David D'Argenio - Academia.edu (original) (raw)

Papers by David D'Argenio

Cancer Research, Jul 1, 2003

Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Posit... more Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[(18)F]FU (PET/5-[(18)F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[(18)F]FU in vivo. This study explored the combined use of PET/5-[(18)F]FU and eniluracil (5-ethynyluracil), a potent inhibitor of 5-FU catabolism, to measure the pharmacokinetics of 5-FU uptake and metabolism in tumors. Rats bearing a s.c. implanted rat colon tumor were given eniluracil and injected i.v. with 5-[(18)F]FU. Dynamic PET and arterial blood sampling were performed 0-2 h. Tumors (n = 5) were then rapidly excised, frozen, and analyzed for labeled metabolites by high performance liquid chromatography. Tumor TACs were analyzed by compartmental modeling. Compartments were identified with molecular species by comparison with ex vivo assays. Tumor extracellular fluid volume was determined in a separa...

CPT: Pharmacometrics & Systems Pharmacology, 2021

A circulatory model of granulopoiesis and its regulation is presented that includes neutrophil tr... more A circulatory model of granulopoiesis and its regulation is presented that includes neutrophil trafficking in the lungs, liver, spleen, bone marrow, lymph nodes, and blood. In each organ, neutrophils undergo transendothelial migration from vascular to interstitial space, clearance due to apoptosis, and recycling via the lymphatic flow. The model includes cell cycling of progenitor cells in the bone marrow, granulocyte colony‐stimulating factor (G‐CSF) kinetics and its neutrophil regulatory action, as well as neutrophil margination in the blood. From previously reported studies, 111In‐labeled neutrophil kinetic data in the blood and sampled organs were used to estimate the organ trafficking parameters in the model. The model was further developed and evaluated using absolute neutrophil count (ANC), band cell, and segmented neutrophil time course data from healthy volunteers following four dose levels of pegfilgrastim (r2 = 0.77–0.99), along with ANC time course responses following fi...

Membranes, 2021

Primary rat alveolar epithelial cell monolayers (RAECM) were grown without (type I cell-like phen... more Primary rat alveolar epithelial cell monolayers (RAECM) were grown without (type I cell-like phenotype, RAECM-I) or with (type II cell-like phenotype, RAECM-II) keratinocyte growth factor to assess passive transport of 11 hydrophilic solutes. We estimated apparent permeability (Papp) in the absence/presence of calcium chelator EGTA to determine the effects of perturbing tight junctions on “equivalent” pores. Papp across RAECM-I and -II in the absence of EGTA are similar and decrease as solute size increases. We modeled Papp of the hydrophilic solutes across RAECM-I/-II as taking place via heterogeneous populations of equivalent pores comprised of small (0.41/0.32 nm radius) and large (9.88/11.56 nm radius) pores, respectively. Total equivalent pore area is dominated by small equivalent pores (99.92–99.97%). The number of small and large equivalent pores in RAECM-I was 8.55 and 1.29 times greater, respectively, than those in RAECM-II. With EGTA, the large pore radius in RAECM-I/-II i...

Open Forum Infectious Diseases

Background The presence of MRSA in the airways of patients with CF is associated with more rapid ... more Background The presence of MRSA in the airways of patients with CF is associated with more rapid lung function decline and a higher mortality. Tedizolid (TDZ) is an oxazolidinone antibiotic with potent activity against MRSA; however, the pharmacokinetics (PK) in CF have not been described. The purpose of this study was to determine the PK of IV/PO tedizolid in plasma in patients being treated for acute pulmonary exacerbations. Methods We conducted a prospective, multiple dose, randomized, crossover study. TDZ phosphate was administered as 200 mg IV over 1h or PO once daily x 3 under fed conditions, with a 2-day washout, followed by crossover. Laboratory studies were performed throughout the study as routine clinical care. Blood samples were obtained prior to the Third dose of IV and PO and at 8 additional timepoints over 48 hours. TDZ concentrations in plasma were determined by LC-MS/MS. The maximum concentration (Cmax) and time to maximum (Tmax) were obtained from the measured data...

Open Forum Infectious Diseases, 2017

Results. Subjects were 60.8% male, solid organ transplant (38.4%), hematopoietic stem cell transp... more Results. Subjects were 60.8% male, solid organ transplant (38.4%), hematopoietic stem cell transplant (31.5%), and/or chemotherapy (17.3%) recipients. 61.4% were on immunosuppressive therapy within 30 days of receiving voriconazole. 64.3% of underweight patients, 61.7% of normal weight patients, 54.3% of overweight patients and 62.5% of obese patients achieved a first voriconazole level that was therapeutic with no statistically significant difference between the categories (P = 0.62). 30.6% and 6.8% of obese patients achieved subtherapeutic and supratherapeutic levels respectively, but did not differ from non-obese patients (P = 0.98 and P = 0.06). Furthermore, when comparing obese patients to all others, there was no statistically significant difference in the mean first voriconazole level (P = 0.26). Conclusion. Despite the speculation about achievement of therapeutic levels and dosing of voriconazole in obese patients, we did not find any difference across the BMI categories. Dosing by total body weight in obese patients did not change therapeutic levels and rates remained similar across all body weight categories. Disclosures. All authors: No reported disclosures.

Translational and Clinical Pharmacology

An analytical solution is not a numerical solution, and it can calculate concentrations at any ti... more An analytical solution is not a numerical solution, and it can calculate concentrations at any time point without calculating the intervening time points (if the input function was not changed meanwhile). On the contrary, it is necessary to calculate concentrations of intervening many time points if one has only a numerical solution (in other words, if you use numerical integration). If a drug is administered without previous dosing and not an endogenous substance, the drug concentration at time 0 (initial condition) will be zero. However, if the drug is cleared insufficiently from the previous dose or an endogenous substance, the drug concentrations of each compartment at time 0 (the initial condition) would not be zero. This condition is called non-zero initial condition here. With zero initial values, it is not so difficult to have an analytical solution. And, if the pharmacokinetic model is a one-compartment model, Non-zero initial value problem can be solved without much difficulty using the rule of superposition for the drug amount (or concentration). However, if the pharmacokinetic model is a multi-compartment model and the initial condition is not-zero for all compartments, one can not simply use the rule of superposition for the concentrations because the drug of each compartment moves between compartments. For the simulation, numerical integration is often sufficient. However, for the fitting or estimation, an analytical solution is usually better because of the speed. Solutions with a single dose or zero-initial value are easily found in textbooks. However, solutions for the multi-compartment model with non-zero initial value are harder to find. Authors would like to present the most elegant way to solve this kind of problems analytically. Reviewer This article was invited and reviewed by the peer experts who are not TCP editors.

Antimicrobial agents and chemotherapy, Jan 18, 2018

Over the past decade, the prevalence of infections involving Methicillin-resistant (MRSA) in pati... more Over the past decade, the prevalence of infections involving Methicillin-resistant (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics has shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate 200 mg PO or IV once daily for 3 doses, with minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetics was performed using maximum-likelihood, expectation maximization method, and the disposition of TZD was described by a 2-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean (%CV) s...

Antimicrobial Agents and Chemotherapy

Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increase... more Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds t...

Peptides, 2017

Circulating insulin is dependent on a balance between insulin appearance through secretion and in... more Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35g/kg i.v.) and following glucose plus glucagon (10μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon...

The Journal of infectious diseases, Jan 21, 2016

CPT: Pharmacometrics & Systems Pharmacology, 2016

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 25, 2015

Currently available models of insulin dynamics are mostly based on the classical compartmental st... more Currently available models of insulin dynamics are mostly based on the classical compartmental structure and thus their physiological utility is limited. In this work, we describe the development of a physiological-based model and its application to data from 154 patients who underwent an insulin modified intravenous glucose tolerance test (IM IVGTT). In order to determine the time profile of endogenous insulin delivery without using C peptide data and to evaluate the transcapillary transport of insulin, the hepatosplanchnic, renal and peripheral beds were incorporated into the circulatory model as separate subsystems. Physiologically reasonable population mean estimates were obtained for all estimated model parameters, including plasma volume, interstitial volume of the peripheral circulation (mainly skeletal muscle), uptake clearance into the interstitial space, hepatic and renal clearance, as well as total insulin delivery into plasma. The results indicate that, at a population l...

Background: PACTG 1041 is a randomized, double-blind, controlled trial of INH for prevention of t... more Background: PACTG 1041 is a randomized, double-blind, controlled trial of INH for prevention of tuberculosis disease and latent infection in African infants with perinatal HIV exposure. Infants are randomized at 91-120 d of life to INH 10-20 mg/kg/d orally once daily or placebo. The appropriate INH infant dose is unknown; thus PACTG 1041 investigated INH PK, and determined N-acetyltransferase-2 (NAT2) genotype to evaluate if PG explains INH PK. Methods: PK study target enrollment is 336 infants. Half of the infants were sampled at wks 0 and 84 at 2 and 4 h post-observed dose, and half at wks 12 and 84 at 1 and 3 h post dose. INH was quantified in plasma (HPLC). NAT2 genotype was determined using RFLP and phenotypes assigned as slow (S), intermediate (I), and fast (F) acetylators. PK modeling employed a 1-compartment model with first-order absorption and elimination (NONMEM v.VI). Covariates, including NAT2 phenotype, age, weight, sex, and HIV status, were evaluated using stepwise fo...

The International Series in Engineering and Computer Science, 2004

Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 1992

A new approach for the parameter estimation of linear stochastic dynamic models from limited data... more A new approach for the parameter estimation of linear stochastic dynamic models from limited data is described in this paper. The method formally incorporates dynamic process noise as well as output error in defining the estimator, and is motivated by previous work on dynamic model maximum likelihood estimation for sparse data systems. The proposed estimator (smoothed-likelihood estimator) uses a smoothing algorithm to estimate the state of the system and its covariance. Simulation results are presented, evaluating the performance of the smoothed-likelihood estimator, the maximum likelihood estimator, and a regression model estimator.

Cancer research, 2003

Respiration physiology, 1982

The nitrogen washout test will yield more information about the distribution of pulmonary ventila... more The nitrogen washout test will yield more information about the distribution of pulmonary ventilation if a pattern of inspired gas concentrations is utilized other than the standard series of 100% oxygen breaths. The input breathing pattern which yields optimal results will vary with the specific features of the lung being studied but typically includes breaths of air, particularly in the last third of the washout. Using computerized, mathematical techniques, optimal inputs were selected for washout tests of duration 10, 20, 30 and 40 breaths for each of six lung models, ranging from a unicompartmental to a highly non-uniform 'diseased' lung. Knowing these optimal inputs we were able to devise a nominal input which was similar to the optimal inputs for all models. For a 10 breath test this nominal input pattern utilized a breath of air at breath 7. For a 20 breath test, air is utilized at breaths 12, 14, 15, 19; for 30, air at 19, 21, 22, 23, 29 and for a 40-breath test, air...