Potential and Toxicity of Intravesical Pemetrexed: a Preclinical Study in Pigs

Abstract

Purpose: In search for a new drug for intravesical use in superficial urothelial cell carcinoma of the bladder, a pig model is used for pharmacokinetics and toxicity measurements after intravesically administered pemetrexed. Experimental Design: In the dose escalation phase, two groups of two pigs received 5 and 10 mg/kg pemetrexed intravesically; four groups of three pigs received 15, 20, 25, and 30 mg/kg, respectively.The well-being of the animals was monitored. Blood was studied for pharmacokinetic analysis and signs of myelosuppression. Posttreatment urine samples were collected to measure the concentration of pemetrexed after instillation. Twenty-four hours posttreatment, the animals were cystectomized and sacrificed. Histopathologic examination of the bladder wall was done. In the second study phase, five pigs were instilled weekly with the maximum tested dose for 6 weeks. The same methods were applied. Results: All doses (5-30 mg/kg) in the first study phase were well tolerated, enabling the use of 30 mg/kg in the second study phase. In both study phases, the pigs' well-being was not influenced. Full blood counts showed no sign of myelosuppression. Systemic absorption was not observed. Urine pemetrexed concentrations remained almost unchanged. Histopathologic examination of the bladder wall did not reveal significant abnormalities. Bladder mucosa remained intact at any time, without hemorrhage. Conclusions: Intravesically administered pemetrexed in pigs is well tolerated, not absorbed systemically, and causes no bladder wall toxicity.Superficial urothelial cell carcinoma of the bladder has a high incidence and even higher prevalence due to a high recurrence rate after primary transurethral resection. Adjuvant intravesical instillations are used to lower the recurrence rate and the chance of progression to muscle-invasive disease. For intravesical instillations, the options are in principle 2-fold: chemotherapy or immunotherapy. Intravesical chemotherapy has modest effect on recurrence rate and, moreover, has repeatedly shown to have no influence on tumor progression. Intravesical immunotherapy, mostly bacillus Calmette-Guerin, clearly reduces recurrence rate significantly more compared with intravesical chemotherapy, although at a cost of inducing more systemic side effects (1). In addition, bacillus CalmetteGuerin is able to delay bladder tumor progression (2). Ultimately, in the treatment of patients with superficial bladder cancer, a new drug should be able to combine the benefits of existing intravesical therapies, with higher efficacy and less toxicity.Pemetrexed (Alimta, LY231514, MTA; Eli Lilly and Company, Indianapolis, IN) is a multitargeted antifolate with structural similarity to methotrexate, the most commonly used antifolate today. It inhibits at least three enzymes involved in folate metabolism and purine and pyrimidine synthesis. Used systemically, pemetrexed has shown broad antitumor activity in human phase II (3 -5) and III (6, 7) trials in a variety of solid tumors. Moreover, in...

Unusually prolonged pemetrexed cytotoxicity in a patient with a lung adenocarcinoma: a case report

“…The hematotoxicity seems more important in patients who had cystectomy. Another study, testing intravesical injections of pemetrexed in pigs, highlighted no myelosuppression and no systemic absorption [ 11 ].…”

Minipigs: Applications in Toxicology

“…Cystourethroscopy using a rigid ureteroscope was possible, as was ureteral catheterization and ureteral dilatation. Hendricksen et al (2006) used domestic female pigs to study cancer drug intravesicular instillation of Pemetrexed; pharmacokinetics and toxicity following intravesicular administered drug were assessed. Miniswine models offer similar kidney anatomy and physiology to humans, are excellent workable models for urological safety studies, and of reasonable size and economy for the large animal research budget.…”