Drugs

, Volume 48, Issue 6, pp 907–929

Piroxicam-β-Cyclodextrin

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Rheumatic Diseases and Pain States
  • C. Rhoda Lee
  • Julia A. Balfour
Drug Evaluation

DOI: 10.2165/00003495-199448060-00007

Cite this article as:
Lee, C.R. & Balfour, J.A. Drugs (1994) 48: 907. doi:10.2165/00003495-199448060-00007

Abstract

Synopsis

Piroxicam-β-cyclodextrin is a complex of the established nonsteroidal antiinflammatory drug (NSAID) piroxicam and an inert cyclic macromolecule, β-cyclodextrin. In clinical trials in patients with rheumatic diseases or pain arising from other conditions, it was as effective an analgesic as standard piroxicam, and showed a faster onset of action on the first day of treatment.

In short term pharmacodynamic studies in healthy volunteers, piroxicam-β-cyclodextrin was equivalent to or tended to show less gastrointestinal mucosal toxicity than standard piroxicam, as assessed by endoscopy and faecal blood loss. However, no data are available on its comparative gastrointestinal mucosal effects from long term clinical trials using similar measures. Preliminary findings from a clinical study suggest piroxicam-β-cyclodextrin caused fewer gas-troduodenal lesions than tenoxicam. As with other NSAIDs, the majority of adverse events associated with piroxicam-β-cyclodextrin in clinical trials were gastrointestinal in origin, with epigastric pain, heartburn and nausea the most common.

Thus, piroxicam-β-cyclodextrin is an effective agent in patients with rheumatic diseases or other pain states. When rapid analgesia is required in the initial treatment of acute pain, the faster onset of action of piroxicam-β-cyclodextrin may be an advantage over the parent compound; however, this is unlikely to be important during long term therapy. The results of further long term trials are awaited before firm conclusions can be reached regarding the gastrointestinal tolerability of piroxicam-β-cyclodextrin compared with that of standard piroxicam and other NSAIDs.

Pharmacodynamic Properties

Piroxicam-β-cyclodextrin is a NSAID with anti-inflammatory, analgesic and antipyretic properties. Limited data available on the analgesic and anti-inflammatory effects of piroxicam-β-cyclodextrin suggest that it is equivalent to piroxicam in animal and human models of pain. The effects of piroxicam-β-cyclodextrin on the gastrointestinal mucosa have been more extensively studied.

Findings from endoscopy and faecal blood loss studies suggest that piroxicam-β-cyclodextrin is equivalent to, or shows a trend to be less toxic than, the parent molecule in healthy volunteers aged 20 to 50 years. However, none of these trends reached statistical significance.

In these studies, total endoscopy scores were similar for both drugs. In 2 studies of 1 month’s duration, piroxicam-β-cyclodextrin 20 mg/day tended to cause less cumulative faecal blood loss than piroxicam 20 mg/day after 2 to 4 weeks’ treatment. In all studies piroxicam-β-cyclodextrin showed a trend towards greater gastric mucosal damage, or significantly more damage, than placebo.

Pharmacokinetic Properties

Administration of piroxicam-β-cyclodextrin as a single dose in fasting volunteers resulted in mean plasma piroxicam concentrations 0.25 and 0.5 hours after administration that were, respectively, 3 to 10 and 1.3 to 3 times higher than after standard piroxicam administration in 2 comparative studies.

Although food slowed the absorption from both products, plasma concentrations of piroxicam were still 2 to 4 and 1.3 to 1.4 times higher 0.5 and 2 hours after administration of piroxicam-β-cyclodextrin than after standard piroxicam. However, after multiple-dose administration the only difference was at 0.25 hours after administration, when the plasma concentration of piroxicam was 1.3 times higher after piroxicam-β-cyclodextrin than piroxicam. The area under the plasma concentration-time curve was similar for piroxicam-β-cyclodextrin 20mg and Piroxicam 20mg, demonstrating a comparable overall extent of absorption.

Post-absorption pharmacokinetic parameters were similar for piroxicam-β-cyclodextrin and piroxicam. The volume of distribution was 0.14 L/kg and the mean terminal elimination half-life was 40 to 63 hours. The main route of elimination of piroxicam is metabolism, with only trace amounts of unchanged drug excreted in the urine.

Therapeutic Potential

In patients with acute pain resulting from arthritis and other rheumatic disease, the analgesic efficacy of piroxicam-β-cyclodextrin was equivalent to that of piroxicam when both were administered once daily at a dose of 20mg for up to 12 weeks. Anti-inflammatory effects of the 2 agents were also equivalent in the study that assessed this. In 2 studies measuring the onset of analgesic effect, piroxicam-β-cyclodextrin was significantly more effective, or showed a trend towards greater efficacy, than piroxicam in the 4 hours after the first dose. In a further 2 studies the analgesic effects of piroxicam-β-cyclodextrin and piroxicam on the second or third day of administration were similar.

In other comparative studies in patients with rheumatic pain, piroxicam-β-cyclodextrin 20 mg/day was superior in analgesic efficacy to dipyrone 500mg 3 times daily, at least as effective as etodolac 200mg twice daily, and equivalent in efficacy to tenoxicam 20 mg/day and nabumetone 1000 mg/day. In studies also investigating the onset of analgesia in the first few hours after the first dose, piroxicam-β-cyclodextrin 20mg appeared to show a faster onset of action than tenoxicam 20mg, nabumetone 1000mg, etodolac 200mg and dipyrone 500mg. Orally administered piroxicam-β-cyclodextrin 20mg as a granule formulation was equivalent in analgesic effect over 12 hours to diclofenac 75mg and ketoprofen 100mg, both administered by deep intramuscular injection.

In patients with postoperative pain or pain arising from acute musculoskeletal disorders, piroxicam-β-cyclodextrin 20 mg/day was equivalent to piroxicam 20 mg/day in relieving pain but the onset of its effect was generally faster in the first hour after the first dose. Piroxicam-β-cyclodextrin has also demonstrated efficacy in the treatment of pain arising from primary dysmenorrhoea, headache or dental extraction.

Tolerability

Piroxicam-β-cyclodextrin would be expected to demonstrate a tolerability profile similar to that of standard piroxicam. However, it has been postulated that reducing the time piroxicam spends in the gastrointestinal tract by complexation with β-cyclodextrin may result in less direct mucosal damage and hence better gastrointestinal tolerability. Short term studies in healthy volunteers suggest a possible trend towards less gastrointestinal toxicity for piroxicam-β-cyclodextrin, but this hypothesis has not been adequately studied in clinical trials. Long term studies comparing piroxicam-β-cyclodextrin with piroxicam in terms of endoscopy score and/or faecal blood loss measurement are awaited.

Data from clinical trials indicate that the principal adverse events involve the gastrointestinal tract. In 2 large short term phase IV studies, 11.3 and 13.5% of patients receiving piroxicam-β-cyclodextrin 20 mg/day reported an adverse event; 67 and 77% of these were gastrointestinal in origin, including epigastric pain, heartburn and nausea. Severe adverse reactions such as gastrointestinal bleeding or gastroduodenal ulcer were seen in 0.2% of 9105 patients. The pattern of adverse events from a longer term trial (3 to 6 months) was broadly similar.

In a double-blind comparative trial in 203 patients with rheumatic disease, the number of gastrointestinal adverse events in piroxicam-β-cyclodextrin recipients was 16 and that in piroxicam recipients was 24; 5 and 8 patients, respectively, withdrew because of the adverse event. In 1 study, piroxicam-β-cyclodextrin 20 mg/day caused fewer upper gastrointestinal tract lesions than tenoxicam 20 mg/day over 8 weeks.

Dosage and Administration

For the treatment of pain and inflammation, the recommended dosage of piroxicam-β-cyclodextrin is 20mg administered once daily as a tablet or granules. Higher dosages of 30 to 40 mg/day may be required in some patients, but these are expected to be associated with a greater incidence of gastrointestinal adverse effects. A maintenance dosage of 10 mg/day may be appropriate in some patients, particularly the elderly.

As with other NSAIDs, the use of piroxicam-β-cyclodextrin is contraindicated in patients with active peptic ulceration, and the drug should be used cautiously in patients with a history of upper gastrointestinal tract disease.

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • C. Rhoda Lee
    • 1
  • Julia A. Balfour
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand