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

Abstract

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 species during CDDP chemotherapy, using high-performance liquid chromatography. Plasma concentration measurements (157) of unchanged CDDP from 26 patients with cancer receiving 80 mg/m2 CDDP by infusion over 2 hours, 3.5 hours, or 4 hours were analyzed according to a one-compartment 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 maximum concentration (Cmax) of unchanged CDDP and maximum blood urea nitrogen (BUNmax), or minimum creatinine clearance (ClCr,min) over a 1-month period after CDDP administration 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 BUNmax and Clcrmin, respectively. The population means and interindividual and residual variability of pharmacokinetics and pharmacodynamics of CDDP were evaluated using the NONMEM program. The results of this study show that the population pharmacokinetic and pharmacodynamic approach could be useful to manage CDDP nephrotoxicity using sparse data in a clinical setting.

Population pharmacokinetics of total and unbound plasma cisplatin in adult patients

“…Relationships between BSA or BW, body size parameters, and CL are frequently observed. The relationship with BSA and cisplatin CL has been reported previously [11–13].…”

Exploitation of differential homeostatic proliferation of T-cell subsets following chemotherapy to enhance the efficacy of vaccine-mediated antitumor responses

“…To address these issues, we chose a Lewis lung carcinoma mouse cell line expressing CEA. To identify sublethal doses of chemotherapy, dose–response studies were performed using various concentrations of cisplatin and vinorelbine based on reported clinical unbound peak plasma concentrations and relative ratios between peak plasma concentrations of both drugs [36, 37]. LL/2-CEA cells were exposed in vitro to cisplatin (5 μg/ml) and vinorelbine (1.5 μg/ml) for 15 min or were left untreated.…”

Presence of Mesenchymal Stem Cells in Human Bone Marrow After Exposure to Chemotherapy: Evidence of Resistance to Apoptosis Induction

“…In proof of this hypothesis, we analyzed the characteristics of hMSCs from unaffected BM after treatment with cisplatin and etoposide in vitro since both substances exert an apoptosis‐inducing, DNA‐damaging activity [17, 18]. The treatment (3 μM cisplatin or etoposide for 2 hours, repeated four times every 24 hours) represented a dose corresponding to clinically relevant serum concentrations and a schedule used in current therapies [19, –21]. Following a lag phase of 7 days for etoposide and 14 days for cisplatin after the end of treatment (data not shown), treated cells resumed growth at PDs similar to those of untreated cells (Fig.…”