Recirculatory Pharmacokinetic Model of the Uptake, Distribution, and Bioavailability of Prochlorperazine Administered as a Thermally Generated Aerosol in a Single Breath to Dogs

Abstract

ABSTRACT:A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.

Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential

“…These data are consistent with clinical and preclinical PK analyses of several different drug substances delivered via the Staccato ® system. These studies have generated consistent results, with peak plasma levels observed 3–5 minutes after inhalation, regardless of the drug substance administered (Alexza Pharmaceuticals 2014c; Avram et al 2007; Avram et al 2009; Avram et al 2013; Macleod et al 2012; Rabinowitz et al 2004; Rabinowitz et al 2006; Spyker et al 2010). Another limitation of the present study is the relatively small sample size (N=14).…”

“…By rapidly heating the metal substrate, the drug film is rapidly vaporized to form a highly pure aerosol. The Staccato ® system has previously been shown to deliver drugs with intravenous-like pharmacokinetics in humans and canines, including a rapid onset of pharmacodynamic effects (Avram et al 2007; Avram et al 2009; Avram et al 2013; Rabinowitz et al 2004; Rabinowitz et al 2006). For example, 1 mg of inhaled alprazolam produced peak plasma levels in 3.84 minutes (Alexza Pharmaceuticals 2014a b).…”

Quantification of prochlorperazine maleate in human plasma by liquid chromatography–mass spectrometry: Application to a bioequivalence study

“…Highly sensitive and selective methods without time-consuming sample pretreatment are desired for bioavailability and bioequivalence studies. The latest assays using LC/MS/MS were reported [8][9][10]. However, due to the low sensitivity (LLOQ of 2.00 ng/ml) [8], long retention time (near 5 min) [9], lacking chromatography and validation details [10], or requirement of special testing equipment (tandem mass spectrometry), those methods were not suitable in most laboratories for studies involving low oral dose for current formulations and samples in high-throughput.…”

Clinical Pharmacokinetic Applications of Recirculatory Models

“…ICG andantipyrine have been used as markers of the vascular space and total body water, respectively. This model is based on catenary compartmental models linked in series [27][28][29][30].…”