Daniel Gonzalez | University of North Carolina at Chapel Hill (original) (raw)

Papers by Daniel Gonzalez

Clinical Medicine: Therapeutics

Ciclesonide is a novel inhaled corticosteroid (ICSs) approved in most countries for the managemen... more Ciclesonide is a novel inhaled corticosteroid (ICSs) approved in most countries for the management of persistent asthma. Although inhaled corticosteroids are first-line therapy in the treatment of asthma, long term use and high-doses of these products may result in significant side effects. When developing a new ICSs, the goal is to identify a drug with comparable (or superior) efficacy to active comparators, and an improved safety profile. Ciclesonide is a prodrug which is administered through a hydrofluoroalkanepropellant metered dose inhaler (HFA-MDI). Once it reaches the lungs, the parent compound is metabolized by esterases to desisobutyryl ciclesonide (des-CIC), an active metabolite with a 100-fold greater affinity for the glucocorticoid receptor. Ciclesonide has a unique pharmacokinetic-pharmacodynamic profile which confers an improved therapeutic ratio. Several clinical trials have shown that its efficacy is superior to placebo and similar to several active comparators. However, its high pulmonary deposition and on-site activation minimizes the risk for local side effects. Also, its low oral bioavailability, high hepatic clearance, and extensive plasma protein binding, among other factors, decrease the risk for systemic side effects. Doses of ciclesonide as high as 1280 µg/day (ex-actuator) result in minimal hypothalamic-pituitary-adrenal (HPA) axis suppression, a measure commonly used to assess systemic bioavailability for an ICSs. This review will provide a summary of ciclesonide's role in the management of asthma, including a discussion of relevant clinical trials designed to evaluate its efficacy and safety.

Seminars in Perinatology, 2015

Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to... more Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. However, federal legislation targeted at pediatric therapeutics, innovative clinical trial design, use of quantitative clinical pharmacology methods, pediatric thought leadership, and collaboration have successfully overcome many existing barriers. This success has resulted in improved knowledge on pharmacokinetics, safety, and efficacy of therapeutics in children. To date, research in pregnant women has not been characterized by similar success. Wide gaps in knowledge remain despite the common use of therapeutics in pregnancy. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women.

BACKGROUND: In HIV prevention trials of microbicides, poor adherence can severely impact the effe... more BACKGROUND: In HIV prevention trials of microbicides, poor adherence can severely impact the effectiveness of the intervention to reduce HIV acquisition. Unfortunately, there are no practical methods available which can evaluate definitive adherence in this population. We hypothesized that a breath test using two food (GRAS) flavorants can be used to evaluate the use of a vaginal product. METHODS: A double-blind randomized study with 13 subjects was conducted. Two flavorants, 2-pentyl acetate (PA) and 2-butyl acetate (BA) were added to a tenofovir placebo gel (with no active ingredient) and hydroxyethylcellulose (HEC) placebo gel, respectively. The tenofovir placebo gel was applied to the vagina using a 5 ml syringe applicator. The HEC gel was used as a lubricant on a condom and applied into the vagina with a dildo (15 thrusts). Subjects were randomized to tagged or untagged products (5:1). Each subject came in for two visits (at least1 day apart); where tenofovir placebo gel (with ...

Antimicrobial Agents and Chemotherapy, 2015

Candida infections are a leading cause of infectious disease-related death in children supported ... more Candida infections are a leading cause of infectious disease-related death in children supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing may result in suboptimal drugexposure. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. PK data were analyzed using nonlinear mixed effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of creatinine (SCR) on CL, and ECMO on V, as follows: CL(L/h)=0.019*Weight*(SCR/0.4)(-0.29)*exp(ηCL) and V(L)=0.93*Weight*1.4(ECMO)*exp(ηV). Fluconazole V was increased in children supported with ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12mg/kg) and treatment (35mg/kg) paired with standard maintenance doses to achieve exposures similar to children not on ECMO.

Die Pharmazie, 2014

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug (NSAID) widely used in humans an... more Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug (NSAID) widely used in humans and animals. There are limited published studies evaluating diclofenac's skin permeation following topical administration. The aim of our study was to evaluate and compare the in vitro permeation of three different diclofenac-containing formulations (patch, gel, solution) over 24 hours. These formulations were applied (n = 6 per formulation) to pig skin sandwiched between the two chambers in a static Franz diffusion cell and aliquots from the receptor medium were sampled at pre-defined time points. An HPLC method with UV detection was developed and validated with the aim of characterizing the transepidermal penetration in the in vitro system. Using this assay to determine the permeation parameters, results at 24 hours showed that the Flector patch released the highest drug amount (54.6%), whereas a lower drug amount was delivered with the Voltaren Emulgel (38.2%) and the solution (34.4...

Clinical pharmacology and therapeutics, 2014

Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (inc... more Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)(0.75) × (PMA(3.1)/(43.6(3.1) + PMA(3.1))); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings sup...

Obstetrics and gynecology, Jan 5, 2015

Children and pregnant women are vulnerable populations lacking clinical data to guide drug dosing... more Children and pregnant women are vulnerable populations lacking clinical data to guide drug dosing. For children, over the past 15 years, the knowledge gap in pharmacokinetic, safety, and efficacy data has been narrowed as a result of the use of innovative clinical trial designs, minimal risk research methods, increased understanding of developmental pharmacology, multidisciplinary research teams, increased clinical pharmacology expertise and training, collaborative research networks, and critical legislative changes. This progress has not been observed to a similar degree for pregnant women. These two populations, however, share similar drug development challenges and, therefore, lessons learned in pediatric clinical trials can be leveraged to advance drug development in pregnant women.

Therapeutic advances in infectious disease, 2014

The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wi... more The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what these effects have on drugs. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling pharmacokinetic/pharmacodynamic targets, suc...

Advances in Pediatrics, 2014

Thrombosis Research, 2014

Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis... more Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis of patients undergoing hip fracture surgery, hip or knee replacement, or abdominal surgery. It is cleared by the kidney and should be used with caution in patients with renal impairment and avoided in patients with severe renal insufficiency. Recently, several studies have demonstrated that a lower dose of fondaparinux in patients with moderate renal impairment appears to be safe and effective. The purpose of this study was to obtain pharmacokinetic and clinical data on the use of prophylactic fondaparinux in patients with renal insufficiency undergoing major abdominal surgery for cancer (n=8) or orthopedic surgery (n=1). Anti-factor Xa levels were obtained, and a published population pharmacokinetic model for fondaparinux was fit to the data. The data were analyzed using NONMEM software. Fondaparinux did not appear to accumulate in these patients, even when the drug was administered for up to twelve days. Pharmacokinetic analysis revealed that the apparent clearance in this population, who were primarily undergoing cancer surgery, was similar to prior studies in orthopedic surgery patients. In contrast, lower estimates were obtained for volume of distribution and absorption rate constant parameters. None of the patients sustained a hemorrhagic complication attributable to fondaparinux. One patient developed hypoxia in the setting of transient atrial fibrillation and clinical suspicion for pulmonary embolism, but this was not confirmed radiographically. These results support the use of 1.5mg of fondaparinux every 24hours for thromboprophylaxis in patients with renal insufficiency undergoing high-risk surgical procedures.

The Pediatric Infectious Disease Journal, 2014

This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribe... more This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two of 3 children with a staphylococcal CSF infection had CSF concentrations greater than minimal inhibitory concentration at the end of the dosing interval.

Expert Review of Clinical Pharmacology, 2014

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in ho... more Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in hospitalized infants. Over the past 15 years, several drugs have been approved for the treatment of S. aureus infections in adults (linezolid, quinupristin/dalfopristin, daptomycin, telavancin, tigecycline, and ceftaroline). The use of there majority of these drugs has extended into the treatment of MRSA infections in infants, frequently with minimal safety or dosing information. Only linezolid is approved for use in infants, and pharmacokinetic data in infants are limited to linezolid and daptomycin. Pediatric trials are underway for ceftaroline, telavancin, and daptomycin; however, none of these studies includes infants. Here, we review current pharmacokinetic, safety, and efficacy data of these drugs with a specific focus in infants.

Current Pharmaceutical Biotechnology, 2011

The complexity of managing critically ill patients has increased since the early establishment of... more The complexity of managing critically ill patients has increased since the early establishment of intensive care units in the 1950s. Despite of the fact that the number of drugs available to clinicians has increased, the understanding of the pharmacokinetics of individual drugs in specific disease states is still a matter of concern. Among the pharmacokinetic processes which may be affected in this patient population, drug distribution is a very important one. Changes in drug distribution may cause inadequate drug exposure at the infection site and consequently influence clinical outcome. Since drug distribution is dependent on a plethora of factors, including the physicochemical characteristics of the drug, we will focus on the most common mechanisms responsible for altered tissue distribution. These include changes in protein binding, fluid shifts, and pH changes. Although less common, alterations in organ perfusion may also play a role, particularly in heart failure patients. Despite great advances in understanding the distribution of antibacterial drugs, further studies are needed to define the consequences of changed drug distribution in critically ill patients on dosing regimens and clinical outcome.

Annals of the New York Academy of Sciences, 2010

Absorption is a critical component of the pharmacokinetics for solid dosage forms administered or... more Absorption is a critical component of the pharmacokinetics for solid dosage forms administered orally. Many barriers must be overcome in order for a drug molecule to reach its effect site. To effectively address each of these barriers, drug-specific properties, formulation issues, and (patho)physiological changes in the gastrointestinal tract must be considered. First-pass metabolism in the gut and/or liver can dictate the extent to which a drug reaches the systemic circulation. Drug-metabolizing enzymes in the gut and liver are very susceptible to inhibition by other drugs, increasing the risk of drug interactions. In this paper, we will discuss absorption-related issues for solid dosage forms used in the management of stroke patients.