Pulmonary drug administration

The Food and Drug Administration (FDA) published a safety alert in 1994 in response to two deaths associated with calcium-phosphate precipitation in PN.16 Autopsy reports from these patients revealed diffuse micro vascular pulmonary emboli containing calcium-phosphate precipitates. Because calcium and phosphate can bind and precipitate in solution, caution must be exercised when mixing these two electrolytes in PN admixtures. Several factors can affect calcium-phosphate solubility, including... 

A study in the guinea pig with experimentally induced tuberculosis [44] did show that sensitivity to both rifampicin and rifaximin of the Mycobacterium (H37RY strain) remained unchanged after 3 months of drug administration, the MIC values being virtually the same before and after treatment. The development of resistance to rifaximin of different strains of M. tuberculosis, isolated from patients with pulmonary and renal tuberculosis, was studied under extremely stringent conditions [45]. 

Tlotropium bromide (54 Spiriva Boehringer-Ingelheim/Pfizer, 2004) has been approved by the US Eood and Drug Administration (EDA) for the treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). Tiotropium, a derivative of atropine from Atropa belladonna (Solanaceae), is a potent reversible nonselective inhibitor of... 

Fractionation techniques have made it possible to recover active o -antitrypsin from blood. Use of this product for intravenous replacement therapy in deficient individuals has shown that it is possible to increase levels in the serum to those of PISZ heterozygotes who experience no increase in pulmonary disease over the general population. Pulmonary lavage of patients transfused with this product showed that functional (Xj-antitrypsin reaches the alveolar structures. The Food and Drug Administration has approved weekly administration of purified serum-derived oq-antitrypsin to PIZZ and PI null individuals with pulmonary disease. Although serum levels of oq-antitrypsin increase to those believed to be protective, it has not been possible to show clinical improvement. Furthermore, viral transmission via blood products is a significant risk factor. 

Drugs for pulmonary administration can be administered via dry powder inhaler or by inhalation of an aerosolized or vaporized formulation. In order to deliver a drug to the deep lung, particles must not be large or heavy enough to remain in the back of the throat or in the upper part of the lung, where... 

The United States Food and Drug Administration issued a safety alert in 1994 regarding the potentially life-threatening formation of precipitates in parenteral nutrition admixtures (148). They had received reports of two deaths and at least two cases of respiratory distress during intravenous infusion of a three-in-one parenteral nutrition mixture (amino acids, carbohydrates, lipids). The mixture contained 10% FreAmine III (amino acids -I- magnesium acetate -I- phosphoric acid -I- potassium chloride -I- sodium acetate -I- sodium chloride), dextrose, calcium gluconate, potassium phosphate, other minerals, and a lipid emulsion. The solution may have contained a precipitate of calcium phosphate. Autopsies revealed diffuse microvascular pulmonary emboli containing calcium phosphate. 

It can never be emphasized enough that the eyes are a potential route for systemic drug administration. This has been illustrated by a British case of pulmonary edema in a child, apparently attributable to systemic absorption of phenylephrine eye-drops (1). 

Figure 1 illustrates the sequence of events relevant to pulmonary drug administration. Once released from the device, a fraction of the delivered dose (respirable fraction) will be deposited in the lung, while larger particles will be... 

For locally acting drugs, such as pulmonary and topical drugs, the assessment based on PK exposures AUC and Cmax is not appropriate. In such situations, plasma concentrations may be irrelevant to efficacy and even unavailable. In the case of metered dose inhalers (MDIs), the US Food and Drug Administration has been basing BE assessment on the dose-scale approach (2), which assesses the relative bioavailabUity (F) of the test and reference drug based on a pharmacodynamic (PD) endpoint, that is, the fraction of the test product dose that causes the same response in the pharmacodynamic endpoint as one dose of the reference product does. Approval of abbreviated new drug applications (ANDAs) would be based on the 90% confidence interval of F. 

Bernard GR, Sopko G, Cerra R et al. Pulmonary artery catheterization and clinical outcomes National Heart, Ltmg, and Blood Institute and Food and Drug Administration Workshop Report. Consensus Statement. JAMA 2000 283 2568-2572. 

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