Drugs Administered Directly into the Respiratory Tract:Modeling of the Duration of Effective Drug Levels

Gonda, Igor

doi:10.1002/jps.2600770413

Cited by 57 publications

(14 citation statements)

References 11 publications

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“…However, this model does not differentiate between drug released (pharmacologically active) and unreleased drug nor does it separate absorption rate from dissolution rate. Therefore, Gonda [133] proposed a compartmental model that simulated the effects of release rate and multiple dosing on the duration of 'free drug levels' in the respiratory tract. This model also accounts for the possibility of accumulation of carrier materials during chronic administration as a function of drug release rate.…”

Section: Pharmacokinetics Models For the Disposition Of Drugs In The mentioning

confidence: 99%

In vivo animal models for drug delivery across the lung mucosal barrier☆

Cryan

Sivadas

García-Contreras

2007

Advanced Drug Delivery Reviews

130

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Section: Pharmacokinetics Models For the Disposition Of Drugs In The mentioning

confidence: 99%

In vivo animal models for drug delivery across the lung mucosal barrier☆

Cryan

Sivadas

García-Contreras

2007

Advanced Drug Delivery Reviews

130

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“…Based on the rationale presented in the following sections, the values selected are consistent with previously published data on particle clearance from the lung and with the assumption that a liposomal formulation of a macromolecular drug is used. Thus for example, as suggested by Gonda (Gonda 1988) and supported by our data (Bennett et ai, 1994a) non-absorptive clearance of soluble drug from the lung is in many cases characterized by a half-life of several hours and therefore kg2 was assigned a value of 0.1 hr" V The rate constants: kei, kj2 and k2i were assigned values previously determined for Detirelix following pulmonary delivery of aqueous solution formulations (Bennett et al, 1994a). The first order rate constant for drug release from liposomes was previously estimated to be 0.01 hr1 (Gonda 1988, Farr et al 1985.…”

Section: Model Solutionsmentioning

confidence: 84%

“…Previously published models (Gonda, 1988) assumed that the drug was released from the sustained release formulation by a simple first order process. This idealization is not necessarily accurate for sustained release formulations exhibiting long-term in vitro stability.…”

Section: Mathematical Modelmentioning

confidence: 99%

“…Therefore, the mathematical models developed to analyze pulmonary drug delivery focused mainly on the active compound's fate in various regions of the respiratory Key words: blood levels, convolution, Detirelix, liposomes, macromolecular drug, pharmacokinetic model, phospholipids, pulmonary delivery, sustained release, system analysis, systemic uptake tract (Byron, 1986;Gonda, 1988). Systemic absorption was usually regarded as an undesirable "spill-over" often leading to adverse effects and consequently these models only rarely addressed the systemic drug levels.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic Modeling of Systemic Uptake Following Pulmonary Delivery of a Macromolecular Drug in a Sustained Release Formulation

Teitelbaum¹,

Bennett²

1995

Journal of Aerosol Medicine

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A pharmacokinetic model was developed to analyze systemic drug levels observed after a controlled release formulation of a macromolecular drug was administered via the lung. In addition to the consideration of classical pharmacokinetic parameters, our four-compartment model addresses issues such as the clearance of intact formulation particles from the lung and the drug's release rate from the formulation into the lung lumen. Using a system-analysis approach, the effect that each of those may have on the resulting plasma drug profiles was assessed, in particular with reference to the potential to generate sustained plasma drug levels. Our analysis indicated that the specifics of the drug's release from the formulation affected those profiles only marginally, while the formulation's residence time in the respiratory tract played a key role in determining the temporal dependence of the plasma drug levels. The implications that these findings may have on the utilization of liposomal formulations for controlled pulmonary delivery of macromolecular drugs were discussed. The model presented was used to analyze the plasma levels observed after a liposomal formulation of a polypeptide drug was administered directly to the lungs of sedated dogs.

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“…In the same studies, bronchoalveolar lavage (BAL) assessment indicated no significant biological effects on any protein or enzyme parameter in the BAL fluid of interim or terminal inhalation groups. Gonda 16 developed a mathematical model that describes the release of drug from a carrier deposited in the respiratory tract and the clearance of the drug by mucociliary and nonmucociliary mechanisms. This model also accounts for the possibility of accumulation of carrier materials during chronic administration as a function of release rate of the drug.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of novel particles as pulmonary delivery systems for insulin in rats

García-Contreras

Morçöl²,

Bell³

et al. 2003

AAPS PharmSci

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KEYWORDS:pulmonary delivery, insulin, CAP-PEG particles, pharmacokinetics, pharmacodynamicsThe purpose of the study was to evaluate the influence of calcium phosphate (CAP) and polyethylene glycol (PEG) particles on the systemic delivery of insulin administered by the pulmonary route. Two methods of pulmonary delivery were employed: intratracheal instillation and spray instillation. Insulin-CAP-PEG particles in suspension (1.2 U/kg, 110-140 μL) were administered to the lungs of fasted rats by intratracheal instillation (INCAPEG) or spray instillation (SINCAPEG). Control treatments consisted of insulin solution (1.2 U/kg) by intratracheal instillation, spray instillation, and subcutaneous administration (SC). Plasma concentrations of insulin and glucose were determined by chemiluminescence and colorimetric methods, respectively. Data were analyzed by compartmental and non-compartmental methods, and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin disposition were determined. PK analysis suggested that insulin administered in particles had a longer half-life, a longer mean residence time, and a smaller rate of elimination than insulin in solution. In addition, insulin bioavailability after SINCAPEG was 1.8-fold that of insulin solution administered SC. PD analysis showed that smaller areas under the effect curve and, conversely, larger areas above the effect curve were obtained after INCAPEG in comparison to insulin solution. The magnitude of this effect was increased after SINCAPEG. The presence of CAP-PEG particles appears to positively influence the disposition of insulin administered to the lungs of Sprague-Dawley rats. Spray instillation appears to be a more efficient method of delivering insulin to the lungs of rats than intratracheal instillation.

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Drugs Administered Directly into the Respiratory Tract:Modeling of the Duration of Effective Drug Levels

Cited by 57 publications

References 11 publications

In vivo animal models for drug delivery across the lung mucosal barrier☆

In vivo animal models for drug delivery across the lung mucosal barrier☆

Pharmacokinetic Modeling of Systemic Uptake Following Pulmonary Delivery of a Macromolecular Drug in a Sustained Release Formulation

Evaluation of novel particles as pulmonary delivery systems for insulin in rats

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