Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma

Summary The pharmacokinetics of carboplatin and etoposide were studied in four testicular teratoma patients receiving four courses each of combination chemotherapy consisting of etoposide (120 mg/m² daily×3), bleomycin (30 mg weekly) and carboplatin. The carboplatin dose was calculated so as to achieve a constant area under the plasma concentration vs time curve (AUC) of 4.5 mg carboplatin/ml x min by using the formula: dose=4.5×(GFR+25), where GFR is the absolute glomerular filtration rate measured by ⁵¹Cr-EDTA clearance. Carboplatin was given on either day 1 or day 2 of each course and pharmacokinetic studies were carried out in each patient on two courses. Etoposide pharmacokinetics were also studied on two separate courses in each patient on the day on which carboplatin was given and on a day when etoposide was given alone. The pharmacokinetics of carboplatin were the same on both the first and second courses, on which studies were carried out with overall mean ± SD values (n=8) of 4.8±0.6 mg/ml x min, 94±21 min, 129±21 min, 20.1±5.41, 155±33 ml/min and 102±24 ml/min for the AUC, beta-phase half-life (t_1/2), mean residence time (MRT), volume of distribution (Vd) and total body (TCLR) and renal clearances (RCLR), respectively. The renal clearance of carboplatin was not significantly different from the GFR (132±32 ml/min). Etoposide pharmacokinetics were also the same on the two courses studied, with overall mean values ±SD (n=8) of: AUC=5.1±0.9 mg/ml x min, t_1/2=40±9 min, t_1/2=257±21 min, MRT=292±25 min, Vd=13.3±1.31, TCLR=46±9 ml/min and RCLR=17.6±6.3 ml/min when the drug was given alone and AUC=5.3±0.6 mg/ml x min, t_1/2=34±6 min, t_1/2=242±25 min, MRT=292±25 min, Vd=12.5±1.81, TCLR=43±6 ml/min and RCLR=13.4±3.5 ml/min when it was given in combination with carboplatin. Thus, the equation used to determine the carboplatin accurately predicted the AUC observed and the pharmacokinetics of etoposide were not altered by concurrent carboplatin administration. The therapeutic efficacy and toxicity of the carboplatin-etoposidebleomycin combination will be compared to those of cisplatin, etoposide and bleomycin in a randomised trial.     

Pharmacokinetics of VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.     

A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m² per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m², three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m², two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 M. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m² per day.     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

In vitro stability,plasma protein binding and blood cell partitioning of 14C-carboplatin

Summary Radiochemically pure ¹⁴C-labeled carboplatin, cis-diammine [1,1-cyclobutane (1-¹⁴C) dicarboxylato (2-)-0,0'] platinum (II), was added to fresh human, dog and rat plasma, at concentrations ranging from 1 to 100 g ¹⁴C-carboplatin/ml. After 10 min incubation at ambient temperature, the plasma was ultrafiltered in Amicon Centrifree micropartition units to generate protein-free plasma ultrafiltrate (PU). Total radioactivity was determined by liquid scintillation counting. A mean (±SD) of 102%±2.0%, 99.5%±1.9%, and 99.0%±1.0% of the ¹⁴C-carboplatin added to fresh human, dog and rat plasma respectibely was recovered in the PU. ¹⁴C-carboplatin was incubated at 37°C with fresh plasma (60g/ml) and urine (200 g/ml) from humans and dogs for 120 h, and samples were removed at appropriate times for analysis of carboplatin, 1,1-cyclobutane dicarboxylic acid and cyclobutane carboxylic acid. The latter were separated by HPLC on a C-18 column with a mobile phase of H₂O/CH₃CN/0.3 M tetrabutylammonium phosphate (880:50:20 v/v/v), and the column eluants at the retention time of each compound were collected and counted for total radioactivity. Carboplatin degraded in each of the matrices with a corresponding release of 1,1-cyclobutane dicarboxylic acid. ¹⁴C-carboplatin (50 g/ml) was incubated at 37°C with fresh human, dog and rat blood and the distribution of radioactivity into the cellular fraction was determined. Radioactivity did not distribute into the blood cells of humans or dogs, but after 5 h, 44% of the radioactivity in rat blood was associated with the cellular fraction. These results show that carboplatin, at physiological concentrations, does not bind instantaneously and reversibly to the plasma proteins of rat, dog or human, and that the molecule slowly degrades in plasma and urine in vitro with the release of 1,1-cyclobutane dicarboxylic acid. The remaining diammine platinum (II) portion of the molecule therefore accounts for the essentially irreversible protein binding of the platinum from carboplatin.     

Pharmacokinetics of carboplatin after intraperitoneal administration

Summary The 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/D_net (D_net=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 administered with lobradimil to pediatric patients with brain tumors

Purpose To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors.Methods Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mgmin/ml per dose ×2 (2.5 mgmin/ml per dose ×2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m²)=target AUC (mgmin/ml) × [0.93 × GFR (ml/min/m²)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min lobradimil infusion (100–600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity.Results The median GFR was 65 ml/min/m² (range 38–95 ml/min/m²) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m²/day (124–235 and 179–360 mg/m²/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2–131%). The median carboplatin AUCs at the 2.5 and 3.5 mgmin/ml target AUCs were 3.4 and 4.8 mgmin/ml (2.51–5.8 and 3.9–7.7 mgmin/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r²=0.14).Conclusions Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.     

The disposition of carboplatin in the beagle dog

Summary Carboplatin was administered i.v. to four groups of three male beagle dogs at doses of 3, 6, 12, and 24 mg/kg (60–580 mg/m²). Plasma samples were obtained at appropriate times and protein-free plasma ultrafiltrates (PU) were generated with Amicon Centrifree micropartition systems. Urine was collected at 24-h intervals for 96 h. PU and urine samples were analyzed for carboplatin by HPLC and for total platinum by atomic absorption spectrophotometry. Carboplatin accounted for about 90% of the free platinum in plasma. The Cmax and AUC_inf values for carboplatin and for free platinum increased linearly with dose. The terminal elimination half-life and mean residence times for carboplatin and free platinum were each about 1 h. Total-body clearances for carboplatin (5.6 l/h per m²) and free platinum (5.1 l/h per m²) were constant over the dose range studied, as were the respective volumes of distribution (5.7 and 5.0 l/m²). A mean of 46% of the dose was excreted as carboplatin in 24-h urine; and by 72 h, 70% of the platinum administered was excreted in the urine. Free platinum was cleared by both renal and nonrenal processes. These results show that a dose of carboplatin is rapidly excreted in the urine and that carboplatin and plasma-free platinum exhibit linear pharmacokinetics in the beagle dog.     

Pharmacokinetics of high-dose etoposide after short-term infusion

Summary The pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m² divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m² cytosine arabinoside (ara-C), 300 mg/m² carmustine (BCNU), or 1,200 mg/m² carboplatin. Plasma etoposide concentrations were determined by²⁵²Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629g min ml^–1 (normalized to a dose of 100 mg/m²); volume of distribution at steady state (Vd_ss), 6.6±1.2l/m²; and clearance (CL), 20.4±2.4 ml min^–1 m^–2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m²). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 g/ml, all patients exhibited undelayed hematopoietic reconstitution.     

Pharmacokinetic study of doxifluridine given by 5-day stepped-dose infusion

Summary Doxifluridine (5-deoxy-5-fluorouridine, 5-dFUR) metabolism has been reported to be saturable and associated with a fall in clearance of the drug as the dose is increased. The aim of the present study was to determine the disposition of 5-dFUR and 5-fluorouracil (5-FU) when 5-dFUR was given as a 5-day infusion, with the infusion rate increased stepwise every 24 h. Measurement of plasma and urinary levels of 5-dFUR and 5-FU at steadystate for each infusion rate enabled the estimation of 5-dFUR renal (Cl_R) and nonrenal (Cl_NR) clearance and 5-FU renal clearance. A total of 28 patients with histologically proven malignancy received 5-day courses of 5-dFUR ranging in dose from 3.75 to 20 g/m² per 120 h. The lowest dose given over 24 h was 0.25 g/m², and the highest was 5 g/m². Steady-state plasma levels of 5-dFUR ranged from 167 to 6.519 ng/ml. At these plasma levels there was no evidence of significant saturation of 5-dFUR metabolism; steady-state plasma levels of 5-dFUR increased approximately linearly with dose, and nonrenal clearance did not change significantly with dose. There was also no evidence of nonlinearity in 5-dFUR renal clearance. The mean (±SD) Cl_R of 5-dFUR was 108.9±53.6 ml/min per m² (range, 45.7–210 ml/min per m²), and the Cl_NR was 728±181 ml/min per m² (range, 444–1,119 ml/min per m²). Renal clearance comprised 13% of the total 5-dFUR clearance. The mean renal clearance of 5-FU was 100.8±48.6 ml/min per m² (range, 23.5–198 ml/min per m²). There was considerable interpatient variability in 5-dFUR renal and nonrenal clearance, event at the same dose level. We concluded that the administration of 5-dFUR by the infusion method described avoided the saturation of nonrenal elimination processes reported to occur with shorter infusion schedules.This study was supported by a grant from F. Hoffmann-La Roche, Basel, Switzerland     

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.     

Carboplatin-based chemotherapy with pharmacokinetic analysis for patients with hemodialysis-dependent renal insufficiency

Summary Three patients with renal insufficiency requiring hemodialysis were treated with carboplatin at 100 mg/m² in combination with etoposide for advanced germ-cell tumor (GCT, two cases) or Adriamycin + vinblastine for a transitional-cell carcinoma of the ureter (one case). Hemodialysis was performed 24 h after the administration of carboplatin. Both patients with GCT achieved a complete response, and the patient with transitional-cell carcinoma of the ureter was inevaluable for response but his disease has not progressed. The dose of carboplatin was increased in one patient as renal function improved on therapy. In two patients, the pharmacokinetics of carboplatin were determined; the pre-dialysis half-lives, AUC, and total body clearances of free carboplatin-derived platinum were estimated to be 32 and 18.3 h, 4.93 and 6.17 mg ml^–1 min, and 18.2 and 18.7 ml/min, respectively. The dialysis elimination half-lives (t_1/2) of 2 and 3 h, respectively, for these two patients were markedly lower than the predialysis values, indicating that carboplatin was dialyzed. In summary, carboplatin can be given to patients with severe renal insufficiency. Adequate AUCs were achieved and dialysis limited systemic exposure to free carboplatin.Robert J. Motzer, M. D., is a recipient of an American Cancer Society Career Development Award     

Preclinical toxicology and tissue platinum distribution of novel oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates

The preclinical toxicology and tissue platinum distribution of a series of six orally given antitumour platinum complexes [ammine/amine platinum(IV) dicarboxylates] with structural variations of their alicyclic amine (c-C₅, c-C₆ or c-C₇), axial dicarboxylate (CH₃, C₃H₇ or NHC₂H₅) or leaving substituents (Cl₂ or OCOOCO) was studied in the mouse. Platinum tissue levels measured at 48 h after a single oral dose at 0.5 of the MTD were highest in the liver (6.0–19 m/g) and second highest in the kidney (2.8–12 g/g), and these levels were up to 5 times higher than those reported with equi-toxic doses of i.v. cisplatin and i.v. carboplatin. Platinum levels in the lung, heart, spleen, skin, skeletal muscle and brain were all<-3.1 g/g at this dose level. Liver platinum levels measured at 2 h, 2 days, 6 days and 10 days after a single oral dose at the MTD ranged widely (from 15 to 109 g platinum/g), were related to the number of carbon atoms in the axial dicarboxylate and alicyclic amine groups (r=0.9389) and showed a diversity of time-course profiles. Elevations of plasma ALT activity were recorded with single oral doses of JM225 and JM256 at the MTD. Accumulation of platinum in the liver with repeated oral dosing weekly for 4 consecutive weeks at 0.5 of the MTD occurred with JM269 (3.3-fold increase,P<0.05) and JM 225 (2.4-fold increase,P<0.05), and elevated plasma ALT activity (44±33 IU/I) was recorded with repeated oral doses of JM269. JM216 was selected from this series of analogues for further study on the basis of the elevated plasma ALT activity (JM225, JM256 and JM269), liver platinum accumulation (JM269 and JM225), poor activity against human ovarian carcinoma xenografts (JM291) or severe emetogenesis (JM221) of other examples. Following a single oral dose of JM216 at the MTD, transient reductions in the WBC (nadir, 1.6×10⁹/ 1,2 days, 74% reduction), platelet count (nadir, 613×10⁹/l, 10 days, 33% reduction) and bone marrow cellularity (nadir, 0.5×10⁷ nucleated cells/femur, 4 days, 75% reduction) were found, and these had recovered by 21 days after treatment. Jejunal mucosal disaccharidase activity following single MTDs indicated that small-intestinal mucosal damage was less severe for oral JM216 (nadir maltase activity, 68%±16% of control, NS) than for i.v. cisplatin (nadir maltase activity, 35%±6.0% of control,P<0.01) and i.v. carboplatin (nadir maltase activity, 38%±6.4% of control,P<0.01). In conclusion, the liver is the major tissue platinum deport for orally delivered ammine/amine platinum(IV) dicarboxylates and is a site of toxicity for examples of this class. Oral JM216 causes dose-limiting leucopenia but produces less gastrointestinal toxicity than either i.v. cisplatin or i.v. carboplatin at the MTD in the mouse.Abbreviations ALP alkaline phosphatase - ALT alanine aminotransferase; carboplatin,cis-diamminecyclobutanedicarboxylatoplatinum(II); cisplatin,cis-diamminedichloroplatinum(II) - EDTA ethylenediaminetetraacetic acid - MTD maximally tolerable dose - NS not significant Institute of Oncology, The Prince of Wales Hospital, High Street, Randwick, Sydney NSW 2031, Australia     

Tumor-tissue and plasma concentrations of platinum during chemotherapy of non-small-cell lung cancer patients

Summary Tumor-tissue and plasma concentrations of platinum were studied prospectively in two groups of eight patients who were suffering from advanced non-small-cell lung cancer. Treatments including two different schedules of cisplatin administration (25 vs 100 mg/m² on day 1) were compared. At 30 min after the beginning of the cisplatin infusion, blood samples and bronchoscopically obtained biopsy specimens were taken for determinations of platinum concentrations by means of flameless atomic absorption spectrophotometry. The procedure did not induce any complication. Total plasma platinum concentrations at 30 min were significantly lower (P<0.01) in patients receiving 25 mg/m² (0.49±0.23 g Pt/ml) than in those receiving 100 mg/m² (1.44±0.62 g Pt/ml), whereas no significant difference was observed in tumor-tissue platinum concentrations (22.49±53.89 ng Pt/mg in patients receiving 25 mg/m² vs 51.13±65.52 ng Pt/mg in those receiving 100 mg/m²). There was a weak correlation between simultaneous plasma and tumor-tissue platinum concentrations at 30 min. Tumor-tissue platinum concentrations seem to be poorly influenced by the cisplatin dose. This finding suggests a great interindividual variability of platinum tumor-diffusion properties in non-small-cell lung cancer.Supported in part by a grant from the Ligue Nationale Française contre le Cancer     

Pharmacokinetics of Amonafide in dogs

Summary Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. [2] has shown significant antitumor activity against a variety of experimental tumors, including L1210 leukemia and P388 leukemia. Along with the clinical trial at our institute, we have studied the disposition of Amonafide in dogs by HPLC and fluorometry. Six dogs received Amonafide i.v. at 5 mg/kg (100 mg/m²) over 15 min; three were sacrificed at 6 h, and three at 24 h. The initial plasma t_1/2, of Amonofide was 2.4±0.4 min, the intermediate t_1/2, 26.8±3.7 min, and the terminal t_1/2, 21.7±4.0 h. the peak plasma concentration achieved was 6.3±1.7 g/ml. The average apparent volume of distribution was 12.84±0.541/kg, and the total clearance was 0.56±0.161/kg/h. In 24 h, 9.5%±0.2% of the administered dose was excreted in the urine as the parent drug, and 7.4%±1.4% in the bile in 6 h. Amonafide penetrated the CSF readily and achieved the highest concentration 20–25 min after administration, which was 30% of the concurrent plasma level. Amonafide underwent extensive metabolism to at least three major metabolites and two or more minor metabolites. The and plasma t_1/2 of the major metabolite, an N-oxide derivative, were 24.8 min and 28.6 h, respectively. The 24-h cumulative urinary excretion was 1.4% of the injected dose, and the cumulative biliary excretion was 16.7% in 6 h. At autopsy 6 h after dosing, the liver contained the highest percentage (0.23% of administered dose) of unchanged Amonafide, followed by the stomach (0.11%), lung (0.04%), kidney (0.04%), and pancreas (0.03%). The rest of the major organs retained less than 0.02% of the Amonafide dose. One day after dosing, no detectable amount of Amonafide was found in any of these tissues, indicating that Amonafide appears to be extensively metabolized and not significantly retained in the dog.     

High-performance liquid chromatographic procedures for the analysis of carboplatin in human plasma and urine

Summary Specific, sensitive and reproducible high-performance liquid chromatographic procedures were developed for the quantitative analysis of carboplatin in human plasma and urine. Plasma and urine were ultrafiltered with an Amicon Centrifree^TM micropartition system, and samples were injected onto a LiChrosorb^TM diol column. The mobile phase was CH₃CN/H₂O (92:8, v/v) for plasma and CH₃CN/0.015% H₃PO₄ (89:11, v/v) for urine. The effluents were monitored at 229 nm. Carboplatin eluted by 10 min. The detector response was linear from 0.5 (plasma) or 5 (urine) to 500 g/ml. The lower limit of quantification was 1.0 g/ml plasma and 5.0 g/ml urine. Constitutents in plasma and urine, and possible degradation products (cyclobutane mono- and dicarboxylic acids) did not interfere. Within-day precision was less than 4% for plasma and 9% and 4% for urine concentrations of 40 and 401 g/ml, respectively. Within-day accuracy was 96% or greater for both matrices. Carboplatin was not bound to the Centrifree^TM membrane and recovery was 94% for plasma and 96% for urine. The storage stability of carboplatin in water, plasma, plasma ultrafiltrate, and urine and the extent of binding to human plasma proteins were evaluated. The percentage of carboplatin reversibly bound to plasma proteins was minimal (10%) over a range of 1–50 g/ml. In human plasma at 37 °C the drug was stable for about 2 h, but then degraded with a half-life of 32 h. Carboplatin had limited stability in water, plasma, and urine stored at-25 °C. Biological samples, therefore, should be stored frozen and analyzed within a week of collection to obtain valid results.     

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.     

Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer

Purpose Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer.Methods PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m². Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection.Results PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55±18 min at the 1.8 g/m² dose and 77±22 min at the 2.5 g/m² dose. The half-life of PAG was 112±53 min at the 1.8 g/m² dose and 135±75 min at the 2.5 g/m² dose. The clearance of PAA was 66±33 ml/min per m² at the 1.8 g/m² dose and 60±24 ml/min per m² at the 2.5 g/m² dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (V_m and K_m) were (means±SD) 18.4±13.8 mg/m² per min and 152±155 g/ml, respectively. The volumes of distribution for PAA and PAG (V_d-PAA and V_d-PAG) were 7.9±3.4 l/m² and 34.4±16.1 l/m², respectively. The first-order elimination rate constant for PAG (k_e-PAG) was 0.0091±0.0039 min^–1.Conclusions The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.This work was supported in part by the National Institutes of Health (M01-RR00188), and the General Clinical Research Center, Baylor College of Medicine.     

Prochlorperazine as a doxorubicin-efflux blocker: phase I clinical and pharmacokinetics studies

Summary Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i. v. administration of 15, 30, 50, and 75 mg/m² PCZ followed by a standard dose of 60 mg/m² DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m². Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were:t ₁/2 (±SE), 20.9±5.3 min;t1/2, 1.8±0.3 h; andt1/2, 21.9±5.3 h. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) for PCZ were 2254±886 l/m², 60.2±13.5 l m^–2h^–1, and 1624±686 ng ml^–1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i. v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.Supported in part by the Joan Levy Cancer Foundation and by NIH-NCI grants CA-44737 and CA-29360     

Pharmacokinetics and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide after i.v. administration in the mouse

Summary The pharmacokinetics, tissue distribution and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide(AC) were studied after i.v. administration to mice. Over the dose range of 9–121 mol/kg (3–40 mg/kg), AC displayed linear kinetics with the following model-independent parameters: clearance (C), 21.0±1.9 l h^–1 kg^–1; steady-state volume of distribution (V_ss), 11.8±1.4 l/kg; and mean residence time (MRT), 0.56±0.02 h. The plasma concentration-time profiles for AC fitted a two-compartment model with the following parameters:C _c, 19.4±2.3 l h^–1 kg^–1; V_c, 7.08±1.06 l/kg;t _1/2 13.1±3.5 min; andt _1/2Z, 1.60±0.65 h. AC displayed moderately high binding in healthy mouse plasma, giving a free fraction of 15.9%–25.3% over the drug concentration range of 1–561 M. After the i.v. administration of 30 mol/kg [³H]-AC, high radioactivity concentrations were observed in all tissues (especially the brain and kidney), showing a hight _1/2c value (37–59 h). At 2 min (first blood collection), the AC concentration as measured by high-performance liquid chromatography (HPLC) comprised 61% of the plasma radioactivity concentration (expressed as AC equivalents/l). By 48 h, 73% of the dose had been eliminated, with 26% and 47% of the delivered drug being excreted by the urinary and faecal routes, respectively; <1% of the total dose was excreted as unchanged AC in the urine. At least five distinct radiochemical peaks were distinguishable by HPLC analysis of plasma extracts, with some similar peaks appearing in urine. The 121-mol/kg dose was well tolerated by mice, with sedation being the only obvious side effect and no significant alterations in blood biochemistry or haematological parameters being recorded. After receiving a dose of 152 mol/kg, all mice experienced clonic seizures for 2 min (with one death occuring) followed by a period of sedation that lasted for up to 2h. No leucopenia occurred, but some mild anaemia was noted. There was no significant change in blood biochemistry. A further 20% increase in the i.v. dose (to 182 mol/kg) resulted in mortality, with death occurring within 2 min of AC administration.Supported by the Auckland Medical Research Foundation and the Cancer Society of New Zealand