Pharmacokinetics of a modified, compounded theophylline product in dogs

Abstract

Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP‐compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6 mg/kg theophylline equivalent) and oral MCT (10 mg/kg). Systemic bioavailability of the MCT was 96.2 ± 32.9%. MCT times to maximum concentration, mean absorption time and terminal half‐life were 8.85 ± 3.63, 6.95 ± 3.42, and 8.67 ± 1.62 hr, respectively. Based on simulations of 10 mg/kg and 12‐hr dosing, steady‐state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7 ± 35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended‐release theophylline products. An oral dose of 10 mg/kg q 12 hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter‐individual variation.

Pharmacokinetics of a 503B outsourcing facility-produced theophylline in dogs

“…However, it is now suspected that these shorter half-lives were the result of increased intrinsic clearance of theophylline by the purpose-bred animals used in these studies rather than an effect of drug formulation [ 4 ]. This is evidenced by the fact that the terminal half-life of intravenous aminophylline in non-Beagle dogs is also fairly long (7.5–9.2 h), although a direct breed comparison has not been conducted [ 4 , 7 , 15 ]. The similarity of intravenous and oral terminal half-lives for theophylline in previous studies suggest that the products investigated do not possess extended-release properties in dogs [ 4 , 7 ].…”

“…This is evidenced by the fact that the terminal half-life of intravenous aminophylline in non-Beagle dogs is also fairly long (7.5–9.2 h), although a direct breed comparison has not been conducted [ 4 , 7 , 15 ]. The similarity of intravenous and oral terminal half-lives for theophylline in previous studies suggest that the products investigated do not possess extended-release properties in dogs [ 4 , 7 ]. The same appears to be true for the OFT as we did not identify a significant difference in terminal half-lives between phases in our study (8.75 ± 2.97 h vs. 9.20 ± 2.87 h, p = 0.472).…”

“…This study was a two-way crossover design with an intravenous phase and an oral phase, separated by a 7-day washout period. This washout period was selected based on a ~12 h half-life reported for other theophylline products in dogs [ 4 , 7 ] leading to > 99.9% elimination of a single dose prior to the next phase. Dogs were randomized to undergo either the intravenous phase (n = 4) or oral phase (n = 4) first.…”

“…Within 4 h of collection, samples were centrifuged at 1,800 x g at 4°C and plasma stored at -80°C until analysis. Plasma theophylline concentrations were measured using a previously validated liquid chromatography-tandem mass spectrometry assay with lower limit of quantification of 2 ng/mL and intra‐ and inter‐ assay coefficients of variation of 1.3–3.8% and 1.6–4.1%, respectively, in the assay range relevant to this study [ 7 , 12 ].…”

“…Theophylline is a methylxanthine drug used as a bronchodilator in the treatment of canine chronic bronchitis and as a therapy for certain bradyarrhythmias [ 1 , 2 ]. Although pharmacokinetics have been established in dogs for several oral theophylline formulations in the past [ 3 – 7 ], most of these are no longer commercially available, likely due to the decline of theophylline use in human medicine [ 1 ]. Other products approved for use in humans are available, but it is important to validate individual products in dogs because pharmacokinetic parameters, particularly bioavailability, differ between formulations [ 6 ].…”