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Veterinary Therapeutics Fall 2010 (Vol 11, No 3)

Pharmacokinetics of Buprenorphine in a Sodium Carboxymethylcellulose Gel After Buccal Transmucosal Administration in Dogs

by Ursula Krotscheck, DVM, DACVS, Dawn Merton Boothe, DVM, PhD, DACVIM (Internal Medicine), DACVCP, Amy A. Little, DVM, Hollis N. Erb, DVM, MS, PhD

    Clinical Relevance

    Alternatives to intravenous administration of opioids are needed in veterinary medicine. Previous research suggests that opioids can be administered through the buccal mucosa in dogs. This study reports the pharmacokinetics of buprenorphine HCl (0.05 mg/kg) administered transmucosally in six dogs compared with those of buprenorphine HCl (0.015 mg/kg) administered intravenously. The results suggest that the pharmacokinetics of buprenorphine HCl administered intravenously or transmucosally are similar and that transmucosal administration may be considered as a noninvasive alternative to intravenous administration.

    Introduction

    Buprenorphine is an effective analgesic in dogs. However, the short half-life of opioids generally requires repeated injections to maintain effective drug concentrations for a reasonable time after parenteral administration. Repeated injections contribute to anxiety associated with the pain of intramuscular or intravenous (IV) injection. Likewise, catheter placement contributes to pain. The need for repeated injections to maintain analgesia might preclude effective outpatient use.

    The need for parenteral administration of opioids is a result of intestinal and hepatic first-pass metabolism, which results in a typical oral bioavailability of 10% to 20%.1,2 Research in human medicine is focused on the evaluation of opioids administered by noninvasive parenteral routes (including buccal administration) that bypass the first-pass metabolism generally associated with oral administration.

    Buprenorphine is more potent when administered as a sublingual solution than when given subcutaneously, presumably reflecting its high lipophilicity, rapid absorption through the mucous membranes, and avoidance of the first-pass effect.3 In people, the bioavailability of buprenorphine after oral transmucosal (TM) administration ranges from 28% to 55%.4–6 A recent study in dogs demonstrated an absolute bioavailability of 38% to 47% when injectable buprenorphine was administered topically into the buccal pouch.7

    Buprenorphine, a semisynthetic partial muopioid agonist, might provide better analgesia for soft tissue pain than for major bone trauma and surgery.8–10 Although its efficacy has been evaluated in dogs,11,12 few studies have described its pharmacokinetics. Recent reports of pharmacokinetics after clinically used doses (0.015 and 0.02 mg/kg) indicate that concentrations thought to be therapeutic are achieved with IV administration but rapidly decline.3,7,11–13

    The purpose of this study was to determine the pharmacokinetics of buprenorphine in dogs when the drug is administered via the buccal TM route as a sodium carboxymethylcellulose (CMC) gel and to compare the pharmacokinetics with those of IV buprenorphine (0.015 mg/kg).

    Materials and Methods

    Animals

    The study protocol was approved by the Cornell University Institutional Animal Care and Use Committee. Six adult dogs (two male, four female) were studied: two golden retrievers, two mixed breeds, one Labrador retriever, and one Chesapeake Bay retriever. No significant abnormalities were found on physical examination, complete blood count, and biochemistry profile. The mean and SD values for age and weight were 27 ± 10 months and 30 ± 6.4 kg, respectively. The study used a crossover design with at least 1 week washout between phases. Study dates were determined and owners were asked to bring their dogs depending on their availability.

    All dogs were fasted at least 8 hours before drug administration. For each dog, one jugular furrow was clipped and a topical anesthetic agent (Lidocaine HCl Jelly USP, Akorn Inc, Buffalo Grove, IL) applied. After 30 min, the jugular furrow was aseptically prepared, and a 19-gauge, 12-in jugular catheter (Intracath, BD Worldwide, Newark, DE) was placed from the jugular vein into the cranial vena cava while the dog was manually restrained. The catheter was secured using tape and a soft padded wrap. This catheter was used only for blood collection.

    Oral pH was determined in all dogs using a pH tape precise up to 0.5 pH unit (phenaphthazine paper, Women First HealthCare, San Diego, CA). Each dog received 0.015 mg/kg buprenorphine IV and 0.05 mg/kg buprenorphine via the buccal TM route. Observers were not blinded to the route of drug administration.

    Drug Administration and Data Collection

    Intravenous Buprenorphine

    Injectable buprenorphine HCl (Bedford Laboratories, Bedford, OH; 0.015 mg/kg bolus) was administered into the cephalic vein via direct injection. Clinical signs typical of opioid administration (vomiting, swallowing, retching, ptyalism, sedation, and recumbency) were recorded at each sampling time. For the duration of the study, clinically apparent effects were recorded based on subjective assessment of an animal’s ability to respond appropriately to being called, recumbency, and normal ambulation.

    Transmucosal Buprenorphine

    For each day of TM drug study, the TM gel was prepared as one batch for all dogs to minimize variability of concentration. Based on previous experience with desired gel consistency, a total of 17 mL of the injectable formulation of buprenorphine HCl (0.3 mg/mL) was mixed with 0.5 g of sodium CMC (Prescription Compounding Centers of America, Houston, TX) using a Luer-lock adapter. After 24 hours, just before use, the gel was mixed again to ensure even distribution of the drug within the gel. The pH of the gel was measured (pH Testr3, Oaktron Instruments, Vernon Hills, IL).

    Each dog’s upper lip was gently everted on one side, and excess saliva was removed with a dry gauze sponge. Half of the calculated volume of the gel to be administered was rubbed into the upper lip and buccal pouch using a gloved hand. This was repeated with the remaining half on the other side. The entire procedure took <2 minutes.

    Sample Collection and Handling

    Sample collection was identical for both routes of administration. Whole blood (3 mL) was collected into clot tubes at times 0 (before drug administration), 2, 5, 10, 15, 20, 30, 40, 60, 90, 120, 180, 240, 360, 540, 720, 1080, and 1440 minutes. Every sample of whole blood withdrawn was immediately replaced with the same volume of 0.9% saline solution. Blood was allowed to clot and was centrifuged for 15 minutes at 2500 rpm (560 ×g). The serum was collected within 2 hours of collection, transferred into polypropylene serum transport tubes (Globe Scientific Inc, Paramus, NJ), and frozen at –70°C until overnight shipment on ice to the Clinical Pharmacology Laboratory at Auburn University.

    Sample Analysis

    Serum samples were analyzed using a commercial iodine 125 radioimmunoassay kit for the quantitative measurement of buprenorphine (Double Antibody, Diagnostics Products Corp, Los Angeles, CA). The lower limit of detection is 0.1 ng/mL. The assay was validated by comparing unknown samples to a standard curve generated by the addition of known amounts of buprenorphine to canine serum. The lower and upper limits of quantification were 0.2 and 8.5 ng/mL, respectively. The coefficient of variation for three controls that spanned the detection range was <15% for high controls and ≤20% for low controls. The kit has extensive cross-reactivity with the N-dealkylated metabolite of buprenorphine.14 For concentrations that exceeded the upper limit of quantitation, samples and comparable controls were diluted so that measured concentrations were within the limit of detection. Diluted controls were predicted as for undiluted controls.

    Pharmacokinetic Analysis

    Serum drug concentration versus time data for each route in each animal were subjected to standard pharmacokinetic analysis using computer-assisted linear regression with a log-linear trapezoidal model to infinity (WinNonlin, Pharsight, Mountain View, CA). Time to maximal concentration (Tmax) and the maximal serum concentration achieved (Cmax) were measured for buccal TM administration. A minimum of three data points was used to calculate kel (the rate constant associated with the terminal elimination phase), which was used to calculate the elimination half-life (t½). For both routes of administration, the area under the time-concentration curve (AUC) and the area under the first moment curve (AUMC) were calculated to infinity. AUC was subsequently used to calculate model-independent parameters, including the following:

    For the IV route, the volume of distribution at steady state (Vdss) was calculated as Vdss = MRT × Cl. The Vdss cannot be calculated for extravascular administration using a noncompartmental model.

    Statistical Analysis

    All pharmacokinetic data were tested for normality by use of a normal probability plot and the Shapiro-Wilk statistic (P ≥.10 was used to indicate nonnormality). The presence of a “flip-flop model,” indicating whether the rate of absorption is driving the elimination of the drug, was determined by statistically comparing kel after IV administration to that after buccal TM administration using a paired t test. All parametric parameters were reported as mean ± SD, with the exception of t½, which was reported as harmonic mean ± pseudostandard deviation. Nonparametric parameters were reported as the median and range. Parametric data were compared using a paired t test. Significance was set at P <.10 (2-sided) with Bonferroni correction for multiple comparisons. This meant that we interpreted individual tests as significant if P ≤.025.

    Results

    Clinical Effects

    The buccal pH of all dogs was 7, and the pH of the gel was 7.35. The drug concentration of all gels was 0.3 mg/mL, and the volume of gel administered ranged from 3.8 to 6.3 mL.

    Administration of the gel was uncomplicated; dogs did not require any habituation to the procedure, nor did they react to the process itself or the gel. Ptyalism, licking, pawing at the mouth, and other signs suggestive of foul taste or discomfort were not evident. Dogs did not display signs of nausea or vomiting, nor did any develop a local reaction in the area to which the gel had been applied at any time throughout the study. Subjectively, all dogs exhibited clinical signs of sedation for a variable amount of time, starting 15 minutes after buccal TM administration of the drug and lasting up to 240 minutes. Five of six dogs preferred sternal or lateral recumbency during this time; one remained standing. For buccal TM buprenorphine, the clinical effects were very similar to those previously reported for IV administration,13 and adverse effects such as swallowing, retching, vomiting, and ptyalism were not observed. Repeated examinations of the oral mucosa up to 24 hours after gel administration did not reveal any hyperemia or other evidence of local irritation. Owners did not report any difficulty eating or other evidence of oral tenderness (such as unwillingness to play with toys or chew on bones) at any time.

    Drug Disposition

    The concentration–time plot for buccal TM buprenorphine is shown in Figure 1 . The concentration declined in a curvilinear manner. Table 1 shows the mean ± SD for the previously reported IV data13 and the buccal TM data.

    Table 1 also summarizes the pharmacokinetic results. The mean absolute bioavailability for buccal TM buprenorphine was 63%, although a wide interindividual variability was present; dog-specific values ranged from 36% to 89%. The buccal TM group had a longer Tmax and a significantly greater AUC (P = .013). Lack of significant difference (P = .09) between kels did not support a flip-flop model, although a larger sample size might have been supportive.

    Discussion

    Our goal was to develop and evaluate an effective, safe method of buprenorphine delivery that could be administered consistently by individuals with a wide spectrum of experience. Gel can be easily dosed for each patient, and the administration is not technically challenging or confusing. Sodium CMC has no known chemical properties at physiologic pH other than as a gelling agent. It can cause an allergic dermatitis with repeated and prolonged skin contact or an allergic reaction after repeated ingestion in susceptible individuals.15

    Buprenorphine’s high lipophilicity and potency make it ideal for TM absorption.16 It is one of two opioids (fentanyl being the other) that has been studied in animals for buccal/oral absorption. A recent study in dogs focusing on sublingual liquid buprenorphine administration at 0.02 and 0.12 mg/kg achieved bioavailabilities of 38% and 47%, respectively.7

    The radioimmunoassay used in this study does not discriminate between buprenorphine and its metabolites. Buprenorphine is metabolized in the liver by glucuronidation and N-dealkylation, resulting in norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide.7 In humans, buprenorphine metabolites are undetectable after a single IV dose (0.3 mg) or constant-rate infusions at rates ranging from 32 to 239 µg/h.17,18 Buprenorphine is less extensively metabolized in dogs than in humans,7 suggesting that in dogs, as in humans, the effect of cross-reaction with metabolites is likely to be minimal after a single dose; therefore, we do not believe that cross-reactivity falsely elevated the absolute bioavailability.

    Clinical signs of buprenorphine sedation were similar for both buccal TM and IV routes of administration in this study, although onset appeared to be more gradual in the buccal TM group. In rats, the hysteresis of buprenorphine has been described by a combined biophase distribution–receptor association/dissociation model with a linear transducer function.19 Buprenorphine is assumed to cross the blood–brain barrier readily because of its high lipophilicity; the delay in onset of its antinociceptive effect is likely due to distribution of the drug within the brain tissue itself.20–22 The decline of the buprenorphine concentration from the brain is significantly slower than that from plasma (t½ = 2.3 hours and 1.4 hours, respectively).23,24 The elimination of buprenorphine from the brain might be the rate-limiting step in termination of the drug’s action.25 If biophase equilibration is indeed the rate-limiting step in the onset of action once buprenorphine has reached the circulation and crossed the blood–brain barrier, it is conceivable that a more gradual increase in plasma levels, as is the case with TM administration, might be of little consequence.

    The buccal TM Tmax in this study is consistent with previous studies in dogs, in which the Cmax was achieved 30 to 42 minutes after oral TM administration of buprenorphine.7,26 Our confidence interval (mean ± 2 SD) indicates that buccal TM Tmax can be achieved 6 to 64 minutes after drug administration.

    AUC (significantly higher for buccal TM than for IV administration) represents the total time course of the drug in the body, irrespective of the rate of absorption. Because oral bioavailability is very low (~3% to 6% in dogs), any drug that is swallowed without being absorbed buccally would contribute very little to overall absorption.26–28 Further investigation into the dose dependence of buprenorphine in dogs is warranted; one previous study of extremely high doses of IV buprenorphine (0.7 to 4.8 mg/kg) in dogs determined the pharmacokinetics of the drug not to be dose dependent.28 However, Abbo et al7 stated that the “longer duration of time to last quantifiable plasma analyte concentration still provides a trend in predicting whether a larger dose of OTM [oral TM] buprenorphine provides a longer duration of effect than a smaller dose.”

    Although the dogs might have received a larger dose of buprenorphine after buccal TM administration than after IV administration, other pharmacokinetic parameters were not affected in our study. No significant difference was noted in MRT or t½, which is consistent with previous reports in cats.29 In humans, on the other hand, the terminal half-life for buprenorphine administered sublingually and via the buccal TM route (28 and 19 hours, respectively) is significantly longer than that for IV buprenorphine (3.2 hours). One proposed explanation is sequestration in oral mucosa, resulting in a shallow depot effect.27,30 A study using a radiolabeled sublingual buprenorphine spray showed 5% of radioactivity remaining in the mouth 8 hours after administration.26 Direct comparisons of clearance between routes of administration are difficult due to the dependence of clearance on the dose administered.

    We acknowledge that for practical reasons, we tested each route of administration in only six dogs. However, this potential lack of power was at least partially offset in two ways. First, the crossover design (and appropriate paired-data analysis) should have lessened the effect of random dog-to-dog variation on our study. Second, by running several t-tests, we probably increased the risk of type I (false-positive) error. For these reasons, finding P values ≥.09 for testing the flip-flop model, Cmax, t½, and MRT suggest to us that those values truly did not differ between routes of administration.

    Conclusion

    The bioavailability of buprenorphine delivered by buccal TM administration in a sodium CMC gel was 63%. Gel administration was tolerated by all six dogs in this study without any adverse effects. We believe the buccal TM route of delivery for buprenorphine holds promise and warrants further study.

    Supported by the Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, and the Barry and Savannah French-Poodle Memorial Fund. Presented in abstract form at the American College of Veterinary Surgeons Symposium, Oct 23-25, 2008, San Diego, CA.

    Correspondence should be sent to Dr. Krotscheck.

    Dr. Little’s current affiliation is VCA Veterinary Specialty Center of Seattle, 20115 44th Avenue West, Lynnewood, WA 98036.

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    24. Shiue CY, Bai LQ, Teng RR, et al. A comparison of the brain uptake of N-(cyclopropyl[11C]methyl)norbuprenorphine ([11C]buprenorphine) and N-(cyclopropyl[11C]methyl)nordiprenorphine ([11C]diprenorphine) in baboon using PET. Int J Radiol Appl Instrum B 1991;18:281-288.

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    26. McInnes F, Clear N, James G, et al. Evaluation of the clearance of a sublingual buprenorphine spray in the beagle dog using gamma scintigraphy. Pharm Res 2008;25:869-874.

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    29. Robertson SA, Lascelles BD, Taylor PM, et al. PK-PD modeling of buprenorphine in cats: intravenous and oral transmucosal administration. J Vet Pharmacol Ther 2005;28:453-460.

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    References »

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