I. Klein

Pharmacokinetics of carboplatin after intraperitoneal administration

SummaryThe phamacokinetics 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 recived 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 The fluid was withdrawn after a 4-h dwell.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 On average, 34%±14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet=Dose — amount recovered from the peritoneal cavity) after i.p. administration was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 free platinum species following rapid, 3-hr and 24-hr infusions of cis-diamminedichloroplatinum (II) and its therapeutic implications

The pharmacokinetics of free platinum species derived from cis-diamminedichloroplatinum (II) (cisplatin) was studied in three patients who received the drug as a single agent for the first time at equal doses (100 mg/m2) but with different infusion times. In rapid, 3-hr and 24-hr infusions, peak levels of free platinum were 8.62, 1.96 and 0.27 microgram Pt/ml respectively; half-lives of disposition calculated 0-30 min after the end of each infusion were 17.4, 22.7 and 26.2 min respectively. Free platinum availability, measured as the area under the curves of the free platinum concentration, was the same for the three modes of administration (290, 321 and 325 micrograms Pt/min/ml-1 respectively). This observation supports the clinical impression that antitumour activity of cisplatin is not dependent on the method of administration.

The chemical reactivity of the modulating agent WR2721 (ethiofos) and its main metabolites with the antitumor agents cisplatin and carboplatin

The antitumor agents cisplatin [cis-diamminedichloroplatinum(II), CDDP] and carboplatin [cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), CBDCA] can react with a nucleophilic agent by a direct ligand exchange of the (labile) anionic ligands or through hydrolysis of these ligands followed by a fast reaction of the hydration product with the nucleophile. At pH 7.4 and 37 degrees, CDDP and CBDCA were incubated with several molar excesses of the modulating agent WR2721, its active thiol metabolite WR1065 or the symmetrical disulphide WR33278. The reaction rate constants for the hydrolysis and the direct inactivation by the WR-compounds were obtained from the pseudo first-order disappearance of the intact Pt-drug, with or without the WR-compounds at molar ratios of 50, 100 and 200. The hydrolysis of carboplatin (kaq,CBDCA = 2 x 10(-8) M-1 sec-1) was 100-fold less rapid than that of cisplatin (kaq,CDDP = 2 x 10(-6) M-1 sec-1). However, direct inactivation by WR2721, WR1065 and WR33278 was only 4-, 4- and 22-fold less rapid for carboplatin than for cisplatin, respectively. This direct inactivation was slow compared to the strong nucleophiles thiosulphate (TS) and diethyldithiocarbamate (DDTC) and decreased for both Pt-drugs in the following order: WR1065 (kWR1065/CDDP = 49.1 x 10(-4) M-1 sec-1, kWR1065/CBDCA = 12.4 x 10(-4) M-1 sec-1) greater than WR2721 (kWR2721/CDDP = 25.3 x 10(-4) M-1 sec-1, kWR2721/CBDCA = 6.07 x 10(-4) M-1 sec-1) greater than WR33278 (kWR33278/CDDP = 8.60 x 10(-4) M-1 sec-1, kWR33278/CBDCA = 0.39 x 10(-4) M-1 sec-1. Thus for CDDP, the hydrolysis-mediated interaction with the WR-compounds contributed more to the disappearance of intact platinum antitumor agent than it did for CBDCA. Considering the relatively low reactivity of WR2721 and its main metabolites with the platinum antitumor agents, in addition to their pharmacokinetic behavior, a significant inactivation of the platinum antitumor drugs by WR2721 and its main metabolites is, in contrast to TS, not expected in the circulation.

Protein binding of five platinum compounds

SummaryAmicon Centriflo CF50A cones and Amicon MPS-1 micropartition systems with YMT filters were compared for the preparation of ultrafiltrates of plasma samples containing cisplatin, spiroplatin, JM-40, carboplatin or iproplatin. The MPS-1 system equipped with YMT membranes showed less adsorption of the platinum compounds than CF50A cones and allowed more rapid processing of smaller plasma volumes. In vitro binding to human plasma proteins measured with YMT filters after 24 h of incubation was 94%, 89%, 83%, 31% and 0 for cisplatin, spiroplatin, JM-40, carboplatin and iproplatin, respectively. These values corresponded with the initial half-lives in plasma and the decomposition half-lives of intact drug in plasma ultrafiltrate as measured by HPLC. It is suggested that the degree of protein binding is related to the stability of the leaving groups.

Quantitative determination of cisplatin in body fluids by liquid chromatography with quenched phosphorescence detection.

Cisplatin [CDDP, cis-dichlorodiammineplatinum(II)], which has a high activity towards solid tumours [1], is widely used in anticancer chemotherapy. After administration, cisplatin is rapidly bound to proteins [2] whereas the unbound, intact cisplatin is thought to be the therapeutically effective agent. Accordingly, study of its pharmacokinetic behaviour may elucidate the therapeutic and toxic effects. Various platinum assay techniques have been applied, including X-ray fluorescence [3], tameless atomic absorption [4-6] (NFAA) and pre-column derivatization with diethyldithiocarbamate (DDTC) combined with high-performance liquid chromatography (HPLC) and on-line UV [7, 8] or off-line NFAA [8, 9] detection. These methods give information about the amount of total platinum or reactive platinum, respectively. Methods for the specific determination of CDDP, and in some cases its metabolites, also have been published. They are based on detection of the different species after HPLC separation. Use has been made of post-column reaction detection [10], chloride-assisted [11] or dual electrode [12] electrochemical detection and fraction collection followed by NFAA [13]. Furthermore, a column switching technique [14] followed by off-line NFAA has been developed. This paper describes the determination of cisplatin in plasma and urine by HPLC with quenched phosphorescence detection a technique that has already been applied to the

Phase I study and pharmacokinetics of intraperitoneal carboplatin

In the early stages of this phase I study the tolerance of carboplatin intraperitoneally was good. Pharmacokinetic profiles suggest a possible therapeutic advantage for giving the drug intraperitoneally for the treatment of tumour nodules situated in the peritoneum. The extent of penetration of carboplatin through tumour nodules has not yet been assessed but tumour nodules are being processed for nuclear activation analysis.

Chemical reactivity of cisplatin bound to human plasma proteins

SummaryHuman plasma was incubated with cisplatin over 24h. Ultrafilterable platinum and platinum reactive with DDTC were determined at regular time intervals during incubation. At each time point more platinum reacted with sodiumN,N1-diethyldithiocarbamate (DDTC) than was available as ultrafilterable platinum. At 24 h 70% of total platinum (10% ultrafiltrable platinum and 60% protein-bound platinum) reacted with DDTC. This means that cisplatin bound to plasma proteins can — at least in part — still react with strong nucleophiles.

Human pharmacokinetics of carboplatin after oral administration

Sir, Carboplatin has proven to be the most promising secondgeneration platinum compound [I, 21. Its spectrum of activity appears comparable with that of cisplatin, with a much more favorable pattern of toxic side effects. The risk for renal damage is very low for carboplatin and a hydration scheme is not required. In contrast to cisplatin, carboplatin has a stable chemical structure, suggesting a role for oral administration [5]. Therefore, we investigated the tolerance of carboplatin following oral administration and determined the pharmacokinetics of total platinum (Pt), non-protein-bound platinum (free Pt), and the parent drug in plasma for this route of administration in two patients. The i.v. formulation of carboplatin (cis-diammine1,l-cyclobutane dicarboxylate platinum 11), as provided by Bristol ~ y e r s , was used for preparing the oral dose by adding 60 ml carboplatin solution (480 mg) to 180 ml water and 60 ml lemonade syrup. Each dose of carboplatin was taken within 5 min. Heparinized blood samples were obtained at 0, 15, 30, 45, 60, 75, 90, 120, 150, 180, and 210 min and at 4, 5, 6, 9, 11, and 24 h after administration. Plasma and plasma ultrafiltrate were prepared immediately after sampling. Pt and free Pt concentrations were determined by flameless atomic absorption spectrometry. Intact carboplatin concentrations were determined by HPLC, according to procedures previously described by us [3]. Both patients suffered from an advanced tumor of the mouth, progressive after previous therapies. The carboplatin solution was taken by the patients on an empty stomach: patient 1 received three oral doses of 300 mg/m2 on 3 consecutive days; patient 2 received 300 mg/m2 orally on day I and 187.5 mg/m2 i.v. on day 2.

Analysis and pharmacokinetics ofN-l-leucyldoxorubicin and metabolites in tissues of tumor-bearing BALB/c mice

SummaryLeucyldoxorubicin (Leu-Dox) was developed as a prodrug of doxorubicin (Dox) with the aim of lowering the cardiotoxicity and improving the therapeutic index produced by Dox. To support the preclinical findings on its antitumor activity and cardiotoxicity, concentrations of Leu-Dox and its metabolites were determined in plasma, heart, and tumor after the administration of Leu-Dox to tumor-bearing mice. A liquid-liquid extraction procedure employing a chloroform/2-propanol/dimethylsulfoxide (DMSO) mixture was developed. By means of high-performance liquid chromatography (HPLC) with fluorescence detection, Leu-Dox and six of its metabolites could be assayed in the tissues with high sensitivity. Detection limits ranged from 0.01 nmol/g tissue for the aglycons to 0.06 nmol/g for Dox. Recoveries were in the range of 82%–110%, and calibration curves were linear over the concentration range tested (0.1–10 nmol/g tissue,r≥0.998). Concentration versus time curves were constructed for plasma, heart, and tumor over the first 72 h, and areas under the curves (AUCs) for the first 48 h were determined by the trapezoidal rule. Dox was rapidly formed from Leu-Dox, reaching peak levels in plasma within 5 min and in tissues within 1 h after i.v administration of Leu-Dox (12 mg/kg). The elimination of Leu-Dox was also fast as illustrated by final half-lives of 1.1, 0.8, and 0.9 h in the plasma, heart, and tumor, respectively. For Dox, the final half-lives were 16.7 h in plasma, 15.3 h in heart tissues, and 27.4 in tumor tissues. AUC values determined for Leu-Dox and Dox were 221 and 51 nmol ml−1 min, 443 and 4,262 nmol g−1 min, and 153 and 1,466 nmol g−1 min in the plasma, heart, and tumor, respectively. Comparison of these values with those obtained after an equimolar dose of Dox indicated 26%, 30%, and 16% of Leu-Dox appeared as Dox in the plasma, heart, and tumor, respectively. Thus, not only is the plasma compartment not representative for calculations of the conversion of Leu-Dox into Dox in tissue, but differences in its appearance also exist between the tissue compartments. The AUC values found for Dox in the heart may explain the reduced cardiotoxicity elicited by Leu-Dox as compared with Dox; however, the values obtained for Dox in the insensitive murine colon tumor cannot explain the enhanced antitumor activity exerted by Leu-Dox in the sensitive human tumor xenografts in nude mice.

Phase I study of spiroplatin

Spiroplatin was investigated in a multicentre phase I study. 67 patients with advanced solid tumours received 151 cycles either by short-term or prolonged infusion, repeated every 3 weeks, at 2.5-40 mg/m2. Myelosuppression and renal toxicity were dose-limiting. Proteinuria, which was dose- and schedule-dependent, indicated glomerular and tubular damage. The maximum tolerated doses (MTD) for poor-risk and good-risk patients were 35 and 40 mg/m2, respectively. The area under the curve (AUC) at the MTD did not correspond with the AUC at the LD10 in mice with ratios of 0.3 for free platinum and 2.6 for total platinum; these were not suitable for predicting the MTD. 1 complete response was observed in a patient with breast cancer and lung metastases and 1 partial response in a patient with adenocarcinoma of the lung. The recommended dose for phase II studies was 30 mg/m2 by 4 h infusion every 3 weeks.