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Clinical pharmacology of the anticancer polypeptide neocarzinostatin
Abstract:
The clinical pharmacology of the anticancer polypeptide neocarzinostatin was studied in 16 patients with disseminated neoplasia using a radioimmunoassay technique. Patients who received 2,400-3,600 U of the drug per square meter BSA by rapid IV infusion had triphasic plasma decay curves. For eight patients with normal hepatic and renal function, neocarzinostatin mean plasma half-lives were 0.14, 0.50, and 7.7 h. The mean plasma drug clearance was 32.4 ml/min/m2 and the apparent volume of distribution 19.3 l/m2. Two patients with liver dysfunction had shorter terminal plasma half-lives and greater drug clearance, while two with renal disease exhibited prolonged plasma half-lives and reduced drug clearances. The mean cumulative urinary excretion of neocarzinostatin was 69.1% of the administered dose at 72 h in three patients with normal hepatic and renal function. One patient with liver disease excreted 90.4%, while a patient with renal disease excreted only 58.1% of the dose in 24 h. In one patient with marked liver disease, biliary excretion accounted for 0.1% of the administered dose in 72 h. Cerebrospinal fluid concentrations of neocarzinostatin studied in two patients showed a CSF penetration of about 16% the plasma concentration at 1-5 h; concentrations persisted for 19 h in one patient with an Omayha reservoir. Neocarzinostatin was rapidly cleared from the plasma and eliminated in the urine. Dosage reductions of 50% are recommended for patients with impaired renal function, while no reduction or escalated doses could be tolerated by patients with liver disease. The pharmacologic data suggest a continuous IV infusion may be a more toxic but perhaps more effective schedule of administration.
Insights
Neocarzinostatin, an anticancer polypeptide, is rapidly cleared by the kidneys. Dosage adjustments are crucial for patients with impaired renal function, while liver dysfunction may necessitate dose escalation.
Area of Science:
- Pharmacology
- Oncology
- Drug Metabolism
Background:
- Neocarzinostatin is an anticancer polypeptide used in treating disseminated neoplasia.
- Understanding its clinical pharmacology is essential for optimizing patient treatment.
Purpose of the Study:
- To investigate the clinical pharmacology of neocarzinostatin in patients with disseminated neoplasia.
- To determine the drug's plasma decay, clearance, volume of distribution, and excretion patterns.
- To assess the impact of hepatic and renal function on neocarzinostatin pharmacokinetics.
Main Methods:
- Radioimmunoassay technique was employed to study neocarzinostatin plasma concentrations.
- Pharmacokinetic parameters including half-lives, clearance, and volume of distribution were calculated.
- Urinary and biliary excretion were quantified, and cerebrospinal fluid penetration was assessed.
Main Results:
- Neocarzinostatin exhibited triphasic plasma decay with short initial half-lives in patients with normal organ function.
- Renal impairment led to prolonged half-lives and reduced clearance, necessitating a 50% dose reduction.
- Liver dysfunction resulted in shorter terminal half-lives and increased clearance, suggesting dose escalation may be tolerated.
Conclusions:
- Neocarzinostatin is primarily eliminated via urine.
- Dosage adjustments are critical based on renal and hepatic function for safe and effective neocarzinostatin therapy.
- Continuous IV infusion might offer improved efficacy but potentially increased toxicity.