Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of aqua (1,1-bis(aminomethyl)cyclohexane) sulfatoplatinum (II) (spiroplatin) during a phase I trial.

The pharmacokinetics of the second generation platinum complex aqua(1,1-bis-(aminomethyl)cyclohexane)sulphatoplatinum(II) (spiroplatin, TNO-6) were studied during a phase I evaluation. Thirty patients received 49 cycles of spiroplatin by short term (less than or equal to 10-min), 1-, 3- or 6-h infusion. Dosages given ranged from 5 to 40 mg/m2. Platinum determinations were performed by atomic absorption spectrometry. Up to 5 days after administration platinum concentrations in plasma decayed triexponentially. Pharmacokinetic parameters of total platinum in plasma after short-term and prolonged infusion were similar in terms of terminal half-life (3.7 +/- 1.1 and 3.6 +/- 0.5 days), AUC/dose (548 +/- 106 and 616 +/- 278 min.m2/l), volume of distribution (20 +/- 6 and 27 +/- 81) and total body clearance (2.9 +/- 1.0 and 3.4 +/- 1.8 ml/min), whereas peak plasma concentrations were two times lower after prolonged infusion. The cumulative urinary platinum excretion after short-term infusion was 20 +/- 6%, 30 +/- 6% and 47 +/- 7% of the administered dose after 6, 24 and 120 h, respectively. These values are comparable to those after administration of cisplatin. The half-life of ultrafilterable platinum was 4.4 +/- 0.7 min. The curves of free and total platinum diverged rapidly, reflecting the high reactivity of spiroplatin towards plasma proteins. This high reactivity, most likely caused by the abundant presence of aquated compounds in the injection fluid, may also account for severe and unpredictable nephrotoxicity induced by spiroplatin.

Pharmacokinetics of carboplatin after intraperitoneal administration.

The pharmacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i.p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had received carboplatin (200-500 mg/m2) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24 +/- 11. The peritoneal clearance of carboplatin was 8 +/- 3 ml/min, which was 12 times less than the plasma clearance (93 +/- 32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34% +/- 14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet = Dose - amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.

Pharmacokinetics of carboplatin after i.v. administration.

Pharmacokinetics of the cisplatin analog carboplatin were studied in ovarian cancer patients who received short-term iv infusions of 290-370 mg/m2. Platinum (Pt) was determined by atomic absorption spectrometry in plasma ultrafiltrate up to 24 hours and in plasma and urine up to 5 days following infusion. Carboplatin was determined in plasma ultrafiltrate and in urine by high-performance liquid chromatography with electrochemical detection. The final half-life of total Pt in plasma was 5.8 +/- 1.6 days. Pharmacokinetics of carboplatin and ultrafilterable Pt (free Pt) were similar with respect to alpha-half-life (16 +/- 6 and 23 +/- 8 mins), beta-half-life (118 +/- 15 and 120 +/- 11 mins), area under curve/dose (18 +/- 5 and 17 +/- 4 min/m2/L), total-body clearance (101 +/- 21 and 107 +/- 19 ml/min), and volume of distribution Vss (9.9 +/- 1.3 and 10.0 +/- 1.4 L/m2). After 6 hours the cumulative urinary excretion of carboplatin and Pt was 41% +/- 14% and 68% +/- 7% of the dose, respectively. After 5 days the cumulative urinary excretion of Pt was 84% +/- 6%. Renal and metabolic clearances of free Pt from plasma were 81 +/- 17 and 26 +/- 11 ml/minute, respectively. The first-order rate constant for metabolic elimination of free Pt (KM = CLM/Vss) was 1.5 X 10(-3) +/- 0.6 X 10(-3) min-1, which is ten times lower than the value calculated from literature data for cisplatin (15 X 10(-3) +/- 1 X 10(-3) min-1). This means that the overall in vivo reactivity of carboplatin is ten times lower than that of cisplatin.

Comparative pharmacokinetics of cisplatin and three analogues in mice and humans.

Pharmacokinetics of cisplatin, spiroplatin, ethylenediaminemalonatoplatinum(II) (JM-40), and carboplatin was studied in BALB/c x DBA/2 F1 mice receiving 10% lethal doses of 15.5, 6.8, 100, and 165 mg/kg, respectively. Blood samples were collected for up to 5 days after a single i.v. bolus injection. Total platinum in plasma and non-protein-bound free platinum in plasma ultrafiltrate were determined by flameless atomic absorption spectrometry. Parent JM-40 and carboplatin were determined by high performance liquid chromatography. Calculated pharmacokinetic parameters (peak concentrations, half-lives, areas under the curve) were compared with the corresponding values in patients at the maximal tolerated dose. Peak plasma concentrations were 2.4- to 20-fold higher in mice than in humans. Initial and terminal half-lives in mice were up to 6 times shorter than in patients. However, the areas under the plasma concentration versus time curves (AUCs) were found to agree. The ratios of the AUCs of free platinum in patients (AUCp) and mice (AUCm) measured over the first part of the plasma concentration versus time curve were 1.2, 0.3, 1.1, and 0.9 for cisplatin, spiroplatin, JM-40, and carboplatin, respectively. These values changed to 1.3, 0.3, 2.5, and 1.0 when the time interval was extended to free platinum levels just above the detection limit. Ratios of the AUCs of total platinum in patients and mice measured over 5 days were 2.7, 2.6, 4.2, and 1.8, respectively. Using a ratio of 1 for free platinum originating from JM-40, the retrospectively calculated maximal tolerated dose from AUCp at low dosages was 1021 mg/m2 (n = 7; range, 836-1282), compared to 1200 mg/m2 as found in the phase I trial. This suggests that the AUCp/AUCm ratio of free platinum over the first part of the concentration versus time curve can possibly be used to predict the maximal tolerated dose of platinum analogues in humans, during the early stage of phase I studies.

Pharmacokinetics of ethylenediaminemalonatoplatinum(II) (JM-40) during phase I trial.

Pharmacokinetics of the cis-platin analog ethylenediaminemalonatoplatinum(II) (JM-410) was studied in 28 cycles of 19 patients during the phase I study of this drug. The drug was administered intravenously by short-term (10-60 min) infusion. Doses ranged from 20 to 1,200mg m-2. JM-40 was determined in plasma ultrafiltrate and urine by HPLC. Platinum (Pt) concentrations were determined in plasma, plasma ultrafiltrate, urine and red blood cells by atomic absorption spectrometry up to 5 days after administration of the drug. Ultrafilterable Pt could be determined up to 45 days after the infusion in one patient sampled over such a long period. Pharmacokinetics of JM-40 showed a linear behaviour. The final half-life of total Pt in plasma was 4.1 +/- 0.9 days. The disposition of JM-40 was similar to that of ultrafilterable Pt in respect to t1/2 alpha (10 and 13 min), t1/2 beta (44 and 57 min), volumes of distribution Vc (11 and 121) and Vss (17 and 201), systemic clearance (256 and 223 ml min-1), renal clearance (69 and 73 ml min-1) and metabolic clearance (183 and 154 ml min-1). During the first 6 h 27 +/- 9% of the administered dose was excreted as JM-40. Cumulative platinum excretion in the urine amounted to 29 +/- 13% and 60 +/- 13% over the first 6 h, 24 h and 5 days, respectively. The uptake of platinum in red blood cells was limited, comprising only 0.24 +/- 0.12% of the administered dose. Although JM-40 and carboplatin are structurally closely related, pharmocokinetics and toxicity of JM-40 were more similar to cis-platin than to carboplatin.

Interaction of cisplatin and carboplatin with sodium thiosulfate: reaction rates and protein binding.

Toxicity of cisplatin can be decreased by concomitant administration of sodium thiosulfate, which perhaps chemically inactivates this platinum compound. We studied the disappearance of cisplatin and carboplatin in aqueous solutions of thiosulfate at 37 degrees C by means of liquid chromatography. At initial concentrations that were similar to therapeutic concentrations in plasma, both drugs disappeared, with half-lives of 66 and 537 min for cisplatin and carboplatin, respectively. At higher thiosulfate concentrations, as found in urine, the respective half-lives were 3.7 and 33.8 min. These values suggest that direct chemical interaction in the plasma compartment has limited therapeutic consequences, whereas the anti-toxic effect of thiosulfate might be explained by the rapid inactivation of cisplatin in the kidneys. Reaction products of cisplatin and thiosulfate bound instantaneously and mainly reversibly to plasma proteins. Protein-bound cisplatin was not released by added thiosulfate--which may explain why thiosulfate, to be effective, must be given in advance of and during cisplatin administration.

Secondary screening of platinum compounds in human ovarian cancer xenografts in nude mice.

Five TNO platinum compounds were evaluated for antitumor activities in two human ovarian carcinoma tumor lines grown in nude mice. The most active drug, TNO-38, was investigated in five additional lines with a known range of sensitivity to cisplatin. None of the new compounds showed superior activity to cisplatin. The slightly lower activity of TNO-38 as compared to the parent compound was reproducible in all tumor lines. Besides the similarity in the antitumor activity, a remarkable correspondence in platinum distribution and retention at 24 hr of TNO-38 and cisplatin could be observed. Chromatographic analysis of the compounds in their injection fluids showed single peaks for TNO-26 and TNO-38. The degradation products of the latter drugs may have affected their activity and toxicity. These human ovarian cancer xenografts may offer a reliable screening model for selection of a cisplatin analog with a higher therapeutic index or without cross-resistance for treatment in ovarian cancer.

Analysis of antitumour [1,1-bis(aminomethyl)cyclohexane]platinum(II) complexes derived from spiroplatin by high-performance liquid chromatography with differential pulse amperometric detection.

A reversed-phase high-performance liquid chromatographic analysis was developed for aqua[1,1-bis(aminomethyl)cyclohexane]sulphatoplatinum(II) (spiroplatin) and its hydrolysis and oligomerization products. The platinum complexes were detected by differential pulse amperometry at a hanging mercury drop electrode, at -540 mV vs. Ag/AgCl. The limit of detection was 0.05 microM. Aqueous solutions of spiroplatin appeared to contain the diaqua, monoaquamonosulphato, monoaquamonochloro, dichloro and hydroxo-bridged dimer complexes of [1,1-bis(aminomethyl)cyclohexane]platinum(II) in mutual equilibrium. The equilibrium shifts after dilution in infusion fluids were studied. Detection of these platinum(II) complexes in untreated human plasma ultrafiltrate and urine demonstrated the selectivity of the described analysis.

Influence of hydrolysis products of aqua(1,1-bis(aminomethyl)cyclohexane)sulfatoplatinum(II) on toxicity in rats.

Aqueous solutions of the cisplatin analog aqua(1,1-bis(aminomethyl)-cyclohexane)sulfatoplatinum(II) (TNO-6, spiroplatin) principally contain hydrolyzed and oligomerized molecules. Sodium sulfate reduces the hydrolysis of the sulfato ligand. We investigated the influence of the equilibrium state on nephrotoxicity of spiroplatin in rats receiving 3 doses of 3 mg/kg with an interval of 8 days. Rats (n = 6) treated with spiroplatin solubilized in isoosmotic sodium sulfate (impaired hydrolysis) showed less toxicity as measured by proteinuria, platinum excretion and body weight, than the group treated with spiroplatin solubilized in 5% glucose. This result indicates that the presence of hydrolysis products plays a role in the toxicity of spiroplatin.

Determination of ethylenediamineplatinum(II) malonate in infusion fluids, human plasma and urine by high-performance liquid chromatography.

A selective and convenient high-performance liquid chromatographic assay was developed for ethylenediamineplatinum(II) malonate (JM-40) in plasma ultrafiltrate and urine. A mu Porasil silica column (30 cm) was used with acetonitrile-water (90:10, v/v) as the mobile phase and the elution of compounds was monitored by ultraviolet absorbance at 214 nm. A linear dynamic range of at least three decades (1-1000 micrograms/ml) was achieved. The detection limit in plasma ultrafiltrate was 0.35 micrograms/ml. The stability of JM-40 was determined in 0.9% sodium chloride, 5% glucose, plasma ultrafiltrate and urine. More stable drug solutions were obtained with 5% glucose than with 0.9% sodium chloride. JM-40 was also determined in plasma ultrafiltrate and urine samples of one patient receiving short-term infusions of the drug. In plasma ultrafiltrate unmetabolized JM-40 was detected during the first 5 h after administration and had a half-life of 21.3 +/- 1.6 min. The parent drug was excreted in the urine in rapidly decreasing amounts. Eighteen per cent of the dose was recovered as unmetabolized drug during the first 6 h.