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Population Pharmacokinetics and Pharmacodynamics of Cisplatin in Patients with Cancer: Analysis with the NONMEM Program

Hiroyasu Ogata, PhD

Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan; Niigata Cancer Center Hospital, Niigata, Japan

Yuji Wada, MD

Daijiro Tsujino, KVID

Kazuhiko Someya, MD

Third Department of Internal Medicine, Niigata, Japan; Niigata Cancer Center Hospital, Niigata, Japan

Tetsuro Ohno, MS

Keisou Masuhara, PhD

Yoshio Tanaka, BS

Department of Pharmacy, Niigata, Japan; Niigata Cancer Center Hospital, Niigata, Japan

Haruki Takahashi, BS

St. Marianna University, School of Medicine and Hospital, Kanagawa, Japan; Departments of Pharmacy, Niigata, Japan; Niigata Cancer Center Hospital, Niigata, Japan

Haruki Nagai, BS

Department of Biopharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan; St. Marianna University, School of Medicine and Hospital, Kanagawa, Japan; Departments of Pharmacy, Niigata, Japan; Niigata Cancer Center Hospital, Niigata, Japan

Katsuhiko Kato, BS

Yoichi Koshiba, BS

Tamotsu lgarashi, BS

St. Marianna University, School of Medicine and Hospital, Kanagawa, Japan; Departments of Pharmacy, Niigata, Japan; Niigata Cancer Center Hospital, Niigata, Japan

Akira Yokoyama, MD

Koichi Kinameri, MD

Toshiyuki Kato, MD

Yuzou Kurita, MD, PhD

Internal Medicine, Niigata, Japan; Niigata Cancer Center Hospital, Niigata, Japan

The population pharmacokinetics and pharmacodynamics of cisplatin (CDDP) were evaluated based on a mixed-effect model using the NONMEM program. Unchanged CDDP in plasma was measured as a biologically active platinum spcies during CDDP chemotherapy, using high-performance liquid chromatography. Plasma concentration measurments (157) of unchanged CDDPfrom 26 patients with cacer receiving 80 mg/m² CDDP by infusion over 2 hours, 3.5 hours, or 4 hours were analyzed according to a one-comparment model. The influences of individual characteristics such as body weight, dose schedule, course, and clinical laboratory values (renal function markers, albumin) on total body clearance (Cl) and volume of distribution (Vd) were examined. In the final pharmacokinetic model, body surface area and dose schedule affected Cl of unchanged CDDP. The Cl of CDDP was increased by 27.3% after the 2-hour infusion schedule compared with Cl after the longer infusions. The Vd was estimated as 13.4 L/m². The interindividual variability for Cl and Vd and residual variability were 22.9%, 30.9%, and 35.5%, respectively. The relationships between maxmum concentration (Cmax) of unchanged CDDP and maxmum blood urea nitrogen (BUNmax), or minimum creatinine clearance (Clr mini over a 1-month period after CDDP aministration were evaluated according to linear, exponential, or maximum response (Emax) models. The linear or Emax model described pharmacodynamics most successfully, with relatively large interindividual variability for both slope and EC₅₀ (more than 25%). Residual variability was 15.3% and 17.1% in BUN,,, and Clcrmin, respectively. The population means and interindividual and residual variability of phamacokinetics and pharmacodynamics of CDDP were evalated using the NONMEM program. The results of this study show that the population pharmacokinetic and pharmacdynamic approach could be useful to manage CDDP neprotoxicity using sparse data in a clinical setting.

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