Pharmacokinetics of carboplatin at a dose of 750 mg m-2 divided over three consecutive days

Pharmacokinetics of the cisplatin analogue carboplatin were studied in patients with disseminated ovarian and testicular cancer. Carboplatin 750 mg m-2 divided over three consecutive days was given as part of an ablative combination regimen followed by autologous bone marrow transplantation. Platinum (Pt) in plasma, plasma ultrafiltrate and urine was determined up to 96 h after the last drug dose by atomic absorption spectrometry. Carboplatin was measured by high performance liquid chromatography. The curves of ultrafiltrated Pt and carboplatin decayed in a bio-exponential way with t1/2 alpha of respectively 65 and 70 min and t1/2 beta of respectively 378 and 1014 min. The volumes of distribution (Vdss) were 18 and 25 l m-2, respectively, and total body clearances (ClTB) 79 and 65 ml min-1 m-2. Both curves overlapped when corrected for the Pt content of carboplatin. A diversion with the three-exponential curve of total Pt occurred between 3 and 6 h. After 10 h approximately 30% of the plasma Pt was protein bound. Total Pt had a larger Vdss (117 l m-2) and a lower total body clearance (14 ml min-1 m-2) than free Pt and carboplatin. Fifty-three per cent of the i.v. administered carboplatin was excreted in the urine in the first 6 h. Plasma ultrafiltrated Pt and carboplatin decreased to undetectable levels within 48 h, but total Pt was detectable until 96 h after the last carboplatin dose. However, this Pt is already bound to protein and unlikely to be cytotoxic to reinfused haemopoietic stem cells, so bone marrow reinfusion can be safely performed at 48 h after repeated dosing of carboplatin on three consecutive days.     

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 unchanged carboplatin (CBDCA) in patients with small cell lung carcinoma

Summary The disposition of the cisplatin analogue carboplatin was studied in seven patients with small cell lung cancer. Carboplatin 100 mg/m² was administered without hydration by a 1-h infusion with VP16-213 120 mg/m² on days 1, 2 and 3 of each course. Plasma and urine collections were made on days 1 and 3 of the first course of treatment. Carboplatin levels in plasma ultrafiltrate and urine were quantitated using a specific and sensitive, highperformance liquid chromatographic assay which involved sample clean-up on a Dowex-2 column prior to injection. Estimates of pharmacokinetic parameters determined using either compartmental or non-compartmental methods were comparable. There was no difference between carboplatin pharmacolinetic parameters determined on days 1 and 3 of treatment. The mean (±SD) carboplatin half-life determined from plasma data on day 1 was 105±30.4 min and was not significantly different from that determined using urinary excretion rate data (107±51.7 min). Urinary excretion rate plots showed that carboplatin elimination was mono-exponential for up to 14 h after infusion. Totalbody clearance was 105±40.0 ml min^-1 m^-2, renal clearance 64.3±44.1 ml min^-1 m^-2, and volume of distribution 17.3±4.2 l/m² on the 1st day of treatment. Of the administered dose, 58.4%±21.2% was recovered in urine over a 24-h period after the start of the infusion. The mean renal clearance of carboplatin was comparable to creatinine clearance. Carboplatin disposition was clearly defined in the patients studied using analytical methodology specific for the unchanged drug.     

Lack of nephrotoxicity of oral ammine/amine platinum (IV) dicarboxylate complexes in rodents.

The comparative nephrotoxicity of i.v. cisplatin, i.v. carboplatin and six p.o. ammine/amine Pt(IV) dicarboxylates was studied in rodents following single MTD treatments. In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days. In contrast, mice treated with i.v. carboplatin or p.o. ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range. In rats, i.v. cisplatin caused 5-fold elevations in plasma creatinine (188 +/- 33 microM) and urea (30.4 +/- 8.9 mM), a 10-fold fall in creatinine clearance (0.54 +/- 0.31 ml min-1 kg-1), a 25-fold elevation in urine/plasma glucose concentration ratio (3.28 +/- 0.17), a 20% increase in kidney weight (7.9 +/- 0.56 mg gm-1 body weight) and extensive histological damage 4 days after treatment. In contrast, i.v. carboplatin and p.o. JM216 (the lead compound of this series) caused neither abnormalities in renal function nor histological damage in rats. The nephrotoxicity of single MTD treatments of p.o. ammine/amine Pt(IV) dicarboxylate complexes appears less than i.v. cisplatin and comparable to i.v. carboplatin.     

Protein binding of five platinum compounds

Summary Amicon 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.     

A phase I study of 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5 days.

A phase I trial was conducted with lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) i.v. bolus daily for 5 days every 4 weeks. After entering five patients toxicity appeared to be related to renal function, therefore the individual dose (total dose 20-100 mg m-2 over 5 days) of lobaplatin was modified according to creatinine clearance (CRCL) and escalated in patients. Twenty-seven patients with refractory solid tumours received 72 courses. Thrombocytopenia was dose-limiting, its degree was related to dose and CRCL at time of drug administration. With a CRCL of 60-80 ml min-1 the maximum tolerated dose was 40 mg m-2, with a CRCL of 81-100 ml min-1 70 mg m-2, and with a CRCL > 100 ml min-1 it was 85 mg m-2. Platelet and leukocyte nadirs were observed around day 21. The percentual platelet nadir (percentage of day 1 platelet count) correlated with CRCL at different dose levels and could be described by 0.76 x CRCL (ml min-1) - (1.45 x dose (mg m-2) + 43.38. This equation tested in 20 patients (28 courses) produced a correlation between observed and predicted percentual platelet nadir (r = 0.82, P < 0.001). No renal function impairment occurred. Urinary excretion of platinum (by A.A.S) was estimated in six patients and revealed that 91.5% (s.e. +/- 7.9) of the platinum dose was excreted within 4 h. Responses (one PR, one CR) occurred in two patients with ovarian cancer (both pretreated with carboplatin and cisplatin). The recommended dose of lobaplatin i.v. bolus daily for 5 days for phase II studies depends on renal function, namely 30 mg m-2 at CRCL 60-80 ml min-1; 55 mg m-2 at CRCL 81-100 ml min-1; 70 mg m-2 at CRCL > 100 ml min-1.     

Regional pharmacokinetic selectivity of intraperitoneal cisplatin in ovarian cancer

Five patients with intraabdominal ovarian cancer, 4 of whom with concomitant ascites, refractory to cisplatin-containing combination chemotherapy were treated with intraperitoneal cisplatin. Cisplatin, 90 mg/m2, was administered intraperitoneally in 2 liters of warm 0.9% NaCl with a 4-hour dwelling time on day 1 q 21 days. Platinum concentrations in plasma, ascites, ultrafiltrates of plasma and ascites, and urine were assayed by flameless atomic absorption spectrophotometry and determinations were verified by neutron activation analysis. Peak total and ultrafiltrable plasma platinum levels were 1.63 +/- 0.6 and 0.76 +/- 0.3 microgram/ml, respectively. Peritoneal clearance of total platinum (PA) was 21 ml/min whereas body clearance of total platinum was on the average 13.8 times PA, varying from 171 to 429 ml/min; the mean AUC (peritoneum) to AUC (plasma) ratio was 11 +/- 3. In 2 patients control of ascites was obtained, in 1 of these patients prior positive cytology became negative after her first intraperitoneal course. No nephrotoxicity was observed and gastrointestinal toxicity was mild. No catheter-related infections were observed. Intraperitoneal cisplatin therapy is well tolerated, pharmacokinetically rational and may be useful in managing ovarian cancer patients with malignant ascites or minimal residual disease at second-look laparotomy.     

Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates.

PURPOSE: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species. EXPERIMENTAL DESIGN: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0-24)/plasma ultrafiltrate AUC(0-24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites. RESULTS: The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 +/- 22, 18 +/- 6, and 211 +/- 64 micromol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 micromol/L hour for oxaliplatin, 0.56 +/- 0.08 micromol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin. CONCLUSIONS: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.     

Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function

cis-Diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) is a nonnephrotoxic analogue of cisplatin currently undergoing clinical evaluation. Pharmacokinetic studies have been performed in patients receiving CBDCA (20 to 520 mg/sq m) as a 1-hr infusion without hydration or diuresis. Following the end of the infusion, plasma levels of total platinum and ultrafilterable (Mr less than 50,000) platinum (free platinum) decayed biphasically with first-order kinetics (total platinum t alpha 1/2 = 98 min; t beta 1/2 range, 399 to greater than 1440 min; free platinum t alpha 1/2 = 87 min; t beta 1/2 = 354 min). During the first four hr, binding of platinum to plasma protein was limited (24%), with most of the free platinum in the form of unchanged CBDCA (94%). However, by 24 hr, the majority of platinum was protein bound (87%). The major route of elimination was renal, 65% of the platinum administered being excreted in the urine within 24 hr, with 32% of the dose excreted as unchanged CBDCA. No evidence was found from studies on the renal clearance of free platinum to indicate renal tubular secretion (mean free platinum renal clearance, 69 ml/min). However, the plasma clearance of free platinum did correlate positively with glomerular filtration rates (p = 0.005). None of the pharmacokinetic parameters determined were dose dependent. In vitro studies with plasma and urine demonstrated that, in contrast to cisplatin, CBDCA is a stable complex [t 1/2 - 37 degrees; plasma, 30 hr, and urine (range), 20 to 460 hr]. The differences in the pharmacokinetics of cisplatin and CBDCA may explain why the latter complex is not nephrotoxic.     

Pharmacokinetics of low-dose carboplatin and applicability of a method of calculation for estimating individual drug clearance.

BACKGROUND: Carboplatin is the only cancer drug for which conventional doses are individually adjusted according to estimated clearance and target area under the curve (AUC). The aim of this prospective study was (i) to evaluate intra- and interpatient variability of ultrafilterable (UF) carboplatin AUC(0-)(infinity) and (ii) to test whether the prediction of carboplatin clearance according to the Chatelut formula established for conventional carboplatin doses was accurate for low carboplatin doses. MATERIALS AND METHODS: Thirty-one head and neck cancer patients (29 men, two women, mean age 55.9 years) received concomitant radiotherapy (Rgamma 2 Gy/day) and chemotherapy (carboplatin 50 mg/m(2)/day i.v.) for 7 weeks: Rgamma was administered 5 days/week (days 1-5) and carboplatin 2 days/week (days 1 and 4). Pharmacokinetics was performed once per week. A limited sample strategy based on Bayesian analysis was first validated and blood was subsequently taken 1 and 4 h after the end of carboplatin administration. RESULTS: A total of 143 cycles was analyzed. Ultrafilterable carboplatin AUC(0-)(infinity) ranged from 0.360 to 4.200 mg.min/ml (mean 0.830, median 0.670). As a corollary, UF carboplatin clearance ranged from 19.1 to 244.7 ml/min. Ultrafilterable carboplatin concentrations were very stable over time: AUC(0-)(infinity) variability due to treatment duration contributed to <1% of the total variance, while interpatient variability contributed to 68.6%. Accordingly, intrasubject effect was not significant (P = 0.38) whereas intersubject effect was highly significant (P <0.001). These results suggest that optimal dosage for targeting a given AUC may vary within a 13-fold range between patients. The Chatelut formula, based on creatininemia, body weight, age and sex, over estimates carboplatin clearance by 40% on average (bias 95% CI 29.6% to 51.1%). No significant relationship was observed between either bone marrow toxicity or creatinine clearance decrease and carboplatin pharmacokinetics. CONCLUSIONS: The Chatelut carboplatin clearance model established for conventional carboplatin dosages (>100 mg/m(2)) is not applicable for targeting low AUC (<1 mg x min/ml).     

Preclinical antitumor activity of orally administered platinum (IV) complexes

Several novel platinum (IV) mixed ammine/amine dicarboxylate dichlorides of general structure [Pt(IV)Cl₂ (OCOY)₂ NH₃(XNH₂)], where Y is aliphatic or aromatic and X is alicyclic or aliphatic, known to be particularly well absorbed following oral administration, were evaluated by that route for their antitumor activity. Testing of the Pt(IV) derivatives took place concomitantly with i.v. administered cisplatin and carboplatin in two s.c. staged tumor models, the murine M5076 sarcoma and human A2780 ovarian carcinoma. Based upon repetitive experiments which included an evaluation of different vehicles and treatment schedules, each of the orally administered Pt(IV) dicarboxylates was reproducibly active in the M5076 tumor, producing mean maximum gross log cell kill (LCK) values of between 1.5 and 2.0, and lifespan increases, reflected by mean maximum treated/control median survival (T/C) values, of 139–151%. Cisplatin and carboplatin given i.v. yielded mean maximum LCK of 3.5 and 2.5, respectively, as well as mean maximum T/C values of 166% and 164%, respectively, in the same tumor model. The best of the derivatives in the M5076 experiments, JM-216 [ammine/cyclohexylamine diacetato dichloride Pt(IV), produced LCK values that averaged only 0.5 lower than that of carboplatin, and increases in lifespan not significantly different than that of carboplatin. Against the A2780 tumor, the Pt(IV) dicarboxylates produced individual best effects of between 0.8–1.1 LCK, based on data from two or three experiments. The mean maximum LCK values for cisplatin and carboplatin were 1.8 and 2.2 LCK, respectively. JM-225, ammine/cyclopentylamine diacetato dichloride Pt(IV), was active in two of three experiments, including one result comparable to that of carboplatin. The Pt(IV) mixed ammine/amine dicarboxylate dichlorides represent a novel class of Pt derivative capable of expressing oral antitumor activity in both murine and human tumor models.     

Pharmacokinetic evaluation of zeniplatin in humans

Zeniplatin, a more water-soluble organoplatinum than cisplatin, was evaluated for clinical pharmacology in the context of a phase II trial in previously treated patients with ovarian carcinoma. A total of 12 patients were given zeniplatin at 120 mg/m² by rapid intravenous infusion over 90 min, with both blood and urine being sampled. All platinum moieties were analyzed in whole blood, plasma, plasma ultrafiltrate, and urine by atomic absorption, and free zeniplatin was analyzed in plasma ultrafiltrate by specific high-performance liquid chromatography (HPLC). In a comparison of the platinum-time concentration curve, AUC (area under the curve) values indicated that approximately 90% of platinum moieties were bound to circulating plasma proteins. There was no evidence of drug accumulation after repetitive dosing. The terminal half-life (t _1/2) of this drug in plasma ultrafiltrate (3.7–7.2 h.) as measured by HPLC was slightly longer than that of carboplatin, whereas total platinum moieties in plasma displayed a longt _1/2 (124–154 h). Approximately 60% of platinum moieties could be recovered in the urine within 24 h. These findings suggest that zeniplatin has a pharmacokinetic profile similar to that of carboplatin.Supported in part by a grant from the American Cyanamid Company and the Don Monti Memorial Foundation     

Pharmacokinetics of (glycolato-0,0′)-diammine platinum (II), a new platinum derivative,in comparison with cisplatin and carboplatin

Summary The pharmacokinetics of (glycolato-0,0)-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m², respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 g/ml and 959 g/min per ml for 254-S, 3.09 g/ml and 208 g/min per ml for cisplatin, and 19.90 g/ml and 3446 g/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.     

Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function.

PURPOSE: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. EXPERIMENTAL DESIGN: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2. RESULTS: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). CONCLUSIONS: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.     

The disposition of carboplatin in ovarian cancer patients

Summary Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170–500 mg/m². The ages, weights, and creatinine clearances (Cl_cr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Cl_cr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t_1/2 of 1.6 h and a t_1/2 of 3.0 h. The mean (±SD) residence time, total body clearance, and apparent volume of distribution were 3.5±0.4 h, 4.4±0.85 l/h, and 16±31l, respectively. C_max and AUC_inf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m². No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t_1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Cl_cr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12–16 h. All of the platinum in 24-h urine was carboplatin, and only 2%–3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Cl_cr of less than about 60 ml/min exhibited dose-disproportional increases in AUC_inf and MRT values. The latter were inversely related to Cl_cr (r=-0.98). Over a dose range of 300–500 mg/m², carboplatin exhibited linear, dose-independent pharmaco-kinetics in patients with a Cl_cr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.Supported in part by CA 16087, CRC-RR-96, AIFCR     

Comparison of platinum concentrations in human head and neck tumours following administration of carboplatin, iproplatin or cisplatin

Tumour tissue levels of platinum were determined in patients with head and neck tumours receiving carboplatin (11 patients, 400 mg/m2) and iproplatin (5 patients, 360 mg/m2). The platinum concentrations ranged from 1.1 +/- 0.4 ng Pt/mg tissue (iproplatin administration) to 1.4 +/- 0.3 ng Pt/mg tissue (carboplatin administration). These results were compared with published platinum levels after cisplatin administration. Although the administered dose of carboplatin (1.08 mmol/m2) and iproplatin (0.86 mmol/m2) was higher than the cisplatin one (0.33 mmol/m2), no significant statistical differences were observed in the resulting platinum tissue levels. The constancy of tumour platinum level after treatment with different platinum complexes could be explained, at least for carboplatin and cisplatin, by both the tumour diffusion properties and the reactivity of the drugs.     

Multi-institutional validation study of carboplatin dosing formula using adjusted serum creatinine level.

Creatinine clearance (Ccr) is widely used as a practical substitute for glomerular filtration rate (GFR) in the Calvert formula: carboplatin dose (mg) = target area under the concentration versus time curve (AUC, mg ml(-1) min) x [GFR (ml min(-1)) + 25]. However, it causes systematic overdosing when the creatinine levels are measured by an enzymatic peroxidase-antiperoxidase method (PAP-Cr). We previously suggested an amended dosing formula to adjust this overdosing: carboplatin dose (mg) = AUC (mg ml(-1) min) x [adjusted Ccr (ml min(-1)) + 25], where the Ccr was adjusted by adding 0.2 (mg dl(-1)) to serum PAP-Cr. In this study, we prospectively validated this formula in 55 patients from six institutions. Target AUC ranged from 3 to 7 mg ml(-1) min, and Ccr was measured by 24-h urine collection. Estimation of carboplatin clearance with the amended formula was unbiased [mean prediction error (MPE) +/- SE = 2.9 +/- 3.4%] and acceptably precise [root mean squared error, (RMSE) = 24.7%], whereas the Calvert formula using non-adjusted Ccr overpredicted carboplatin clearance systematically (MPE +/- SE = 24.9 +/- 4.9% and RMSE = 36.1%). The improvement in the bias and precision of the estimation was seen in all of the participating institutions as shown by decrease in the absolute value of MPE and RMSE for each institution. The Chatelut formula also highly overestimated carboplatin clearance when PAP-Cr was used, but the adjustment of PAP-Cr yielded a decrease in MPE by 30.4% and in RMSE by 21.3%. These results confirmed the necessity of adjusting the serum PAP-Cr in carboplatin dosing formulas.     

A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors.

PURPOSE: This Phase I study was designed to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of AP5280 in patients with solid tumors. Furthermore, the platinum (Pt) pharmacokinetics after AP5280 administration and preliminary antitumor activity were evaluated. AP5280 is a Pt agent linked to the water-soluble, biocompatible copolymer N-(2-hydroxypropyl)methacrylamide, which potentially increases Pt accumulation in tumors via the enhanced permeability and retention effect. In this way, it is anticipated that a higher activity of therapeutic Pt can be reached. The pharmaceutical product contains approximately 8.5% of Pt by weight and has a molecular weight of approximately 25,000. EXPERIMENTAL DESIGN: Adult patients with solid tumors received AP5280 as a 1-h i.v. infusion every 21 days. Pharmacokinetics of total and unbound Pt were determined during the first treatment course and before the start of each new cycle using noncompartmental pharmacokinetic analysis. Pt-DNA adduct concentrations in WBCs and, if available, in tumor tissue were quantified using a sensitive (32)P postlabeling assay. RESULTS: Twenty-nine patients were treated at eight dose levels (90-4500 mg Pt/m(2)). The dose-limiting toxicity was Common Toxicity Criteria grade 3 vomiting and was experienced at 4500 mg Pt/m(2) in two of six patients. The maximum tolerated dose on this schedule was therefore 4500 mg Pt/m(2), and the recommended dose for a Phase II study is 3300 mg Pt/m(2). Renal toxicity and myelosuppression, toxicities typically observed with cisplatin and carboplatin, were minimal for AP5280. The area under the curve of total Pt increased with increasing AP5280 dose. Plasma clearance of total Pt was 644 +/- 266 ml/h, and the terminal half-life was 116 +/- 46.2 h. After AP5280 administration, Pt-guanine-guanine DNA adduct concentrations in WBCs ranged from 70 to 1848 amol/microg DNA, concentrations that were substantially lower than concentrations measured after administration of therapeutic doses of cisplatin. CONCLUSIONS: AP5280 can be administered safely as a 1-h i.v. infusion at a dose of 3300 mg Pt/m(2) once every 3 weeks and produces prolonged plasma exposure compared with any of the free Pt-containing drugs. However, it remains to be determined whether AP5280 can actually increase Pt delivery to the DNA of tumor cells in man as has been shown in experimental models.     

Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer.

In phase I studies, lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mg m-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3/4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P < 0.01). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 +/- 0.5, 3.0 +/- 0.6, and 3.2 +/- 1.1 h mgl-1 for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt/TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 +/- 5% and 24 h after infusion 74 +/- 3% of the lobaplatin dose was excreted in the urine. In conclusion, lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.     

Continuous infusion carboplatin on a 21-day schedule: a phase I and pharmacokinetic study

A phase I study with continuous infusion carboplatin for 21 days every 6 weeks using a venous access port and portable pump was performed over a dose range of 12 to 32 mg/m2/d, with increments of 2 mg/m2/d. Forty-four patients received 107 courses (median, two; range, one to nine). World Health Organization (WHO) grade III/IV leukopenia and thrombocytopenia occurred in one of seven patients at 30 mg/m2/d, and in two of six and four of six patients at 32 mg/m2/d. Cumulative platelet depression was found at dose levels of 28 mg/m2/d or more. Median glomerular filtration rate (GFR) and effective renal plasma flow, monitored by radioisotope clearances at doses greater than or equal to 20 mg/m2/d, decreased 8.2% (P less than .05) and 10.9% (P less than .01) after two courses. There was a relationship (r = .50, P less than .0002) between the percentage of platelet depression and GFR. No other toxicity was observed. Of the 17 patients who were evaluable, one complete response and four partial responses were observed. In addition, six patients had stable disease. Pharmacokinetic analysis of total and ultrafiltrable platinum (UFPt) was performed by atomic absorption spectrophotometry. Steady-state plasma levels for UFPt were reached after 8 hours. These levels could be detected from the 20 mg/m2/d dose. During steady state, carboplatin dose and UFPt plasma levels were not correlated, but steady-state UFPt and GFR (r = -.27, P less than .05) were. Twenty-four percent of total platinum (Pt) was present as UFPt during steady state (x = 160 +/- 10 micrograms/L). Total body clearance of UFPt exceeded GFR 2.2 times. Mean area under the curve (AUC) for UFPt during continuous infusion was 4,921.8 +/- 301.72 mg.min/L. For total Pt, steady-state plasma levels were not reached; total Pt plasma levels increased between day 7 and day 21 (P less than .0001). There was a significant relation between total Pt serum levels day 7, 14, and 21 and the drug dose administered. Immunohistochemical analysis of DNA-bound Pt in leukocytes showed a linear increase from day 7 to day 14 to day 21 (r = .97) between DNA-bound Pt and duration of infusion in individual patients. The maximum-tolerable dose of carboplatin is 30 mg/m2/d for 21 days (total dose 630 mg/m2) and is recommended for phase II studies.