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Studies on age-dependent plasma platinum pharmacokinetics and ototoxicity of cisplatin
T Murakami1, S Inoue, K Sasaki
1Department of Pediatrics, Aichi Medical University, Japan.
Insights
Pediatric cisplatin (CDDP) pharmacokinetics and ototoxicity differ by age. Younger children exhibit slower drug elimination and larger distribution volumes, increasing their risk of hearing loss from CDDP treatment.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Toxicology
Background:
- Cisplatin (CDDP) is a vital chemotherapy agent used in treating various solid tumors in children.
- Understanding age-related differences in CDDP pharmacokinetics and ototoxicity is crucial for optimizing pediatric cancer treatment and minimizing side effects.
Purpose of the Study:
- To investigate the age-related pharmacokinetic differences of cisplatin (CDDP) in children with solid tumors.
- To evaluate the correlation between CDDP pharmacokinetics and the incidence and severity of ototoxicity in different pediatric age groups.
Main Methods:
- Plasma-free platinum concentrations were measured using atomic absorption spectrophotometry after intravenous CDDP infusion.
- Pharmacokinetic parameters, including elimination rate constant (Ke), clearance (Cl), half-life (T1/2), and volume of distribution (Vd), were analyzed using a one-compartment open model.
- Ototoxicity was assessed by evaluating hearing loss at various frequencies in relation to cumulative CDDP dosage.
Main Results:
- Younger children (1.7-6.5 years) showed a larger volume of distribution (Vd) and slower elimination (lower Ke, longer T1/2) compared to older children (12.2-15.7 years).
- Ototoxicity, specifically high-frequency hearing loss, was observed in younger children at lower cumulative CDDP doses (200 mg/m2) compared to older children, who experienced minimal ototoxicity up to 600 mg/m2.
- Pharmacokinetic parameters indicated significantly different drug handling between the age groups, with younger children having slower drug clearance.
Conclusions:
- Age-dependent pharmacokinetic variations, particularly a larger volume of distribution and slower elimination in younger children, are significant factors contributing to cisplatin-induced ototoxicity.
- These findings underscore the need for age-specific dosing strategies and monitoring for ototoxicity in pediatric patients receiving cisplatin chemotherapy.
Abstract:
The age-related difference of cisplatin (CDDP) pharmacokinetics and ototoxicity were studied in 6 children with solid tumors who received CDDP infusion. CDDP was administered intravenously for 6 hours at a dosage of 30-120 mg/m2 and plasma-free platinum concentrations were determined by atomic absorption spectrophotometry. Plasma-free platinum concentrations ranged from 1.0 to 2.1 micrograms/ml at the end of infusions and declined rapidly with T1/2 of 0.6-1.5 hours. Pharmacokinetic parameters of plasma-free platinum were analyzed in 13 CDDP infusions by the one-compartment open model method. Parameters (Ke, Cl, T1/2 and Vd) of free platinum pharmacokinetics were 0.66 hr-1, 7.71l/hr, 1.35 hr and 15.71l in the younger group (age: 1.7-6.5 years old) and 1.44 hr-1, 11.41l/hr, 0.61 hr and 8.99l in the older group (age: 12.2-15.7 years old), respectively. Up to 600 mg/m2 of the cumulative dosage of CDDP caused minimal ototoxicity in the older group; however, in the younger group, hearing loss at a high frequency zone (6000 and 8000 Hz) began to appear at a cumulative dosage of 200 mg/m2 and progressed to middle zone (3000 Hz) when dosages surpassed 400 mg/m2. These data indicate that the pharmacokinetic difference in age possesses a large distribution volume (Vd) and that slower elimination of the drug in a younger age group is an important factor for age-dependent ototoxicity.