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Clinical pharmacokinetics of encapsulated oral 9‐aminocamptothecin in plasma and saliva
Author(s) -
Jonge Maja J.A.,
Verweij Jaap,
Loos Walter J.,
Dallaire Brian K.,
Sparreboom Alex
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(99)70068-8
Subject(s) - pharmacokinetics , pharmacology , saliva , camptothecin , pharmacodynamics , chemistry , oral administration , coefficient of variation , medicine , chromatography , biochemistry
Objective To study the pharmacokinetics and pharmacodynamics of the novel topoisomerase I inhibitor and antitumor agent 9‐amino‐20( S )‐camptothecin in patients with solid tumors after repeated oral administration. Methods Thirty‐two patients with cancer received oral 9‐aminocamptothecin formulated in capsules with polyethylene glycol–1000 as excipient at doses that ranged from 0.25 to 1.5 mg/m 2 /day. Serial plasma and saliva samples were obtained on days 1 and 6 or days 1 and 8 of the first cycle and analyzed for the lactone and carboxylate forms of 9‐aminocamptothecin by HPLC. Results 9‐Aminocamptothecin showed linear and dose‐independent pharmacokinetics, with extremely small intrapatient kinetic variability (coefficient of variation: <10%). However, interpatient variability in plasma pharmacokinetics was large (coefficient of variation: 99%). The relative extent of lactone to carboxylate interconversion was large (>90%) and predictable from individual pretreatment serum albumin values ( P = .0099). The 9‐aminocamptothecin concentration ratio in plasma and saliva was strongly patient dependent, and highly variable around a mean value of <0.8, suggesting that saliva is an unreliable matrix for kinetic monitoring. The area under the curve of the lactone form of 9‐aminocamptothecin was significantly correlated with the dose‐limiting hematologic toxicity ( P < .001). Conclusion Our data indicate that the large interindividual pharmacodynamic variability in response to 9‐aminocamptothecin is caused mainly by a variability in kinetic characteristics, suggesting that a kinetic‐dynamic guided study design is warranted in future clinical investigations. Clinical Pharmacology & Therapeutics (1999) 65 , 491–499; doi: