Publications by authors named "William J Jusko"

230 Publications

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women.

J Pharmacokinet Pharmacodyn 2021 Jun 5;48(3):411-438. Epub 2021 May 5.

School of Pharmacy and Pharmaceutical Sciences, State University of New York, University at Buffalo, Buffalo, NY, USA.

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/SC 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), 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.
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http://dx.doi.org/10.1007/s10928-021-09755-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099395PMC
June 2021

Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

J Pharmacokinet Pharmacodyn 2021 Jun 25;48(3):361-374. Epub 2021 Mar 25.

Biomedical Engineering Department, Rutgers University, Piscataway, NJ, USA.

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.
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http://dx.doi.org/10.1007/s10928-021-09750-3DOI Listing
June 2021

Synergistic Pharmacodynamic Effects of Gemcitabine and Fibroblast Growth Factor Receptor Inhibitors on Pancreatic Cancer Cell Cycle Kinetics and Proliferation.

J Pharmacol Exp Ther 2021 Jun 22;377(3):370-384. Epub 2021 Mar 22.

Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York (R.M.S.; Z.Q., W.J.J., D.E.M.); Departments of Cell Stress Biology (Q.L., R.M.S.) and Pharmacology and Therapeutics (R.M.S.), Roswell Park Comprehensive Cancer Center, Buffalo, New York; and Department of Medicine, Mayo Clinic, Rochester, Minnesota (W.W.M.)

Median survival of pancreatic ductal adenocarcinoma cancer (PDAC) is 6 months, with 9% 5-year survival. Standard-of-care gemcitabine (Gem) provides only modest survival benefits, and combination therapies integrating novel targeted agents could improve outcomes. Fibroblast growth factor (FGF) receptors (FGFRs) play important roles in PDAC growth and invasion. Therefore, FGFR inhibitors (FGFRi) merit further investigation. Efficacy of Gem combined with NVP-BGJ398, a pan-FGFRi, was investigated in multiple PDAC cell lines exposed to the drugs alone and combined. Cell cycle distribution and cell numbers were quantified over time. Two pharmacodynamic models were developed to investigate Gem/BGJ398 interactions quantitatively: a drug-mediated cell proliferation/death model, and a drug-perturbed cell cycle progression model. The models captured temporal changes in cell numbers, cell cycle progression, and cell death during drug exposure. Simultaneous fitting of all data provided reasonable parameter estimates. Therapeutic efficacy was then evaluated in a PDAC mouse model. Compared with Gem alone, combined Gem + FGFRi significantly downregulated ribonucleotide-diphosphate reductase large subunit 1 (RRM1), a gemcitabine resistance (GemR) biomarker, suggesting the FGFRi inhibited GemR emergence. The cell proliferation/death pharmacodynamic model estimated the drug interaction coefficient = 0.798, suggesting synergistic effects. The mechanism-based cell cycle progression model estimated drug interaction coefficient = 0.647, also suggesting synergy. Thus, FGFR inhibition appears to synergize with Gem in PDAC cells and tumors by sensitizing cells to Gem-mediated inhibition of proliferation and cell cycle progression. SIGNIFICANCE STATEMENT: An integrated approach of quantitative modeling and experimentation was employed to investigate the nature of fibroblast growth factor receptor inhibitor (FGFRi)/gemcitabine (Gem) interaction, and to identify mechanisms by which FGFRi exposure reverses Gem resistance in pancreatic cancer cells. The results show that FGFRi interacts synergistically with Gem to sensitize pancreatic cancer cells and tumors to Gem-mediated inhibition of proliferation and cell cycle progression. Thus, addition of FGFRi to standard-of-care Gem treatment could be a clinically deployable approach to enhance therapeutic benefit to pancreatic cancer patients.
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http://dx.doi.org/10.1124/jpet.120.000412DOI Listing
June 2021

Mathematical modeling of mammalian circadian clocks affecting drug and disease responses.

J Pharmacokinet Pharmacodyn 2021 Jun 16;48(3):375-386. Epub 2021 Mar 16.

State University of New York, School of Pharmacy and Pharmaceutical Sciences, University of Buffalo, Buffalo, NY, USA.

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.
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http://dx.doi.org/10.1007/s10928-021-09746-zDOI Listing
June 2021

Across-species meta-analysis of dexamethasone pharmacokinetics utilizing allometric and scaling modeling approaches.

Biopharm Drug Dispos 2021 May 17;42(5):191-203. Epub 2021 Mar 17.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.

The pharmacokinetic (PK) parameters of dexamethasone (DEX) in 11 species were collected from the literature and clearances (CL) assessed by basic allometric methods, and concentration-time course profiles were fitted using two PK models incorporating physiological or allometric scaling. Plots of log CL vs. log body weights (BW) correlated reasonably with R  = 0.91, with a maximum ratio of actual to fitted CL of 6 (for pig). A minimal physiologically-based pharmacokinetic (mPBPK) model containing blood and two lumped tissue compartments and integrated utilization of physiological parameters was compared to an allometric two-compartment model (a2CM). The plasma PK profiles of DEX from 11 species were analyzed jointly, with the mPBPK model having conserved partition coefficients (K ), physiologic blood and tissue volumes, and species-specific CL values. The DEX PK profiles were reasonably captured by the mPBPK model for 9 of 11 species in the joint analysis with three fitted parameters (besides CL) including an overall tissue-to-plasma partition coefficient of 1.07. The a2CM with distribution CL and central and peripheral volumes scaled allometrically fitted the plasma concentration profiles similarly but required a total of six parameters (besides CL). Overall, the literature reported that DEX CL values exhibit moderate variability (mean = 0.64 L/h/kg; coefficient of variation = 105%), but distribution parameters were largely conserved across most species.
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http://dx.doi.org/10.1002/bdd.2266DOI Listing
May 2021

Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women.

J Pharmacokinet Pharmacodyn 2021 Apr 3;48(2):261-272. Epub 2021 Jan 3.

School of Pharmacy and Pharmaceutical Sciences, State University of New York, University of Buffalo, Buffalo, NY, USA.

Population analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for 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). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs. Clearances and volumes were divided by the IM bioavailability [Formula: see text]. The homogeneous ages, body weights, and ethnicity of the women obviated covariate analysis. Parameter estimates were obtained by the Laplace estimation method implemented in NONMEM 7.4. Typical values for dexamethasone were clearance ([Formula: see text] of 9.29 L/h, steady-state volume ([Formula: see text] of 56.4 L, IM absorption constant [Formula: see text] of 0.460 1/h and oral absorption constant ([Formula: see text] of 0.936 1/h. Betamethasone parameters were CL/F of 5.95 L/h, [Formula: see text] of 72.4 L, [Formula: see text] of 0.971 1/h, and [Formula: see text] of 1.21 1/h. The PO to IM F values were close to 1.0 for both drugs. The terminal half-lives averaged about 7.5 h for DEX, 17 h for BET, and 78 h for BET from BET-PA with the latter reflecting very slow release of BET from the acetate ester. Overall, BET exhibited slower clearance, larger volume of distribution, faster absorption, and longer persistence than DEX. These data may be useful in considering exposures when substituting one form of corticosteroid for another.
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http://dx.doi.org/10.1007/s10928-020-09730-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778726PMC
April 2021

Physiologically Based Pharmacokinetics of Lysosomotropic Chloroquine in Rat and Human.

J Pharmacol Exp Ther 2021 02 4;376(2):261-272. Epub 2020 Dec 4.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York

A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human concentration versus time data. The PBPK model in rat featured plasma and red blood cell (RBC) concentrations, extensive and apparent nonlinear tissue distribution, fitted hepatic and renal intrinsic clearances, and a plasma half-life of about 1 day. Tissue-to-plasma CQ ratios at 50 hours after dosing were highest in lung, kidney, liver, and spleen (182-318) and lower in heart, muscle, brain, eye, and skin (11-66). The RBC-to-plasma ratio of 11.6 was assumed to reflect cell lipid partitioning. A lysosome-based extended model was used to calculate subcellular CQ concentrations based on tissue mass balances, fitted plasma, interstitial and free cytosol concentrations, and literature-based pH and pKa values. The CQ tissue component concentrations ranked as follows: lysosome > > acidic phospholipid > plasma = interstitial = cytosol ≥ neutral lipids. The extensive lysosome sequestration appeared to change over time and was attributed to lowering pH values caused by proton pump influx of hydrogen ions. The human-to-rat volume of distribution () ratio of 7 used to scale rat tissue partitioning to human along with estimation of hepatic clearance allowed excellent fitting of oral-dose PK (150-600 mg) of CQ with a 50-day half-life in humans. The prolonged PK of chloroquine was well characterized for rat and human with this PBPK model. The calculated intratissue concentrations and lysosomal effects have therapeutic relevance for CQ and other cationic drugs. SIGNIFICANCE STATEMENT: Sequestration in lysosomes is a major factor controlling the pharmacokinetics and pharmacology of chloroquine and other cationic drugs. This report provides comprehensive physiologic modeling of chloroquine distribution in tissues and overall disposition in rat and human that reveals expected complexities and inferences related to its subcellular association with various tissue components.
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http://dx.doi.org/10.1124/jpet.120.000385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841423PMC
February 2021

Pharmacokinetics of Hormonal Contraception in Individuals with Obesity: a Review.

Curr Obstet Gynecol Rep 2020 Jun 4;9(2):72-78. Epub 2020 May 4.

Oregon Health & Science University, Portland, OR 97239, USA.

Purpose Of Review: Obesity continues to affect many women globally. In the USA, almost 40% of all women are obese and many of these women use hormonal contraception for pregnancy prevention. How well hormonal contraceptive works for these individuals has been an area of ongoing research. Pharmacokinetics (PK), the study of drug passage through the body, can shed light on how differences in physiology between obese and non-obese populations can impact drug disposition and subsequent efficacy. This review aims to reflect on these types of studies and empower clinicians with information to help tackle the challenges of the obesity epidemic and help them provide the best contraceptive options to their patients. Here, we present the basics of the mechanisms of action of hormonal contraception, fundamental pharmacokinetic principles, and the latest research into pharmacokinetics, obesity, and hormonal contraception.

Recent Findings: New studies focused on the PK of hormonal contraception in women with obesity have shown that while there are distinct differences in how steroid hormones are processed in women with different body mass indices, contraceptive efficacy is likely the same. This is replicated in studies involving a variety of hormonal contraceptive methods.

Summary: PK studies allow for a detailed analysis of steroid hormone processing in individuals with obesity. Observing PK parameters at each stage of the passage of these hormones through the body, researchers have drilled down on physiologic differences that accompany obesity. In reviewing these PK parameter differences, however, it appears that while processes are different, the end result of pregnancy prevention is likely not compromised in the setting of obesity. Emergency contraception, which functions by a different mechanism from that of continuous hormonal contraception, is the one area in which obesity has been demonstrated to impact efficacy.
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http://dx.doi.org/10.1007/s13669-020-00284-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591152PMC
June 2020

Physiologically Based Pharmacokinetic Modeling Involving Nonlinear Plasma and Tissue Binding: Application to Prednisolone and Prednisone in Rats.

J Pharmacol Exp Ther 2020 11 3;375(2):385-396. Epub 2020 Sep 3.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences (X.L., D.C.D., R.R.A., W.J.J.) and Department of Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York

The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN), and renal elimination. Blood and 11 tissues were collected from male Wistar rats after steady-state (SS) infusion and after subcutaneous boluses of 50 mg/kg of PNL. Concentrations of PNL and PN were measured by liquid chromatography-tandem mass spectrometry. Plasma and tissue profiles were described using a complex physiologically based pharmacokinetics (PBPK) model. Concentrations of PN and PNL were in rapid equilibrium in plasma and tissues. The tissue partition coefficients ( ) of PNL calculated from most subcutaneously dosed tissue and plasma areas were similar to SS infusion and in silico values. The blood-to-plasma ratio of PNL was 0.71 with similar red blood cell and unbound-plasma concentrations. Plasma protein binding (60%-90%) was related to corticosteroid-binding globulin (CBG) saturation. Tissue distribution was nonlinear. The equilibrium dissociation constant ( ) of PNL shared by all tissues was 3.01 ng/ml, with the highest binding in muscle, followed by liver, heart, intestine, and bone and the lowest binding in skin, spleen, fat, kidney, lung, and brain. Fat and bone distribution assumed access only to interstitial space. Brain PNL concentrations ( = 0.05) were low owing to presumed P-glycoprotein-mediated efflux. Clearances of CBG-free PNL were 1789 from liver and 191.2 ml/h from kidney. The PN/PNL ratio was nonlinear for plasma, spleen, heart, intestine, bone, fat, and linear for the remaining tissues. Our PBPK model with multiple complexities well described the PK profiles of PNL and PN in blood, plasma, and diverse tissues. SIGNIFICANCE STATEMENT: Because steroids, such as prednisolone and prednisone, have similar and complex pharmacokinetics properties in various species, receptors in most tissues, and multiple therapeutic and adverse actions, this physiologically based pharmacokinetics (PBPK) model may provide greater insights into the pharmacodynamic complexities of corticosteroids. The complex properties of these compounds require innovative PBPK modeling approaches that may be instructive for other therapeutic agents.
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http://dx.doi.org/10.1124/jpet.120.000191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604337PMC
November 2020

Modeling Pathway Dynamics of the Skeletal Muscle Response to Intravenous Methylprednisolone (MPL) Administration in Rats: Dosing and Tissue Effects.

Front Bioeng Biotechnol 2020 14;8:759. Epub 2020 Jul 14.

Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, United States.

A model-based approach for the assessment of pathway dynamics is explored to characterize metabolic and signaling pathway activity changes characteristic of the dosing-dependent differences in response to methylprednisolone in muscle. To consistently compare dosing-induced changes we extend the principles of pharmacokinetics and pharmacodynamics and introduce a novel representation of pathway-level dynamic models of activity regulation. We hypothesize the emergence of dosing-dependent regulatory interactions is critical to understanding the mechanistic implications of MPL dosing in muscle. Our results indicate that key pathways, including amino acid and lipid metabolism, signal transduction, endocrine regulation, regulation of cellular functions including growth, death, motility, transport, protein degradation, and catabolism are dependent on dosing, exhibiting diverse dynamics depending on whether the drug is administered acutely of continuously. Therefore, the dynamics of drug presentation offer the possibility for the emergence of dosing-dependent models of regulation. Finally, we compared acute and chronic MPL response in muscle with liver. The comparison revealed systematic response differences between the two tissues, notably that muscle appears more prone to adapt to MPL.
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http://dx.doi.org/10.3389/fbioe.2020.00759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371857PMC
July 2020

Seeking Nonspecific Binding: Assessing the Reliability of Tissue Dilutions for Calculating Fraction Unbound.

Drug Metab Dispos 2020 10 5;48(10):894-902. Epub 2020 Aug 5.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo New York.

It has become commonplace (270+ article citations to date) to measure the fraction unbound (FrUn) of drugs in tissue homogenates and diluted plasma and then use a Correction Factor Equation (CFE) to extrapolate to the undiluted state. The CFE is based on assumptions of nonspecific binding with experimental use of very low drug concentrations. There are several possible determinants of apparent nonspecific binding as measured by methods such as equilibrium dialysis: true macromolecule binding and lipid partitioning along with receptor, enzyme, and transporter interactions. Theoretical calculations based on nonlinear protein binding indicate that the CFE will be most reliable to obtain FrUn when added drug concentration is small, binding constants are weak, protein concentrations are relatively high, and tissue dilution is minimal. When lipid partitioning is the sole factor determining apparent tissue binding, the CFE should be perfectly accurate. Use of very low drug concentrations, however, makes it more likely that specific binding to receptors and other targets may occur, and thus FrUn may reflect some binding to such components. Inclusion of trapped blood can clearly cause minor to marked discrepancies from purely tissue binding alone, which can be corrected. Furthermore, assessment of the occurrence of ionization/pH shifts, drug instability, and tissue metabolism may be necessary. Caution is needed in the use and interpretation of results from tissue dilution studies and other assessments of nonspecific binding, particularly for very strongly bound drugs with very small FrUn values and in tissues with metabolic enzymes, receptors, and trapped blood. SIGNIFICANCE STATEMENT: The use of tissue, plasma, and cell preparations to help obtain fraction unbound and tissue-to-plasma partition coefficients in pharmacokinetics has grown commonplace, especially for brain. This report examines theoretical, physiological, and experimental issues that need consideration before trusting such measurements and calculations.
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http://dx.doi.org/10.1124/dmd.120.000118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497620PMC
October 2020

Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia.

Cancer Chemother Pharmacol 2020 09 3;86(3):325-337. Epub 2020 Aug 3.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.

Background: AML patients with FLT3/ITD mutations have poor response to cytarabine-based chemotherapy. FLT3 inhibitors (FLT3i) may resensitize cells to cytarabine (CYT). Improving treatment outcome of this combination may benefit from a mechanistic extrapolation approach from in vitro data.

Methods: The effects of CYT and several FLT3i on cell proliferation and cell cycle kinetics were examined in AML cell lines. The effect of FLT3i (quizartinib, midostaurin, sorafenib) on cell proliferation and cell cycle kinetics was assessed in AML cell lines with differing FLT3 status; HEL (negligible expression of wild-type FLT3), EOL1 (wild-type FLT3), MV4-11 (FLT3-ITD resulting in constitutively active isoform). Semi-mechanistic cell cycle models for CYT and FLT3i were developed. Clinical CYT and quizartinib pharmacokinetic dosage regimens were modeled. Survival of AML patients was described via a hazard model. Simulations exploring different CYT/quizartinib regimens were conducted with the goal of improving treatment outcome.

Results: FLT3 status was associated with sensitivity to CYT (HEL cells most sensitive > EOL1 > MV4-11 cells). This order of sensitivity is reversed for FLT3i. Cytarabine induced apoptosis in the S-phase while all FLT3i induced apoptosis and cell cycle arrest at G1 phase. Simulations of candidate clinical regimens predict better cell kill upon adding quizartinib simultaneously with or immediately after CYT exposure. Overall survival was predicted to be significantly better with quizartinib 200 mg administered every 48 h vs every 24 h in patients with FLT3 aberrations.

Conclusion: Simultaneous administration of quizartinib and CYT every other day is a promising combination regimen for AML patients with FLT3 mutations.
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http://dx.doi.org/10.1007/s00280-020-04114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539618PMC
September 2020

Physiologically Based Pharmacokinetics of Dexamethasone in Rats.

Drug Metab Dispos 2020 09 29;48(9):811-818. Epub 2020 Jun 29.

Departments of Pharmaceutical Sciences (D.S., L.S., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York; and Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang, China (S.M.)

Blood and multitissue concentration-time profiles for dexamethasone (DEX), a synthetic corticosteroid, were measured in male rats after subcutaneous bolus and infusion dosing. A physiologically based pharmacokinetics (PBPK) model was applied for 12 measured tissues. Tissue partition coefficients ( ) and metabolic clearance were assessed from infusion studies. Blood cell to plasma partitioning (0.664) and plasma free fraction (0.175) for DEX were found to be moderate. DEX was extensively partitioned into liver ( = 6.76), whereas the calculated values of most tissues ranged between 0.1 and 1.5. Despite the moderate lipophilicity of DEX (log = 1.8), adipose exhibited very limited distribution ( = 0.17). Presumably due to P-glycoprotein-mediated efflux, DEX concentrations were very low in brain compared with its expected high permeability. Infusion studies yielded values from male and female rats at steady state that were similar. In silico values calculated for different tissues by using GastroPlus software were similar to in vivo values except for adipose and liver. Glucocorticoid receptors are found in diverse tissues, and these PBPK modeling results may help provide exposure profiles driving pharmacodynamic effects of DEX. SIGNIFICANCE STATEMENT: Our physiologically based pharmacokinetics model describes the experimentally determined tissue and plasma dexamethasone (DEX) pharmacokinetics (PK) profiles in rats reasonably well. This model can serve for further investigation of DEX tissue distribution in rats as the PK driving force for PD effects in different tissues. No major sex differences were found for DEX tissue distribution. Knowledge gained in this study may be translatable to higher-order species including humans.
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http://dx.doi.org/10.1124/dmd.120.091017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448200PMC
September 2020

Interactions of Tofacitinib and Dexamethasone on Lymphocyte Proliferation.

Pharm Res 2020 May 26;37(6):105. Epub 2020 May 26.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 404 Pharmacy Building, Buffalo, NY, 14214-8033, USA.

Purposes: Lymphocyte proliferation is a major factor determining the magnitude of the immune response. Both dexamethasone (DEX) and tofacitinib (TOF) exert marked immunosuppressive effects and are mainstay drugs in the treatment of rheumatoid arthritis (RA). This study was aimed to explore the single and combined anti-proliferative action of DEX and TOF on lymphocytes and their sex differences.

Methods: The single-drug effects and dual-drug interactions of TOF and DEX were assessed on the in vitro concanavalin A-stimulated proliferation of lymphocytes isolated from male and female rat and human peripheral blood.

Results: DEX was more potent than TOF across species and sex. DEX showed greater inhibition on rat lymphocytes compared to those from humans, which was reflected in both I and IC. The antiproliferative action of TOF was comparable in rats and humans with exception of a higher IC in male rats. Both sex- and species-related differences were detected in DEX/TOF interactions with synergistic effects in male lymphocytes, and additive and antagonistic effect for females in humans and rats.

Conclusion: TOF has a promising steroid-sparing potential with the beneficial effects of the combination therapy more likely in males than females.
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http://dx.doi.org/10.1007/s11095-020-02827-7DOI Listing
May 2020

Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy.

J Clin Pharmacol 2020 10 20;60(10):1385-1396. Epub 2020 May 20.

Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.

Exposure-response relationships of vamorolone, a novel dissociative steroidal anti-inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia-corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (C ), with a sigmoid E model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E  = 186 ng·h/mL), followed by time to climb 4 stairs (E  = 478 ng·h/mL), time to run/walk 10 m (E  = 1220 ng·h/mL), and 6-minute walk test (E  = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/β2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and C in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.
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http://dx.doi.org/10.1002/jcph.1632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494537PMC
October 2020

Pharmacokinetics of Inter-Alpha Inhibitor Proteins and Effects on Hemostasis After Hypoxic-Ischemic Brain Injury in Neonatal Rats.

Curr Pharm Des 2020 ;26(32):3997-4006

Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, United States.

Background: Hypoxic-ischemic (HI) brain injury is a leading cause of long-term neurodevelopmental morbidities in neonates. Human plasma-derived Inter-Alpha Inhibitor Proteins (hIAIPs) are neuroprotective after HI brain injury in neonatal rats. The light chain (bikunin) of hIAIPs inhibits proteases involved in the coagulation of blood. Newborns exposed to HI can be at risk for significant bleeding in the brain and other organs.

Objective: The objectives of the present study were to assess the pharmacokinetics (PK) and the duration of bleeding after intraperitoneal (IP) administration of hIAIPs in HI-exposed male and female neonatal rats.

Methods: HI was induced with the Rice-Vannucci method in postnatal (P) day-7 rats. After the right common carotid artery ligation, rats were exposed to 90 min of 8% oxygen. hIAIPs (30 mg/kg, IP) were given immediately after Sham or HI exposure in the PK study and serum was collected 1, 6, 12, 24, or 36 h after the injections. Serum hIAIP concentrations were measured with a competitive ELISA. ADAPT5 software was used to fit the pooled PK data considering first-order absorption and disposition. hIAIPs (60 mg/kg, IP) were given in the bleeding time studies at 0, 24 and 48 h after HI with tail bleeding times measured 72 h after HI.

Results: IP administration yielded significant systemic exposure to hIAIPs with PK being affected markedly including primarily faster absorption and reduced elimination as a result of HI and modestly of sex-related differences. hIAIP administration did not affect bleeding times after HI.

Conclusion: These results will help to inform hIAIP dosing regimen schedules in studies of neuroprotection in neonates exposed to HI.
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http://dx.doi.org/10.2174/1381612826666200421123242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545274PMC
January 2021

Transitioning from Basic toward Systems Pharmacodynamic Models: Lessons from Corticosteroids.

Pharmacol Rev 2020 04;72(2):414-438

Department of Pharmaceutical Sciences University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York

Technology in bioanalysis, , and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology of diverse corticosteroids. Such studies have advanced pharmacokinetic and pharmacodynamic (PK/PD) concepts and models that often generalize across various classes of drugs. These models encompass the "pillars" of pharmacology, namely PK and target drug exposure, the mass-law interactions of drugs with receptors/targets, and the consequent turnover and homeostatic control of genes, biomarkers, physiologic responses, and disease symptoms. Pharmacokinetic methodology utilizes noncompartmental, compartmental, reversible, physiologic [full physiologically based pharmacokinetic (PBPK) and minimal PBPK], and target-mediated drug disposition models using a growing array of pharmacometric considerations and software. Basic PK/PD models have emerged (simple direct, biophase, slow receptor binding, indirect response, irreversible, turnover with inactivation, and transduction models) that place emphasis on parsimony, are mechanistic in nature, and serve as highly useful "top-down" methods of quantitating the actions of diverse drugs. These are often components of more complex quantitative systems pharmacology (QSP) models that explain the array of responses to various drugs, including corticosteroids. Progressively deeper mechanistic appreciation of PBPK, drug-target interactions, and systems physiology from the molecular (genomic, proteomic, metabolomic) to cellular to whole body levels provides the foundation for enhanced PK/PD to comprehensive QSP models. Our research based on cell, animal, clinical, and theoretical studies with corticosteroids have provided ideas and quantitative methods that have broadly advanced the fields of PK/PD and QSP modeling and illustrates the transition toward a global, systems understanding of actions of diverse drugs. SIGNIFICANCE STATEMENT: Over the past half century, pharmacokinetics (PK) and pharmacokinetics/pharmacodynamics (PK/PD) have evolved to provide an array of mechanism-based models that help quantitate the disposition and actions of most drugs. We describe how many basic PK and PK/PD model components were identified and often applied to the diverse properties of corticosteroids (CS). The CS have complications in disposition and a wide array of simple receptor-to complex gene-mediated actions in multiple organs. Continued assessments of such complexities have offered opportunities to develop models ranging from simple PK to enhanced PK/PD to quantitative systems pharmacology (QSP) that help explain therapeutic and adverse CS effects. Concurrent development of state-of-the-art PK, PK/PD, and QSP models are described alongside experimental studies that revealed diverse CS actions.
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http://dx.doi.org/10.1124/pr.119.018101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058984PMC
April 2020

Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India.

Clin Transl Sci 2020 03 13;13(2):391-399. Epub 2019 Dec 13.

State University of New York, School of Pharmacy and Pharmaceutical Sciences, University of Buffalo, Buffalo, New York, USA.

High-dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women. Intramuscular or oral betamethasone has a terminal half-life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate shows an immediate release of betamethasone followed by a slow release where plasma betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery.
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http://dx.doi.org/10.1111/cts.12724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070803PMC
March 2020

Journal editor's final report.

Authors:
William J Jusko

J Pharmacokinet Pharmacodyn 2019 Dec;46(6):511-512

State University of New York at Buffalo, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, 14214-8033, USA.

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http://dx.doi.org/10.1007/s10928-019-09665-0DOI Listing
December 2019

Modeling Combined Anti-Inflammatory Effects of Dexamethasone and Tofacitinib in Arthritic Rats.

AAPS J 2019 07 24;21(5):93. Epub 2019 Jul 24.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 404 Pharmacy Building, Buffalo, NY, 14214-8033, USA.

Tofacitinib (TOF), a Janus kinase (JAK) inhibitor, which was approved in 2012, has been recommended for the treatment of clinically active rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid, is also used in RA therapy but with limited usefulness due to dose- and time-dependent adverse effects. This pilot study examines the single and combined effects of DEX and TOF in order to explore the steroid-sparing potential of TOF. Collagen-induced arthritic (CIA) rats were subcutaneously (SC) dosed with vehicle, 1.5 mg/kg TOF, 5 mg/kg TOF, 0.225 mg/kg DEX, or a combination of 1.5 mg/kg TOF and 0.225 mg/kg DEX. Paw sizes were measured as an index of disease and drug efficacy and dynamically depicted using a logistic function for natural paw growth, a turnover model for disease progression, an indirect response model for inhibitory effects of TOF and DEX and a non-competitive interaction model for the combined effect of DEX and TOF. TOF alone exerted only a slight inhibitory effect on RA paw edema compared to DEX, which reduced edema by 40%. In combination, TOF and DEX had additive effects with an interaction factor of 0.76. Using model simulations, a single SC dose of TOF does not have a visible steroid-sparing potential, although BID oral dosing has such potential. The current study suggests an additive effect of TOF and DEX and simulations indicate that further exploration of TOF and DEX administration timing may produce desirable drug efficacy with lower DEX doses.
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http://dx.doi.org/10.1208/s12248-019-0362-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132335PMC
July 2019

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part I: Determination and Prediction of Dexamethasone and Methylprednisolone Tissue Binding in the Rat.

J Pharmacol Exp Ther 2019 08 13;370(2):318-326. Epub 2019 Jun 13.

Departments of Pharmaceutical Sciences (V.S.A., D.S., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York

The plasma and tissue binding properties of two corticosteroids, dexamethasone (DEX) and methylprednisolone (MPL), were assessed in the rat in anticipation of developing physiologically based pharmacokinetic and pharmacokinetic/pharmacodynamic models. The tissue-to-plasma partition coefficients () of DEX and MPL were measured in liver, muscle, and lung in vivo after steady-state infusion and bolus injection in rats. Since is often governed by reversible binding to macromolecules in blood and tissue, an attempt was made to assess values of DEX and MPL by in vitro binding studies using rat tissue homogenates and to compare these estimates to those obtained from in vivo kinetics after dosing. The values of both steroids were also calculated in rat tissues using mechanistic tissue composition-based equations. The plasma binding of DEX and MPL was linear with moderate binding (60.5% and 82.5%) in male and female rats. In vivo estimates of steroid uptake appeared linear across the tested concentrations and was highest in liver and lowest in muscle for both steroids. Assessment of hepatic binding of MPL in vitro was severely affected by drug loss at 37°C in male liver homogenates, whereas DEX was stable in both male and female liver homogenates. With the exception of MPL in liver, in vitro-derived estimates reasonably agreed with in vivo values. The mechanistic equations modestly underpredicted for both drugs. Tissue metabolism, saturable tissue binding, and active uptake are possible factors that can complicate assessments of in vivo tissue binding of steroids when using tissue homogenates. SIGNIFICANCE STATEMENT: Assuming the free hormone hypothesis, the ratio of the unbound drug fraction in plasma and in tissues defines the tissue-to-plasma partition coefficient (), an important parameter in physiologically based pharmacokinetic modeling that determines total drug concentrations within tissues and the steady-state volume of distribution. This study assessed the plasma and tissue binding properties of the synthetic corticosteroids, dexamethasone and methylprednisolone, in rats using ultrafiltration and tissue homogenate techniques. In vitro-in vivo and in silico-in vivo extrapolation of was assessed for both drugs in liver, muscle, and lung. Although the extrapolation was fairly successful across the tissues, in vitro homogenate studies severely underpredicted the of methylprednisolone in liver, partly attributable to the extensive hepatic metabolism.
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http://dx.doi.org/10.1124/jpet.119.257519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658919PMC
August 2019

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part II: Sex Differences in Methylprednisolone Pharmacokinetics and Corticosterone Suppression.

J Pharmacol Exp Ther 2019 08 13;370(2):327-336. Epub 2019 Jun 13.

Departments of Pharmaceutical Sciences (V.S.A., D.C.D., T.N., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York; and DMPK Research Department, Teijin Institute for Biomedical Research, Teijin Pharma, Tokyo, Japan (T.N.)

Methylprednisolone (MPL), a corticosteroid of intermediate potency, remains an important immunomodulatory agent for autoimmune diseases. Although sex differences in corticosteroid pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, comprehensive preclinical assessments of such differences have not been conducted. Limited in vitro evidence indicates possible sex differences in corticosteroid PK and PD. Therefore, it is hypothesized that comparative PK/PD assessments of MPL disposition and selected PD actions in both sexes will provide insights into factors controlling sex differences in steroid responses. This report focused on the plasma and tissue pharmacokinetics of MPL and its adrenal suppressive effects. Because time-dependent (estrous) regulation of sex hormones in females can influence drug responses, female rats were studied in the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the reproductive cycle. Cohorts of male and female rats were given a 50 mg/kg bolus dose of MPL intramuscularly. Plasma and liver concentrations of MPL as well as plasma corticosterone concentrations were assayed using high-performance liquid chromatography. An enhanced minimal physiologically-based PK/PD model was developed to characterize MPL kinetics and corticosterone dynamics. The clearance of MPL was ∼3-fold higher in males compared with females, regardless of estrous phase, likely attributable to sex-specific hepatic metabolism in males. Strong inhibitory effects on adrenal suppression were observed in all animals. These temporal steroid profiles in plasma and tissues will be used to drive receptor/gene-mediated PD effects of MPL in both sexes, as described in a companion article (Part III). SIGNIFICANCE STATEMENT: Sex is a relevant factor influencing the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Few preclinical PK/PD studies, however, include sex as a variable. Sex differences in the PK and adrenal suppressive effects of the synthetic corticosteroid, methylprednisolone, were assessed in male and female rats as a function of the 4-day rodent reproductive cycle. Drug exposure was 3-fold higher in females, regardless of estrous stage, compared with males. An extended minimal physiologically-based PK/PD model utilizing in vitro and in vivo measurements was developed and applied. These studies provide a framework to account for sex-dependent variability in drug and endogenous agonist (corticosterone) exposures, serving as a prelude to more intricate assessments of sex-related variability in receptor/gene-mediated PD corticosteroid actions.
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http://dx.doi.org/10.1124/jpet.119.257527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184193PMC
August 2019

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor-Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids.

J Pharmacol Exp Ther 2019 08 13;370(2):337-349. Epub 2019 Jun 13.

Departments of Pharmaceutical Sciences (V.S.A., D.C.D., R.R.A., W.J.J.) and Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York

Our previous report examined the pharmacokinetics (PK) of methylprednisolone (MPL) and adrenal suppression after a 50 mg/kg IM bolus in male and female rats, and we described in detail the development of a minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model. In continuation of such assessments, we investigated sex differences in genomic MPL responses (PD). Message expression of the glucocorticoid-induced leucine zipper (GILZ) was chosen as a multitissue biomarker of glucocorticoid receptor (GR)-mediated drug response. Potential time-dependent interplay between sex hormone and glucocorticoid signaling in vivo was assessed by comparing the enhancement of GILZ by MPL in the uterus [high estrogen receptor (ER) density] and in liver (lower ER density) from male and female rats dosed within the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the rodent estrous cycle. An expanded-systems PD model of MPL considering circadian rhythms, multireceptor (ER and GR) control, and estrous variations delineated the determinants controlling receptor/gene-mediated steroid responses. Hepatic GILZ response was ∼3-fold greater in females, regardless of estrous stage, compared with males, driven predominantly by increased MPL exposure in females and a negligible influence of estrogen interaction. In contrast, GILZ response in the uterus during proestrus in females was 60% of that observed in estrus-phased females, despite no PK or receptor differences, providing in vivo support to the hypothesis of estrogen-mediated antagonism of glucocorticoid signaling. The developed model offers a mechanistic platform to assess the determinants of sex and tissue specificity in corticosteroid actions and, in turn, reveals a unique PD drug-hormone interaction occurring in vivo. SIGNIFICANCE STATEMENT: Mechanisms relating to sex-based pharmacodynamic variability in genomic responses to corticosteroids have been unclear. Using combined experimental and systems pharmacology modeling approaches, sex differences in both pharmacokinetic and pharmacodynamic mechanisms controlling the enhancement of a sensitive corticosteroid-regulated biomarker, the glucocorticoid-induced leucine zipper (GILZ), were clarified in vivo. The multiscale minimal physiologically based pharmacokinetics/pharmacodynamic model successfully captured the experimental observations and quantitatively discerned the roles of the rodent estrous cycle (hormonal variation) and tissue specificity in mediating the antagonistic coregulation of GILZ gene synthesis. These findings collectively support the hypothesis that estrogens antagonize pharmacodynamic signaling of genomic corticosteroid actions in vivo in a time- and estrogen receptor-dependent manner.
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http://dx.doi.org/10.1124/jpet.119.257543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658921PMC
August 2019

Effects of ritonavir-boosted protease inhibitors on combined oral contraceptive pharmacokinetics and pharmacodynamics in HIV-positive women.

Contraception 2019 10 10;100(4):283-287. Epub 2019 Jun 10.

Department of Obstetrics and Gynecology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.

Objective: To assess the pharmacokinetics of combined oral contraceptive (COC) components and prevalence of ovulation in HIV-positive women using ritonavir-containing antiretroviral regimens compared to those using regimens previously found not to interact with COCs or not using any antiretrovirals.

Study Design: We conducted a prospective cohort pharmacokinetic pilot study comparing the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE) in HIV-positive women taking ritonavir-containing antiretroviral regimens to those in women using non-ritonavir-containing regimens or no antiretrovirals. Participants received COCs containing LNG/EE 150/30 mcg for 21 days. Beginning day 21, we collected serial blood samples over 72 h. The primary outcome was area under the curve (AUC) of LNG, with secondary outcomes including other LNG pharmacokinetic measures, EE pharmacokinetics and ovulation as measured by serum progesterone.

Results: Pharmacokinetic parameters of LNG showed a trend toward increased exposure in women on ritonavir. LNG AUC increased by 32.6% (312±60.9 vs. 243±82.6 ng/mL*h, p=.033, n=5) in women taking ritonavir compared to the control group (n=10). The C (9.68±1.81 vs. 7.62±2.29 ng/mL) and C (4.97±1.15 vs. 3.70±1.29 ng/mL) were also higher in the ritonavir arm. After excluding the inconsistent users (n=2), CL of LNG was reduced in the ritonavir arm (p=.032). EE pharmacokinetic profiles were not different between groups. The progesterone concentrations were similar in women of both groups, and none were consistent with ovulation during the treatment cycle.

Conclusion: Women on ritonavir showed an approximately 30% increase in LNG exposure but no difference in EE exposure.

Implications: The current data suggest that ritonavir does not have a clinically significant impact on oral contraceptive pharmacokinetics.
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http://dx.doi.org/10.1016/j.contraception.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778019PMC
October 2019

ATLAS mPBPK: a MATLAb-based tool for modeling and Simulation of minimal Physiologically Based PharmacoKinetic models.

CPT Pharmacometrics Syst Pharmacol 2019 Jun 2. Epub 2019 Jun 2.

University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.

Minimal physiologically-based pharmacokinetic (mPBPK) models are frequently used to model plasma PK data and utilize and yield physiologically-relevant parameters. Compared to classical compartment and whole-body PBPK modeling approaches, mPBPK models maintain a structure of intermediate physiological complexity that can be adequately informed by plasma PK data. In this tutorial, we present a MATLAb-based tool for modeling and Simulation of mPBPK models (ATLAS mPBPK) of small and large molecules. This tool enables the users to perform: i) PK data visualization, ii) simulation, iii) parameter optimization, and iv) local sensitivity analysis (SA) of mPBPK models in a simple and efficient manner. Along with the theoretical background and implementation of the different tool functionalities, this tutorial includes simulation and SA showcases of small and large molecules with and without target-mediated drug disposition. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/psp4.12441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709424PMC
June 2019

Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing.

Gene Regul Syst Bio 2019 15;13:1177625019840282. Epub 2019 Apr 15.

Department of Biomedical Engineering, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway.
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http://dx.doi.org/10.1177/1177625019840282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466473PMC
April 2019

Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy.

J Clin Pharmacol 2019 07 11;59(7):979-988. Epub 2019 Feb 11.

Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder occurring in boys and caused by mutations in the dystrophin gene. Vamorolone is a first-generation delta-9,11 compound that has favorable efficacy and side effect profiles relative to classical glucocorticoids. The pharmacokinetics (PK) of oral vamorolone were assessed in parallel-group studies in healthy men (phase 1, n = 86) and boys with DMD (phase 2a, n = 48) during 14 days of once-daily dosing with a range of doses. Vamorolone exhibited moderate variability in PK, with the maximum plasma concentration usually occurring at 2-4 hours and a half-life of approximately 2 hours for all doses and days examined. Population PK modeling of all data together indicated that the PK of vamorolone can be well described by a 1-compartment model with zero-order absorption. Both men and boys showed a dose-linearity of PK parameters for the doses examined, with no accumulation of the drug during daily dosing. Ingestion with food resulted in markedly enhanced absorption of the drug, as tested in healthy men. There were similar PK of vamorolone in healthy men and DMD boys with apparent clearance averaging 2.0 L/h/kg in men and 1.7 L/h/kg in boys. Overall, vamorolone exhibited well-behaved linear PK, with similar profiles in healthy men and boys with DMD, moderate variability in PK parameters, and absorption and disposition profiles similar to those of classical glucocorticoids.
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http://dx.doi.org/10.1002/jcph.1388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548694PMC
July 2019

Pharmacokinetics of the 1.5 mg levonorgestrel emergency contraceptive in women with normal, obese and extremely obese body mass index.

Contraception 2019 05 28;99(5):306-311. Epub 2019 Jan 28.

Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York.

Objective: To assess the pharmacokinetics (PK) of levonorgestrel after 1.5 mg oral doses (LNG-EC) in women with normal, obese and extremely obese body mass index (BMI).

Study Design: The 1.5 mg LNG dose was given to healthy, reproductive-age, ovulatory women with normal BMI (mean 22.0), obese (mean 34.4), and extremely obese (mean 46.6 kg/m) BMI. Total serum LNG was measured over 0 to 96 h by radioimmunoassay while free and bioavailable LNG were calculated. The maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the curve (AUC) of LNG were assessed. Pharmacokinetic parameters calculated included half-life (t1/2), clearance (CL) and volume of distribution (Vss).

Results: Ten normal-BMI, 11 obese-BMI, 5 extremely obese-BMI women were studied. After LNG-EC, mean total LNG metrics were lower in the obese and extremely obese groups compared to normal (Cmax 10.5 and 10.5 versus 16.2 ng/mL, both p<.01; AUC 208 and 197 versus 360 h × ng/mL, both p<.05). Mean bioavailable LNG Cmax was lower in obese (7.03 ng/mL, p<.05) and extremely obese (7.53 ng/ml, p=.198) compared to normal BMI (9.39 ng/mL). Mean bioavailable LNG AUC values were lower in obese and extremely obese compared to normal (131.6 and 127.5 vs 185.0 h × ng/mL, p<.05 for both).

Conclusions: Obese and extremely obese women were exposed to lower total and bioavailable LNG than normal BMI women.

Implications: Lower 'bioavailable' (free plus albumin bound) LNG AUC in obese women may play a role in the purported reduced efficacy of LNG-EC in obese users.
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http://dx.doi.org/10.1016/j.contraception.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499670PMC
May 2019

Indirect pharmacodynamic models for responses with circadian removal.

J Pharmacokinet Pharmacodyn 2019 02 29;46(1):89-101. Epub 2019 Jan 29.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.

Rhythmicity in baseline responses over a 24-h period for an indirect pharmacological effect R(t) can arise from either a periodic time-dependent input rate [Formula: see text] or a periodic time-dependent loss constant [Formula: see text]. If either [Formula: see text] or [Formula: see text] follows some nonstationary biological rhythm (e.g., circadian), then the response R(t) also displays a periodic behavior. Indirect response models assuming time-dependent input rates [Formula: see text] have been utilized to capture drug effects on various physiological responses such as hormone suppression, immune cell trafficking, and gene expression in tissues. This paradigm was extended to consider responses with circadian-controlled loss [Formula: see text] mechanisms. Theoretical equations describing this model are presented and simulations were performed to examine expected response behaviors. The model was able to capture the chronobiology and pharmacodynamics of applicable drug responses, including the uricosuric effects of lesinurad in humans, suppression of the beta amyloid (Aβ) peptide by a gamma-secretase inhibitor in mouse brain, and the modulation of extracellular dopamine by a dopamine transporter inhibitor in rat brain. This type of model has a mechanistic basis and shows utility for capturing drug responses displaying nonstationary baselines controlled by removal mechanism(s).
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http://dx.doi.org/10.1007/s10928-019-09620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447046PMC
February 2019

Pharmacokinetics and pharmacodynamics of liposomal chemophototherapy with short drug-light intervals.

J Control Release 2019 03 23;297:39-47. Epub 2019 Jan 23.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA. Electronic address:

Chemophototherapy (CPT) merges photodynamic therapy with chemotherapy and can substantially enhance drug delivery. Using a singular liposomal formulation for CPT, we describe a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to investigate observed antitumor effects. Long-circulating, sterically-stabilized liposomes loaded with doxorubicin (Dox) stably incorporate small amounts of a porphyrin-phospholipid (PoP) photosensitizer in the bilayer. These were administered intravenously to mice bearing low-passage, patient-derived pancreatic cancer xenografts (PDX). Dox PK was described with a two-compartment model and tumor drug disposition kinetics were modeled with first-order influx and efflux rates. Tumor irradiation with 665 nm laser light (200 J/cm) 1 h after liposome administration increased tumor vascular permeabilization and drug accumulation, which was accounted for in the PK/PD model with increased tumor influx and efflux rates by approximately 12- and 4- fold, respectively. This modeling approach provided an overall 7-fold increase in Dox area under the curve in the tumor, matching experimental data (7.4-fold). A signal transduction model based on nonlinear direct cell killing accounted for observed tumor growth patterns. This PK/PD model adequately describes the CPT anti-PDX tumor response based on enhanced drug delivery at the short drug-light interval used.
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http://dx.doi.org/10.1016/j.jconrel.2019.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399029PMC
March 2019