Naomi Nagai

Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients

Abstract Purpose: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). Methods: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary β2-microglobulin (BMGp and BMGu), urinary N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. Results: The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dtmax), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. Conclusion: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 μg/ml in a standard continuous infusion schedule over 2 h and 4 h.

Quantitative relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-time curve (AUC) as the major toxicodynamic determinant in vivo

Abstract Purpose: The major pharmacokinetic parameters of unchanged cisplatin (CDDP) related to nephrotoxicity were evaluated in rats in vivo using a pharmacodynamic model. Methods: CDDP was administered according to various dosing schedules (single bolus, intermittent bolus, or continuous infusion). Unchanged CDDP in plasma and urine was quantified using high-performance liquid chromatography (HPLC). The pharmacokinetics were assessed by model-independent methods. The relationship between pharmacokinetics and BUN levels was evaluated using a sigmoid maximum response (Emax) model. Results: Unchanged CDDP showed linear pharmacokinetics after single bolus injections of 1 to 5 mg/kg CDDP. Nephrotoxicity was ameliorated following intermittent bolus injection (1 mg/kg per day for 5 days) and continuous infusions (over 2 and 3 h) of the same CDDP doses (5 mg/kg), although these dosing schedules did not change the area under the concentration-time curve (AUC), total clearance (Clt), urinary excretion of unchanged CDDP or kidney platinum levels significantly. The maximum BUN level, as a nephrotoxicity marker, showed dose-related increases after single bolus injection of 1 to 5 mg/kg CDDP and after 3-h infusion of 5 to 25 mg/kg. The pharmacodynamic relationship between the maximum BUN level and Cmax and between the maximum BUN level and AUC were apparently different between single bolus injection and 3-h infusion. The maximum BUN level was related to the AUC calculated by plasma concentrations of unchanged CDDP greater than the threshold level (AUC>Cmin), a relationship most successfully described by the signoid Emax model, regardless of CDDP dose and schedule. The plasma threshold level of unchanged CDDP was determined as 0.9 μgPt/ml in rats. Conclusions: The present results substantiated the importance of C×T (AUC) value as an indicator of CDDP-induced nephrotoxicity in vivo as well as of tumor cell-killing effect of CDDP in vitro. The AUC>Cmin of unchanged CDDP was found to be an important pharmacokinetic parameter predicting CDDP nephrotoxicity.

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

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.

Quantitative determination of unchanged cisplatin in rat kidney and liver by high-performance liquid chromatography

A quantitative analytical method for measuring unchanged cisplatin (CDDP) and high- and low-molecular-mass metabolites (fixed and mobile metabolites) in rat kidney and liver was developed. Unchanged CDDP, separated from fixed and mobile metabolites in tissue homogenates by consecutive procedures of fractionation and ultrafiltration, was determined by high-performance liquid chromatography (HPLC) with post-column derivatization. Although unchanged CDDP was found to be partly metabolized to fixed metabolites during the preparation of cytosolic ultrafiltrates, the recovery of unchanged CDDP gave a constant value (about 70%), which was independent of tissue type and CDDP concentration (from 1 to 10 micrograms/ml). The detection limit for unchanged CDDP in the cytosolic ultrafiltrate was 20 ng/ml, corresponding to a concentration detection limit of 65 ng Pt per g of tissue in the kidney and liver. The concentrations of fixed and mobile metabolites were determined as platinum concentrations in the tissue homogenate and in the cytosolic ultrafiltrate using atomic absorption spectrometry after correcting for transformation of unchanged CDDP to fixed metabolites. The distribution of unchanged CDDP, mobile metabolites and fixed metabolites in rat kidney and liver, after bolus injection of CDDP (5 mg/kg), was determined using this method.

Effects of sodium thiosulfate on the pharmacokinetics of unchanged cisplatin and on the distribution of platinum species in rat kidney: protective mechanism against cisplatin nephrotoxicity

To investigate the mechanism underlying the protective effect against cisplatin (CDDP) nephrotoxicity of its antidote, sodium thiosulfate (STS), the effects of STS on the pharmacokinetics of unchanged CDDP and on the distribution of unchanged CDDP and high and low molecular mass metabolites (fixed and mobile metabolites) in the kidney 1 min after a bolus injection of CDDP (5 mg/kg) to rats were studied. A decrease in the plasma concentration of unchanged CDDP and an increase in the plasma concentration of mobile metabolites were observed in the rats after the bolus injection of CDDP in combination with STS infusion for 30 min (1200 mg/kg). Although STS accelerated platinum excretion during the first 10 min after CDDP injection, unchanged CDDP was not excreted in the urine in the STS-treated rats. Total kidney platinum 1 min after the bolus injection of CDDP was detected mainly as unchanged CDDP (86% of the total platinum) in the rats given CDDP alone. However, in the STS-treated rats, the total kidney platinum was decreased to 62% of the level in the rats given CDDP alone, and the platinum species detected in the kidney were mainly mobile metabolites. Only 24% of the total kidney platinum was detected as unchanged CDDP in the STS-treated rats. The loss of body weight and increases in BUN and serum creatinine levels usually observed after a bolus injection of CDDP were completely prevented by STS coadministration. The present study provides information about unchanged CDDP pharmacokinetics and the distribution of unchanged CDDP and some of its generic metabolites in the kidney when STS is coadministered as an antidote. These results show that the protective effect of STS against CDDP nephrotoxicity can be attributed to the formation of inactive mobile metabolites by a direct reaction between unchanged CDDP and STS in the systemic circulation, resulting in a reduction in the amount of unchanged CDDP in the kidney.

PHARMACOKINETICS AND POLYMORPHIC OXIDATION OF DEXTROMETHORPHAN IN A JAPANESE POPULATION

The plasma concentration and cumulative urinary excretion over 34 h of dextromethorphan, free and conjugated dextrorphan, and 3-hydroxymorphinan were determined in seven healthy Japanese subjects after oral administration of 30 mg dextromethorphan hydrobromide. Conjugated metabolites were extensively present, whereas no detectable dextromethorphan or free metabolites were observed in the plasma of any subject. On average, 72% of the dose was excreted in urine within 34 h. This was detected mainly as conjugated metabolites with only slight traces of dextromethorphan and free metabolites. From the time-courses of the metabolic ratio (the ratio of urinary output of dextromethorphan to dextrorphan), the metabolic ratios seemed to become constant 7.5 h after oral administration. Phenotyping was performed using metabolic ratios in 75 unrelated healthy Japanese subjects (43 males and 32 females). The logarithmic metabolic ratio was bimodally distributed and one subject (1.3%) was identified as a poor metabolizer.