Circadian variability of pharmacokinetics of cisplatin in patients with non-small-cell lung carcinoma: analysis with the NONMEM program.
OBJECTIVE
The aim of this study was to describe the nonlinear pharmacokinetics of total and unbound plasma cisplatin under different administered time in patients with non-small-cell lung carcinoma.


METHODS
Patients receiving chemotherapy with cisplatin were included in this analysis. Patients were divided into two groups depending on the administrated time of cisplatin: 6:00 (Group A) and 18:00 (Group B). The population pharmacokinetics of cisplatin was calculated using nonlinear mixed-effects modeling (NONMEM) method, and the possible influence of covariates on the population pharmacokinetics of cisplatin was also explored.


RESULTS
The pharmacokinetics of total and unbound cisplatin could be described well by a linear two-compartment model. The mean population estimates for total and unbound drug were, respectively, 0.463 (17.0 %) and 25.4 (14.0 %) l h⁻¹ for clearance (CL), 24.2 (19.9 %) and 20.5 (27.1 %) l for central distribution volume (V₁), 10.2 (18.2 %) and 9.82 (28.1) l h⁻¹ for intercompartmental clearance (Q) and 32.0 (24.1 %) and 6.77 (25.4 %) l for peripheral compartment volume (V₂). The CL for total and unbound cisplatin was dependent on body surface area (BSA). When cisplatin was administered at 18:00, the CL was 1.38- and 1.22-fold higher than those administered at 6:00 for total and unbound cisplatin, respectively (P < 0.05). The mean parameter estimates from a nonparametric bootstrap procedure were comparable and within 5 % of the estimates from NONMEM.


CONCLUSIONS
The results showed that circadian could influence the metabolism of cisplatin and suggested the conventional dose adjustment of cisplatin based on BSA.
Department of Pharmacy and Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiang Su, China.
Rong
R
Chen
Jie
J
Li
Wen-wei
WW
Hu
Ming-li
ML
Wang
Su-lan
SL
Zou
Li-yan
LY
Miao
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001830:Body Surface Area; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002940:Circadian Rhythm; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D051437:Renal Insufficiency / Q000139:chemically induced / Q000503:physiopathology; D015203:Reproducibility of Results; D012984:Software
D000970:Antineoplastic Agents; D002945:Cisplatin