternal clearances of DEX and BET confirmed the literature values, and the expected fetal-to-maternal plasma ratios ranged from 0.3 to 0.4 for both drugs. Simulations of maternal plasma concentrations for the dosing regimens of BET and DEX recommended by the World Health Organization based on our findings revealed up to 60% lower exposures than found in nonpregnant women and offers a means of devising alternative dosing regimens. Our hybrid mPBPK model and meta-analysis approach could facilitate assessment of other classes of drugs indicated for the treatment of pregnant women., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Among the basic hepatic clearance models, the dispersion model (DM) is the most physiologically sound compared with the well-stirred model and the parallel tube model. However, its application in physiologically-based pharmacokinetic (PBPK) modeling has been limited due to computational complexities. The series compartment models (SCM) of hepatic elimination that treats the liver as a cascade of well-stirred compartments connected by hepatic blood flow exhibits some mathematical similarities to the DM but is easier to operate. This work assesses the quantitative correlation between the SCM and DM and demonstrates the operation of the SCM in PBPK with the published single-dose blood and liver concentration-time data of six flow-limited compounds. The predicted liver concentrations and the estimated intrinsic clearance ( CL int ) and PBPK-operative tissue-to-plasma partition coefficient ( K p ) values were shown to depend on the number of liver sub-compartments ( n ) and hepatic enzyme zonation in the SCM. The CL int and K p decreased with increasing n , with more remarkable differences for drugs with higher hepatic extraction ratios. Given the same total CL int , the SCM yields a higher K p when the liver perivenous region exhibits a lower CL int as compared with a high CL int at this region. Overall, the SCM nicely approximates the DM in characterizing hepatic elimination and offers an alternative flexible approach as well as providing some insights regarding sequential drug concentrations in the liver. SIGNIFICANCE STATEMENT: The SCM nicely approximates the DM when applied in PBPK for characterizing hepatic elimination. The number of liver sub-compartments and hepatic enzyme zonation are influencing factors for the SCM resulting in model-dependent predictions of total/internal liver concentrations and estimates of CL int and the PBPK-operative K p . Such model-dependency may have an impact when the SCM is used for in vitro-to-in vivo extrapolation (IVIVE) and may also be relevant for PK/PD/toxicological effects when it is the driving force for such responses., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Dexamethasone (DEX) is a potent synthetic glucocorticoid used for the treatment of variety of inflammatory and immune-mediated disorders. The RECOVERY clinical trial revealed benefits of DEX therapy in COVID-19 patients. Severe SARS-CoV-2 infection leads to an excessive inflammatory reaction commonly known as a cytokine release syndrome that is associated with activation of the toll like receptor 4 (TLR4) signaling pathway. The possible mechanism of action of DEX in the treatment of COVID-19 is related to its anti-inflammatory activity arising from inhibition of cytokine production but may be also attributed to its influence on immune cell trafficking and turnover. This study, by means of pharmacokinetic/pharmacodynamic modeling, aimed at the comprehensive quantitative assessment of DEX effects in lipopolysaccharide-challenged rats and to describe interrelations among relevant signaling molecules in this animal model of cytokine release syndrome induced by activation of TLR4 pathway. DEX was administered in a range of doses from 0.005 to 2.25 mg·kg -1 in LPS-challenged rats. Serum DEX, corticosterone (CST), tumor necrosis factor α , interleukin-6, and nitric oxide as well as lymphocyte and granulocyte counts in peripheral blood were quantified at different time points. A minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model was proposed characterizing the time courses of plasma DEX and the investigated biomarkers. A high but not complete inhibition of production of inflammatory mediators and CST was produced in vivo by DEX. The mPBPK/PD model, upon translation to humans, may help to optimize DEX therapy in patients with diseases associated with excessive production of inflammatory mediators, such as COVID-19. SIGNIFICANCE STATEMENT: A mPBPK/PD model was developed to describe concentration-time profiles of plasma DEX, mediators of inflammation, and immune cell trafficking and turnover in LPS-challenged rats. Interrelations among DEX and relevant biomarkers were reflected in the mechanistic model structure. The mPBPK/PD model enabled quantitative assessment of in vivo potency of DEX and, upon translation to humans, may help optimize dosing regimens of DEX for the treatment of immune-related conditions associated with exaggerated immune response., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

In minimal physiologically based pharmacokinetic (mPBPK) models, physiological (e.g., cardiac output) and anatomical (e.g., blood/tissue volumes) variables are utilized in the domain of differential equations (DEs) for mechanistic understanding of the plasma concentration-time relationships [Formula: see text]. Although fundamental biopharmaceutical variables in terms of distribution (e.g., [Formula: see text] and [Formula: see text]) and elimination kinetics (e.g., [Formula: see text]) in mPBPK provide greater insights in comparison to classical compartment models, an absence of kinetic elucidation of slopes and intercepts in light of such DE model parameters hinders more intuitive appreciation of [Formula: see text]. Therefore, this study seeks the tangible physical meanings of slopes and intercepts of the plasma concentration-time relationships in one- and two-tissue mPBPK models (i.e., m2CM and m3CM), with respect to time parameters that are readily understandable in PK analyses, i.e., the mean residence ([Formula: see text]) and transit ([Formula: see text]) times. Utilizing the explicit equations (EEs) for the slopes, intercepts, and areas of each exponential phase in the m2CM and m3CM, we theoretically and numerically examined the limiting/boundary conditions of such kinetic properties, based on the ratio of the longest tissue [Formula: see text] to the [Formula: see text] in the body (i.e., [Formula: see text]) that is useful for dissecting complex PBPK systems. The kinetic contribution of the area of each exponential phase to the total drug exposure was assessed to identify the elimination phase between the terminal and non-terminal phases of the [Formula: see text] in the m2CM and m3CM. This assessment provides improved understanding of the complexities inherent in all PBPK profiles and models., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The primary models used in pharmacokinetics (PK) to assess hepatic clearance ( CL h ) are the well-stirred (WSM), parallel tube (PTM), and dispersion model (DM) that differ in their internal flow patterns and assumed unbound liver concentrations. Physiologically-Based Pharmacokinetic (PBPK) models require a hepatic intrinsic clearance ( CL int ) and tissue-to-plasma partition coefficient ( K p ). Given measured systemic and liver concentration-time profiles, these hepatic models perform similarly but yield model-specific CL int and K p estimates. This work provides mathematical relationships for the three basic hepatic models and assesses their corresponding PBPK-relevant K p values with literature-reported single-dose blood and liver concentration-time data of 14 compounds. Model fittings were performed with an open-loop approach where the CL h and extraction ratio ( ER ) were first estimated from fitting the blood data yielding CL int values for the three hepatic models. The pre-fitted blood data served as forcing input functions to obtain PBPK-operative K p estimates that were compared with those obtained by the tissue/plasma area ratio (AR), Chen & Gross (C&G) and published in silico methods. The CL int and K p values for the hepatic models increased with the ER and both showed a rank order being WSM > DM > PTM. Drugs with low ER showed no differences as expected. With model-specific CL int and K p values, all hepatic models predict the same steady-state K p ( K p ss ) that is comparable to those from the AR and C&G methods and reported by direct measurement. All in silico methods performed poorly for most compounds. Hepatic model selection requires cautious application and interpretation in PBPK modeling. Significance Statement The three hepatic models generate different single-dose (non-steady-state) values of CL int and K p in PBPK models especially for drugs with high ER ; however, all K p ss values expected from constant rate infusion studies were the same. These findings are relevant when using these models for IVIVE where a model-dependent CL int is used to correct measured tissue concentrations for depletion by metabolism. This model-dependency may also have an impact when assessing the PK/pharmacodynamic relationships when effects relate to assumed hepatic concentrations., (Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics.)

Therapeutic responses of most drugs are initiated by the rate and degree of binding to their receptors or targets. The law of mass action describes the rate of drug-receptor complex association (k on ) and dissociation (k off ) where the ratio k off /k on is the equilibrium dissociation constant (K d ). Drugs with slow reversible binding (SRB) often demonstrate delayed onset and prolonged pharmacodynamic effects. This report reviews evidence for drugs with SRB features, describes previous pharmacokinetic/pharmacodynamic (PK/PD) modeling efforts of several such drugs, provides a tutorial on the mathematics and properties of SRB models, demonstrates applications of SRB models to additional compounds, and compares PK/PD fittings of SRB with other mechanistic models. We identified and summarized 52 drugs with in vitro-confirmed SRB from a PubMed literature search. Simulations with a SRB model and observed PK/PD profiles showed delayed and prolonged responses and that increasing doses/k on or decreasing k off led to greater expected maximum effects and a longer duration of effects. Recession slopes for return of responses to baseline after single doses were nearly linear with an inflection point that approaches a limiting value at larger doses. The SRB model newly captured literature data for the antihypertensive effects of candesartan and antiallergic effects of noberastine. Their PD profiles could also be fitted with indirect response and biophase models with minimal differences. The applicability of SRB models is probably commonplace, but underappreciated, owing to the need for in vitro confirmation of binding kinetics and the similarity of PK/PD profiles to models with other mechanistic determinants., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pancreatic adenocarcinoma (PDAC) is highly refractory to treatment. Standard-of-care gemcitabine (Gem) provides only modest survival benefits, and development of Gem resistance (GemR) compromises its efficacy. Highly GemR clones of Gem-sensitive MIAPaCa-2 cells were developed to investigate the molecular mechanisms of GemR and implemented global quantitative differential proteomics analysis with a comprehensive, reproducible ion-current-based MS1 workflow to quantify ∼6000 proteins in all samples. In GemR clone MIA-GR8, cellular metabolism, proliferation, migration, and 'drug response' mechanisms were the predominant biological processes altered, consistent with cell phenotypic alterations in cell cycle and motility. S100 calcium binding protein A4 was the most downregulated protein, as were proteins associated with glycolytic and oxidative energy production. Both responses would reduce tumor proliferation. Upregulation of mesenchymal markers was prominent, and cellular invasiveness increased. Key enzymes in Gem metabolism pathways were altered such that intracellular utilization of Gem would decrease. Ribonucleoside-diphosphate reductase large subunit was the most elevated Gem metabolizing protein, supporting its critical role in GemR. Lower Ribonucleoside-diphosphate reductase large subunit expression is associated with better clinical outcomes in PDAC, and its downregulation paralleled reduced MIAPaCa-2 proliferation and migration and increased Gem sensitivity. Temporal protein-level Gem responses of MIAPaCa-2 versus GemR cell lines (intrinsically GemR PANC-1 and acquired GemR MIA-GR8) implicate adaptive changes in cellular response systems for cell proliferation and drug transport and metabolism, which reduce cytotoxic Gem metabolites, in DNA repair, and additional responses, as key contributors to the complexity of GemR in PDAC. These findings additionally suggest targetable therapeutic vulnerabilities for GemR PDAC patients., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In pharmacokinetic (PK) analyses, the biological half-life T 1/2 is usually determined in the terminal phase after drug administration, which is readily calculated from the relationship T 1/2 = ln2/λ z where λ z is the terminal-phase slope obtainable from non-compartmental analysis (NCA). Since kinetic understanding of λ z has been limited to the theory of a one-compartment model, this study seeks kinetic determinants of λ z in more complex plasma concentration-time profiles. We utilized physiologically based pharmacokinetic (PBPK) systems that are consistent with the assumptions of NCA (e.g., linear PK and elimination occurring from plasma) to interrelate λ z and disposition kinetic parameters of PBPK models. In a mammillary form of PBPK models, the two boundary conditions of λ z are the inverses of the mean residence time in the body (1/MRT B  = CL/V SS ) and the mean transit time through the kinetically largest tissue (1/MTT max  = Q T f d R b /V T K p ). Importantly, the limiting conditions of λ z between 1/MRT B and 1/MTT max are dependent on a simple product MRT B λ z (P det ) and a simple ratio MTT max /MRT B (K det ), leading to introduction of the unitless product-ratio plot for determination of the limiting condition of λ z in linear PK. We found that the MRT B λ z value of 0.5 serves as a practical threshold determining whether λ z is more closely associated with 1/MRT B or 1/MTT max . The current theory was applied for assessment of the terminal slope λ z for observed PK data of various compounds in man and rat., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Autoimmune hepatitis (AIH) is a life-threatening disorder currently treated with nonspecific immunosuppressive drugs. It is postulated that phosphodiesterase (PDE) inhibitors, as agents exerting anti-inflammatory and immunomodulatory activities, may constitute a possible treatment of autoimmune disorders. This study develops a pharmacokinetic/pharmacodynamic (PK/PD) model to assess the effects of PDE-selective inhibitors, namely, cilostazol (PDE3), rolipram (PDE4), and BRL-50481 (PDE7), in a mouse model of AIH. The pharmacokinetics of the PDE inhibitors (PDEi) were assessed in male BALB/c mice after intraperitoneal administration. In pharmacodynamic studies, mice received PDEi and AIH was induced in these animals by intravenous injection of concanavalin A (ConA). Serum drug concentrations, tumor necrosis factor α (TNF α ), interleukin 17 (IL-17), and aminotransferase activities were quantified. The PK/PD analysis was performed using ADAPT5 software. The PK/PD model assumes inhibition of cAMP hydrolysis in T cells by PDEi, ConA-triggered formation of TNF α and IL-17, suppression of TNF α and IL-17 production by cAMP, and stimulatory effects of TNF α and IL-17 on the hepatic release of aminotransferases. Selective blockage of PDE4 leads to the highest inhibition of cAMP degradation in T cells and amelioration of disease outcomes. However, inhibition of both PDE3 and PDE7 also contribute to this effect. The proposed PK/PD model may be used to assess and predict the activities of novel PDEi and their combinations in ConA-induced hepatitis. A balanced suppression of different types of PDE appears to be a promising treatment option for AIH; however, this hypothesis warrants testing in humans based on translation of the PK/PD model into clinical settings. SIGNIFICANCE STATEMENT: A novel PK/PD model of PDE inhibitor effects in mice with ConA-induced autoimmune hepatitis was developed involving a mechanistic component describing changes in cAMP concentrations in mouse T cells. According to model predictions, inhibition of PDE4 in T cells causes the highest cAMP elevation in T cells, but suppression of PDE3 and PDE7 also contribute to this effect. A balanced inhibition of PDE3, PDE4, and PDE7 appears to be a promising treatment strategy for AIH., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: The tissue-to-plasma partition coefficient (K p ) describes the extent of tissue distribution in physiologically-based pharmacokinetic (PBPK) models. Constant-rate infusion studies are common for experimental determination of the steady-state K p,ss , while the tissue-plasma concentration ratio (C T /C p ) in the terminal phase after intravenous doses is often utilized. The Chen and Gross (C&G) method converts a terminal slope C T /C p to K p,ss based on assumptions of perfusion-limited distribution in tissue-plasma equilibration. However, considering blood flow (Q T ) and apparent tissue permeability (f up PS in ) in the rate of tissue distribution, this report extends the C&G method by utilizing a fractional distribution parameter (f d )., Methods: Relevant PBPK equations for non-eliminating and eliminating organs along with lung and liver were derived for the conversion of C T /C p values to K p,ss . The relationships were demonstrated in rats with measured C T /C p and K p,ss values and the model-dependent f d for 8 compounds with a range of permeability coefficients. Several methods of assessing K p were compared., Results: Utilizing f d in an extended C&G method, our estimations of K p,ss from C T /C p were improved, particularly for lower permeability compounds. However, four in silico methods for estimating K p performed poorly across tissues in comparison with measured K p values. Mathematical relationships between K p and K p,ss that are generally applicable for eliminating organs with tissue permeability limitations necessitates inclusion of an extraction ratio (ER) and f d ., Conclusion: Since many different types/sources of K p are present in the literature and used in PBPK models, these perspectives and equations should provide better insights in measuring and interpreting K p values in PBPK., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first-in-human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose-related PD effects were observed (e.g., a mechanism-based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically-based pharmacokinetic (mPBPK) models with target-mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa-mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development., (© 2021 CSL Behring LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This report reviews concepts related to operation of the classic parallel-tube model (PTM) for hepatic disposition and examines two recent proposals of a newly derived equation to describe hepatic clearance (CL H ). It is demonstrated that the proposed equation is identical to a re-arrangement of an earlier relationship from Pang and Rowland and provides a means of calculation of intrinsic clearance (CL int,PTM ) rather than CL H as posed. We further demonstrate how classic hepatic clearance models with an assumed CL int , while subject to numerous limitations, remain highly useful and necessary in both traditional pharmacokinetics (PK) and physiologically based pharmacokinetic (PBPK) modeling., (© 2021. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The objective of this study was to systematically assess literature datasets and quantitatively analyze metformin PK in plasma and some tissues of nine species. The pharmacokinetic (PK) parameters and profiles of metformin in nine species were collected from the literature. Based on a simple allometric scaling, the systemic clearances (CL) of metformin in these species highly correlate with body weight (BW) (R 2 = 0.85) and are comparable to renal plasma flow in most species except for rabbit and cat. Reported volumes of distribution (VSS) varied appreciably (0.32 to 10.1 L/kg) among species. Using the physiological and anatomical variables for each species, a minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue compartments (Tissues 1 and 2) was used for modeling metformin PK in the nine species. Permeability-limited distribution (low fd1 and fd2) and a single tissue-to-plasma partition coefficient (Kp) value for Tissues 1 and 2 were applied in the joint mPBPK fitting. Nonlinear regression analysis for common tissue distribution parameters along with species-specific CL values reasonably captured the plasma PK profiles of metformin across most species, except for rat and horse with later time deviations. In separate fittings of the mPBPK model to each species, Tissue 2 was considered as slowly-equilibrating compartment consisting of muscle and skin based on in silico calculations of the mean transit times through tissues. The well-fitted mPBPK model parameters for absorption and disposition PK of metformin for each species were compared with in vitro/in vivo results found in the literature with regard to the physiological details and physicochemical properties of metformin. Bioavailability and absorption rates decreased with the increased BW among the species. Tissues such as muscle dominate metformin distribution with low permeability and partitioning while actual tissue concentrations found in rats and mice show likely transporter-mediated uptake in liver, kidney, and gastrointestinal tissues. Metformin has diverse pharmacologic actions, and this assessment revealed allometric relationships in its absorption and renal clearance but considerable variability in actual and modeled tissue distribution probably caused by transporter differences.

A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle). A genome-wide pathway-centric analysis enables us to develop a comprehensive picture on how the observed circadian variation at the individual gene level, orchestrates functional responses at the pathway level. Such pathway-based "meta-data" analysis enables the rational integration and comparison across platforms and/or experimental designs evaluating emergent dynamics, as opposed to comparisons of individual elements. One of our key findings is that when considering the dynamics at the pathway level, a complex behavior emerges. Our work proposes that tissues tend to coordinate gene's circadian expression in a way that optimizes tissue-specific pathway activity, depending of each tissue's broader role in homeostasis.

To align with daily environmental changes, most physiological processes in mammals exhibit a time-of-day rhythmicity. This circadian control of physiology is intrinsically driven by a cell-autonomous clock gene network present in almost all cells of the body that drives rhythmic expression of genes that regulate numerous molecular and cellular processes. Accordingly, many aspects of pharmacology and toxicology also oscillate in a time-of-day manner giving rise to diverse effects on pharmacokinetics and pharmacodynamics. Genome-wide studies and mathematical modeling are available tools that have significantly improved our understanding of these nonlinear aspects of physiology and therapeutics. In this manuscript current literature and our prior work on the model-based approaches that have been used to explore circadian genomic systems of mammals are reviewed. Such basic understanding and having an integrative approach may provide new strategies for chronotherapeutic drug treatments and yield new insights for the restoration of the circadian system when altered by diseases.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Overall, BET exhibited slower clearance, similar volume of distribution, faster absorption, and longer persistence than DEX with BET acetate producing extremely slow absorption but full bioavailability of BET. Six biomarkers were assessed over a 24-h baseline period with four showing circadian rhythms with complex baselines. These baselines and the strong responses seen after drug dosing were fitted with various indirect response models using the Laplace estimation methods in NONMEM 7.4. Both the PK and six biomarker responses were well-described with modest variability likely due to the homogeneous ages, weights, and ethnicities of the women. The drugs either inhibited or stimulated the influx processes with some models requiring joint inclusion of drug effects on circadian cortisol suppression. The biomarkers and order of sensitivity (lowest IC 50 /SC 50 to highest) were: cortisol, T-helper cells, basophils, glucose, neutrophils, and T-cytotoxic cells. DEX sensitivities were generally greater than BET with corresponding mean ratios for these biomarkers of 2.86, 1.27, 1.72, 1.27, 2.69, and 1.06. Overall, the longer PK (e.g. half-life) of BET, but lesser PD activity (e.g. higher IC 50 ), produces single-dose response profiles that appear quite similar, except for the extended effects from BET-PA. This comprehensive population modeling effort provides the first detailed comparison of the PK profiles and six biomarker responses of five commonly used dosage forms of DEX and BET in healthy women.