Background: Hyperthermic administration of MMC with the Synergo has proved effective with acceptable tolerability profile in high risk non muscle invasive bladder cancer. The major drawback is the high costs of both the device and disposable catheters. We report data on drug stability and safety of Unithermia, a new hyperthermia device for intravesical administration of MMC. Patients and Methods: Ten patients with a BCG recurrent intermediate risk NMIBC were enrolled in the phase I part of the study and received 6 weekly instillations of MMC Unithermia. In all, 20 mg MMC diluted in 50 ml were administered via the Unithermia device for 45 minutes at a temperature of 42°C. A fresh drug solution was replaced at 23 minutes of every cycle. Pharmacological stability was tested by HPLC analysis of residual MMC on the drug solutions retrieved at mid and end of each instillation. Blood samples were taken at 0, 12, 23, 34 and 45 minute time intervals for the evaluation of plasmatic pharmacokinetic of MMC. Adverse events were graded according to the CTCAEv6. Cystoscopy was planned every 3 months for the first year. Results: MMC stability was evaluated for 39 cycles: the median recovery of MMC was 66% and 99% in the drug solution retrieved at 23 and 45 minutes respectively. Pharmacokinetic data demonstrated only a minimal systemic absorption of MMC administered with Unithermia: Cmax levels were always far below the levels observed after IV administration. Urinary side-effects did not go beyond grade 2, 1 patient developed grade 3 systemic skin reaction and 3 patients discontinued the treatment at the 4th, 5th and 5th instillation respectively. Necrotic area on the posterior bladder wall was observed in 1/10 at cystoscopy. Conclusion: The analysis of drug solutions retrieved at mid and end of instillation demonstrates that MMC stability was not affected by Unithermia administration, and that absorption of drug occours mainly during the first 23 minutes. The almost negligible plasmatic levels of MMC agree with the absence of systemic adverse events.
PHARMACOKINETICS, PHARMACOLOGICAL STABILITY AND SAFETY OF MMC ADMINISTERED WITH A NEW HYPERTHERMIA DEVICE
GONTERO, Paolo;MILLA, Paola;SERRA, NICOLETTA MARIA;FIORITO, CHIARA;MARSON, FRANCESCO;CATTEL, Luigi;TIZZANI, Alessandro
2010-01-01
Abstract
Background: Hyperthermic administration of MMC with the Synergo has proved effective with acceptable tolerability profile in high risk non muscle invasive bladder cancer. The major drawback is the high costs of both the device and disposable catheters. We report data on drug stability and safety of Unithermia, a new hyperthermia device for intravesical administration of MMC. Patients and Methods: Ten patients with a BCG recurrent intermediate risk NMIBC were enrolled in the phase I part of the study and received 6 weekly instillations of MMC Unithermia. In all, 20 mg MMC diluted in 50 ml were administered via the Unithermia device for 45 minutes at a temperature of 42°C. A fresh drug solution was replaced at 23 minutes of every cycle. Pharmacological stability was tested by HPLC analysis of residual MMC on the drug solutions retrieved at mid and end of each instillation. Blood samples were taken at 0, 12, 23, 34 and 45 minute time intervals for the evaluation of plasmatic pharmacokinetic of MMC. Adverse events were graded according to the CTCAEv6. Cystoscopy was planned every 3 months for the first year. Results: MMC stability was evaluated for 39 cycles: the median recovery of MMC was 66% and 99% in the drug solution retrieved at 23 and 45 minutes respectively. Pharmacokinetic data demonstrated only a minimal systemic absorption of MMC administered with Unithermia: Cmax levels were always far below the levels observed after IV administration. Urinary side-effects did not go beyond grade 2, 1 patient developed grade 3 systemic skin reaction and 3 patients discontinued the treatment at the 4th, 5th and 5th instillation respectively. Necrotic area on the posterior bladder wall was observed in 1/10 at cystoscopy. Conclusion: The analysis of drug solutions retrieved at mid and end of instillation demonstrates that MMC stability was not affected by Unithermia administration, and that absorption of drug occours mainly during the first 23 minutes. The almost negligible plasmatic levels of MMC agree with the absence of systemic adverse events.
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