Daniel Gonzalez (1), Timothy E. Morey (2), Scott Wasdo (2), Judith Wishin (2), Brian Quinn (3), Matthew Booth (2), Hartmut Derendorf (1,2), Richard J. Melker (2,3), Donn M. Dennis (2,3,4,5)
(1) Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, FL, USA; (2) Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA; (3) Xhale, Inc., Gainesville, FL, USA; (4) Department of Pharmacology and Experimental Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA; (5) Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, USA.
Objectives: The availability of a breath test to measure medication adherence in real-time, either at home or in a clinic, may facilitate medical decision making, streamline clinical trials, and improve therapeutic outcomes. Recent studies indicate that both 2-butyl acetate and 2-pentyl acetate, safe food flavorants, are rapidly converted to volatile alcohol and ketone metabolites which can be measured in breath [1,2]. The goal of the analyses described herein was to conduct a population pharmacokinetic analysis for two volatile markers, 2-butanone and 2-pentanone, measured in exhaled breath, after the oral ingestion of 2-butanol and 2-pentanone.
Methods: Five fasting, healthy subjects were administered a size zero hard gel capsule (Capsugel, Inc., Greenwood, SC) containing 2-butanol (60 mg), 2-pentanone (60 mg), and L-carvone (30 mg) on six separate occasions. Breath concentrations of 2-butanone and 2-pentanone were measured at 0, 5, 10, 15, 20, 30, 45, and 60 minutes post-ingestion of the capsule using a miniature gas chromatograph (Xhale, Inc., Gainesville, FL, USA). A population pharmacokinetic analysis was conducted using the software NONMEM (Version 7.2, Icon Development Solutions, Ellicott City, Maryland) and a first-order conditional estimation method with interaction.
Results: A one-compartment body model with first-order absorption and elimination adequately described the breath pharmacokinetics of 2-butanone and 2-pentanone. For 2-butanone, the typical model estimates for the first-order absorption (KA) and elimination (K) rate constants were 0.034 and 0.129 minutes-1, respectively. Inter-individual variability was moderate and more pronounced for K (73.7% K and 39% KA); whereas the opposite was true for the inter-occasion variability (27.7% K and 62.2% KA). For 2-pentanone, the typical model estimates for KA and K were 0.061 and 0.078 minutes-1, respectively. A similar pattern was observed with the inter-individual and inter-occasion variability. Inter-individual variability was more pronounced for K (56.5% K and 38.7% KA), but the opposite was true for the inter-occasion variability (36.3% K and 85.6% KA).
Conclusions: The results of this pilot study demonstrate that 2-butanone and 2-pentanone could be quantified in breath following oral administration of food flavorants. The availability of a validated method which uses a portable device for detection of these volatile markers can allow for a real-time assessment of medication adherence.
References:
[1] Morey TE, Wasdo S, Wishin J, van der Straten A, Booth M, Gonzalez D, Derendorf H, Melker RJ, Dennis DM. Feasibility of a breath test for monitoring adherence to vaginal administration of anti-retroviral microbicide gels. J Clin Pharmacol 2011; In Press.
[2] Morey TE, Wasdo S, Wishin J, Booth M, Gonzalez D, Derendorf H, McGorray SP, Simoni J, Melker RJ, Dennis DM. Measuring oral medication adherence using a breath test. In press.
Reference: PAGE 21 () Abstr 2396 [www.page-meeting.org/?abstract=2396]
Poster: Other Modelling Applications