The pharmacokinetics of cytarabine in dogs when administered via subcutaneous and continuous intravenous infusion routes

Abstract

This crossover study compared the pharmacokinetics of cytarabine in six healthy dogs following intravenous constant rate infusion (CRI) and subcutaneous (SC) administrations, as these are two routes of administration commonly employed in the treatment of meningoencephalitis of unknown etiology. Each dog received a SC cytarabine injection of 50 mg/m(2) or an 8 h CRI of 25 mg/m(2) per hour, with a 7-day washout before receiving the alternative treatment. Blood samples were collected for 16 h after CRI initiation and for 8 h after SC injection. Plasma concentrations were measured by high-pressure liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the best-fit compartmental analysis for both CRI and SC routes. Terminal half-life (T(1/2) ) of cytarabine was 1.35 ± 0.3 and 1.15 ± 0.13 h after SC administration and CRI, respectively. Mean peak concentration (Cmax ) was 2.88 and 2.80 μg/mL for SC and CRI administration, respectively. Volume of distribution was 0.66 ± 0.07 l/kg. The 8-h CRI produced steady-state plasma concentrations as determined by consecutive measurement that did not decline until the end of the infusion. The SC administration did not achieve steady-state concentrations because cytarabine administered by this route was rapidly absorbed and eliminated quickly. The steady state achieved with the cytarabine CRI may produce a more prolonged exposure of cytarabine at cytotoxic levels in plasma compared to the concentrations after SC administration.

The pharmacokinetics of cytarabine administered at three distinct subcutaneous dosing protocols in dogs with meningoencephalomyelitis of unknown origin

“…The C max , T max , half‐life (T 1/2 ), area under the concentration versus time curve (AUC), and clearance averages for each dose are presented in Table . The T 1/2 of Ara‐C in this study ranged from 1.4–1.6 hr, which is similar to previous reports (Crook et al, ; Pastina et al, ; Scott‐Moncrieff et al, ). A single 200 mg/m 2 injection resulted in the greatest overall drug exposure (AUC) at 32,510 ng × hr/ml, with a linear relationship between dose and AUC (Figure ).…”

“…Cytarabine (Ara‐C) is an antimetabolite that is rapidly deaminated to an inactive metabolite and also phosphorylated to an active form which is then incorporated into DNA resulting in inhibition of DNA polymerase (Crook et al, ; Rustum & Raymakers, ; Seymour, Huang, & Plunkett, ). It is approved for intravenous (IV), subcutaneous (SQ), and intrathecal administration (Fischer, Knobf, & Durivage, ).…”

“…A single 50 mg/m 2 SQ dose has been evaluated in both healthy beagles and dogs with MUO and yielded similar maximum plasma concentration (C max ) and time to maximum plasma concentration (T max ) results. Mean plasma concentrations of Ara‐C were above 1 µg/ml (Crook et al, ; Pastina et al, ).…”

Plasma and serum concentrations of cytarabine administered via continuous intravenous infusion to dogs with meningoencephalomyelitis of unknown etiology

“…Despite the limitations of this small study, we are able to conclude that the drugs commonly used in the treatment of MUE do not appear to alter the C MAX and AUC of CA delivered by CRI. Additionally, our findings for C MAX and AUC values obtained after a CRI of CA alone in the population of dogs diagnosed with MUE are lower than those of healthy beagle dogs (Crook et al ., ). These results may be due to differences in diseased vs. healthy dogs, or due to differences in sampling time points, as the beagle dogs were sampled intensively and up to 16 h after the infusion was initiated, whereas the clinical population of dogs was sampled up to 12 h and sparsely.…”

Perspectives on Meningoencephalomyelitis of Unknown Origin

“…A pharmacokinetic study comparing subcutaneous bolus administration versus intravenous infusion revealed that based on Fick's first law of diffusion, intravenous infusion may produce a more prolonged exposure of cytosine arabinoside at cytotoxic levels in plasma in comparison with the concentrations after subcutaneous administration. 161 However, further study in dogs with MUO is needed to identify whether the sustained concentrations produced by intravenous infusion would improve penetration of cytosine arabinoside across the BBB and produce higher efficacy for the treatment of MUO. Alternative approaches include prolonged use of oral leflunomide or cyclosporine in combination with prednisone tapered over approximately 6 to 12 weeks.…”