Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants

Intranasal administration is a non-invasive route for drug delivery, which is widely used for the local treatment of rhinitis or nasal polyposis. Since drugs can be absorbed into the systemic circulation through the nasal mucosa, this route may also be used in a range of acute or chronic conditions requiring considerable systemic exposure. Indeed, it offers advantages such as ease of administration, rapid onset of action, and avoidance of first-pass metabolism, which consequently offers for example an interesting alternative to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in the management of pain with opioids. Given these indisputable interests, fentanyl-containing formulations have been recently approved and marketed for the treatment of breakthrough cancer pain. This review will outline the relevant aspects of the therapeutic interest and limits of intranasal delivery of drugs, with a special focus on opioids, together with an in-depth discussion of the physiological characteristics of the nasal cavity as well as physicochemical properties (lipophilicity, molecular weight, ionisation) and pharmaceutical factors (absorption enhancers, devices for application) that should be considered for the development of nasal drugs. Copyright © 2012 Elsevier Inc. All rights reserved. Show more

To compare the performance of the standard lag time model (LAG model) with the performance of an analytical solution of the transit compartment model (TRANSIT model) in the evaluation of four pharmacokinetic studies with four different compounds. The population pharmacokinetic analyses were performed using NONMEM on concentration-time data of glibenclamide, furosemide, amiloride, and moxonidine. In the TRANSIT model, the optimal number of transit compartments was estimated from the data. This was based on an analytical solution for the change in drug concentration arising from a series of transit compartments with the same first-order transfer rate between each compartment. Goodness-of-fit was assessed by the decrease in objective function value (OFV) and by inspection of diagnostic graphs. With the TRANSIT model, the OFV was significantly lower and the goodness-of-fit was markedly improved in the absorption phase compared with the LAG model for all drugs. The parameter estimates related to the absorption differed between the two models while the estimates of the pharmacokinetic disposition parameters were similar. Based on these results, the TRANSIT model is an attractive alternative for modeling drug absorption delay, especially when a LAG model poorly describes the drug absorption phase or is numerically unstable. Show more

As a non-invasive route, intranasal administration offers patient comfort and compliance which are hurdled in parenteral drug therapy. In addition, the current recognition that the high permeability and vascularization of nasal mucosa coupled to the avoidance of the first-pass elimination and/or gastrointestinal decomposition ensure higher systemic drug absorption than oral route has contributed to the growing interest for intranasal delivery of drugs that require considerable systemic exposure to exert their therapeutic actions (systemic-acting drugs). Nevertheless, several features may hamper drug absorption through the nasal mucosa, particularly the drug molecular weight and intrinsic permeability, and, therefore, several strategies have been employed to improve it, propelling a constant challenge during nasal drug (formulation) development. This review will firstly provide an anatomical, histological and mechanistic overview of drug systemic absorption after nasal administration and the relevant aspects of the therapeutic interest and limitations of the intranasal systemic delivery. The current studies regarding the nasal application of systemic-acting small drugs (analgesic drugs, cardiovascular drugs and antiviral drugs) and biomacromolecular drugs (peptide/protein drugs and vaccines) will also be outlined, addressing drug pharmacokinetics and pharmacodynamic improvements. Show more