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.     

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.     

Cerebrospinal fluid pharmacokinetics of carboplatin in children with brain tumors

Summary The pharmacokinetics of carboplatin in cerebrospinal fluid (CSF) and plasma was studied in five children with brain tumors (four medulloblastomas and one ependimoblastoma) who underwent preirradiation treatment with carboplatin. Carboplatin pharmacokinetics was studied following the administration of 600 mg/m² as a 1-h infusion. Four children were treated a few weeks after surgery, whereas one child with an unresectable tumor was treated prior to surgery. All patients had a ventricular-peritoneal CSF shunt connected to a subcutaneous reservoir. Total platinum and free carboplatin were measured. The mean AUC values for free carboplatin in CSF and plasma were 2.29±1.20 and 8.18±1.27 mg ml^–1 min, respectively. The mean ratio of CSF AUC to plasma AUC was 0.28 (range, 0.17–0.46). Both plasma peak levels and AUC values showed limited interpatient variability. On the other hand, carboplatin levels in CSF showed substantial interpatient variability, with a>5-fold difference in peak levels and a 3-fold difference in AUC values being recorded. The interpatient difference in CSF pharmacokinetics may have been related at least in part to the different anatomical alterations induced by the surgical procedures or by the presence of a large tumor mass. In the four evaluable patients exhibiting macroscopic residual tumor, we observed one complete remission (CR) and two partial remissions (PR) following two cycles that consisted of two doses of 600 mg/m² carboplatin given on 2 consecutive days (total dose, 1200 mg/m²) and were separated by a l-month interval. These results may give some indication as to the optimal dose and schedule for carboplatin administration in the treatment of primitive neuroectodermic tumors (PNET).This work was partially supported by the AIRC     

Disposition of total and unbound etoposide following high-dose therapy

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18–61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35–60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0±0.4 g/dl and 0.5±0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (% unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. Te mean (±SD) parameters for total etoposide included: clearance (CL), 31.8±17.7 ml min^–1 m^–2; volume of distribution (V_ss), 11.5±5.9 l/m², and terminal half-life (t _1/2 ), 7.2±3.7 h. Mean unbound CL was 209.6±62.7 ml min^–1 m^–2 and %unbound was 16%±5%. The mean etoposide %unbound was inversely related to serum albumin (r ²=0.45,P=0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively;P=0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of 3.0 g/dl than in those with levels of >3.0 g/dl (34.6 vs 23.5 ml min^–1 m^–2,P=0.05). Total CL was directly related to %unbound (r ²=0.61,P=0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.This study was supported in part by Bristol-Myers. Oncology Division     

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 pharmacokinetics in young children with brain tumors

 Purpose: The pharmacokinetic parameters and maximal tolerated systemic exposure were determined for carboplatin in young children given in combination with cyclophosphamide and etoposide. Patients and methods: Carboplatin was administered as part of a multiagent chemotherapy regimen to 21 pediatric patients less than 5 years of age with newly diagnosed, malignant central nervous system tumors. Patients received cyclophosphamide, 1.2 g/m², on day 1 and carboplatin on day 2 followed by etoposide, 100 mg/m², each day. Carboplatin doses were calculated to achieve a targeted area under the serum concentration versus time curve (TAUC) of 5, 6.5 or 8 mg/ml . min based on each patient’s measured glomerular filtration rate (GFR). Carboplatin pharmacokinetic parameters were determined after course 1 and then after every third course of therapy. Results: The median carboplatin clearance and GFR after course 1 were 118 and 98 ml/min per m², respectively. Targeted doses based on measured GFR reliably achieved the TAUC for carboplatin. The median (range) carboplatin clearance for four children less than 1 year of age was 76 (66–84) ml/min per m², significantly lower (P=0.05) than the value of 131 (80–158) ml/min per m² for children from 1 to 4 years of age. The mean carboplatin clearance declined by 23% in 12 patients studied from course 1 to course 4 of therapy. The decrease was greater than 20% (range 20–53%) in 7 of the 12 patients studied. Conclusion: Carboplatin clearance for children aged between 1 and 4 years at diagnosis is approximately 45% higher than previously reported for pediatric patients, but declines after four courses of therapy. For children less than 1 year of age, carboplatin clearance per square meter is approximately 40% lower than patients 1 to 4 years of age. There are corresponding differences in GFR that provide a plausible explanation for the age and therapy-related changes in carboplatin clearance. Toxicity was acceptable for patients treated at a TAUC of 6.5 mg/ml . min for carboplatin given with etoposide and cyclophosphamide. The average carboplatin dose required for this AUC was 767 mg/m². Received: 13 July 1995/Accepted: 18 December 1995     

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.     

Phase I pharmacokinetics study of high-dose fotemustine and its metabolite 2-chloroethanol in patients with high-grade gliomas

The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I–II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III–IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2×300 to 2×500 mg/m². Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination halflives of 4.15±2.57 and 28.8±12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96±2.89 to 12.22±3.95 mg l^–1h. Drug clearance was independent of the dose given and equal to 109±65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r=0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.     

Relationship between calculated carboplatin area under the curve, using the Cockcroft-Calvert formula and the Chatelut formula, and thrombocytopenia induced by intraperitoneal carboplatin in combination with intravenous cyclophosphamide

Background. There is no standard formula to estimate doses for the intraperitoneal (IP) administration of carboplatin. We evaluated a combination of the Cockcroft and the Calvert (Cockcroft-Calvert) formula to determine the area under the curve (AUC) for IP carboplatin co-administered with intravenous (IV) cyclophosphamide (CPM). We also evaluated the correlation of carboplatin clearance determined by the Chatelut formula with carboplatin clearance determined by the Cockcroft-Calvert formula. Methods. We performed a retrospective study of the records of 149 treatments in 30 patients who received IP carboplatin and IV CPM for ovarian carcinoma. The glomerular filtration rate was calculated with the Cockcroft formula. Carboplatin doses were determined based on the body surface area. The Cockcroft-Calvert formula was used to calculate the AUC. The Chatelut formula was also used to calculate the clearance of carboplatin and the AUC. Results. The AUC calculated with the Cockcroft-Calvert formula was well correlated to the AUC calculated with the Chatelut formula (r ² = 0.965). During the first four courses of IP carboplatin combined with IV CPM (300–500mg/m²), the correlation between the percent decrease in platelet count and the calculated carboplatin AUC varied among methods: Cockcroft-Calvert formula AUC:r ² = 0.460; Chatelut formula AUC:r ² = 0.431; body surface area dose:r ² = 0.204; total dose:r ² = 0.143. Conclusion. To decrease patient platelet count by 67%, the optimal target AUC following IP administration of carboplatin in combination with 300–500mgCPM/m²IV was calculated as 6.5, using the Cockcroft-Calvert formula, and as 7.5, using the Chatelut formula. Considerable modification of the IP carboplatin dose is required after the fourth course. A prospective study is ongoing to confirm these results.     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Influence of infusion time on unchanged cisplatin disposition in patients with ovarian cancer

Summary The disposition of unchanged cisplatin in ten patients with ovarian cancer receiving 2-h infusions of 100 mg/m² was compared with that of ten patients receiving 6-h infusions. A high-performance liquid chromatographic assay specific for the unchanged drug was used and all collected samples were rapidly processed. Patients were catheterized for urine collections. Cisplatin renal clearance was significantly lower after 6-hour infusions (52.8±16.2 ml/min per m²) than after 2-h infusions (87.1±38.2 ml/min per m²) (P=0.026). Total clearance was also lower and less variable, although not significantly, in patients receiving the longer infusion. No differences in nonrenal clearance, volume of distribution, or half-life were observed between the two groups. There was only a poor relationship between cisplatin renal clearance and creatinine clearance after 2-h (r ²=0.02; P=0.66) and 6-h infusions (r ²=0.18; P=0.23). A single cisplatin plasma level obtained at the end of the infusion proved to be a good predictor of total cisplatin clearance after both 2-h (r ²-0.70; P=0.0096) and 6-h infusions (r ²=0.97; P=0.0001). This level was not significantly related to the relatively small changes in creatinine clearance that occurred after three courses of treatment.This study was supported by grants from the National Health and Medical Research Council of Australia and the Anti-Cancer Foundation of the Universities of South Australia     

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.     

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     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993     

A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve

 The aim of this study was to develop and validate a simple and rapid method for the estimation of the area under the free carboplatin plasma concentration versus time curve (AUC). The relationship between the carboplatin AUC and the total plasma platinum (Pt) concentration 24 h after treatment was studied using data from 49 patients treated with 20–1600 mg/m² carboplatin as a 60–100 min infusion (median 60 min). The relationship was confirmed by the in vitro incubation of carboplatin in human plasma and prospectively validated in 13 ovarian cancer patients. Free carboplatin was separated by ultrafiltration (MW cut off 30,000), and free and total Pt measured by atomic absorption spectrophotometry. There was a linear relationship in vivo between the 24 h (median 24.4; range 16.3–27.3 h) total plasma Pt concentration (μM) and free carboplatin AUC (mg/ml.min): AUC=(24 h Pt+0.3)/0.82 (r ²=0.93, AUC median 5.8 (0.13–28)mg/ml.min, 24 h Pt median 4.4 (0.1–23) μM). A similar relationship was observed in vitro [AUC=(24 h Pt +0.1)/0.93 (r ²=0.98, AUC median 7.9 (2.0–17) mg/ml.min, 24 h Pt median 7.1 (1.8–15) μM)]. The relationship derived from the in vivo data gave an unbiased and reasonably accurate estimate of the measured carboplatin AUC in 13 patients (AUC=5.1–8.7 mg/ml.min, GFR=59–129 ml/min, infusion time 30–45 min, 24 h sampling time 22.9–24.5 h), giving a percentage mean error of −4.2% and root mean squared percentage error of 11.5%. These results show that the analysis of a single blood sample taken 24 h after carboplatin administration can be used to produce an unbiased and reasonably accurate measure of the free carboplatin AUC. Unlike published limited sampling strategies, this method is not complicated by the need to accurately control the duration of the carboplatin infusion or the time at which the sample is taken. Received: 13 January 1995/Accepted: 14 May 1995     

Dosing of thioTEPA for myeloablative therapy

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150–250 mg/m² given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thio TEPA and TEPA were measured by gas chromatography. At 22–24 h after initiation of a 4-h infusion, the mean ±SE plasma concentration of thioTEPA was 124±63 ng/ml, while that of TEPA was 235±69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC₅₀s of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC₅₀s of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a twocompartment model, the mean thioTEPA Vc was 47.4±4.7 l/m², t_1/2 19±5 min,t _1/2 3.7±0.5 h, and plasma clearance 302±21 ml/min per m². The mean AUCs were 6.9–16.2 mg h/l for thioTEPA and 8.9–21.2 mg h/l for TEPA, while the mean peak concentrations were 0.95–2.08 g/ml for thioTEPA and 0.88–1.90 g/ml for TEPA. There was a significant association of grades 2–4 maximum regimen-related toxicity (RRT) with TEPA peak >1.75 g/ml and with combined thioTEPA and TEPA AUC >30 mgh/l (5/6 vs 0/9,P=0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r=0.74,P=0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m² in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0,P=0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.Supported in part by a grant from the American Cyanamid Corporation     

A study of sequential high dose cyclophosphamide and high dose carboplatin with peripheral stem-cell rescue in resistant or recurrent pediatric brain tumors

Purpose: To determine the maximum tolerated dose (MTD) of carboplatin with autologous hematopoietic stem-cell rescue, in children with poor-prognosis brain tumors.Patients and methods: A previously determined dose of cyclophosphamide with stem-cell rescue was used as a first course. In a second course, carboplatin was given for 3days with stem-cell rescue to 20 children. The starting dose of carboplatin was 400mg/m²/day with increments of 75mg/m²/day in subsequent cohorts. Toxicity and tumor response were recorded.Results: There were two grade IV toxicities at the dose level of 775mg/m²/day. There were no toxic deaths. Thus, the MTD of carboplatin was 700mg/m²/day for 3days. There were six complete responses (33%, 95% confidence interval [CI], 13–59%), two partial responses (11%; 95% CI, 1–35%), four with stable diseases (22%; 95% CI, 6–48%) and six progressed (33%; 95% CI, 13–59%) out of 18 assessable. Seven of the eight responses were in primitive neuroectodermal tumors (PNETs) or Germinomas. One child with a metastatic anaplastic astrocytoma had a CR. The median duration of tumor response was 10 months (range: 1.5–87months) with two children disease free at 66 and 87months. Actuarial survival is 21%. Median follow-up of survivors is 35months (range: 15–87months).Conclusion: The MTD of carboplatin with stem-cell rescue is 700mg/m²/day for 3days. Sequential stem-cell supported cyclophosphamide and carboplatin was tolerable in children with brain tumors and produced responses in PNETs and Germinomas.     

A limited sampling method for estimation of the carboplatin area under the curve

Summary A limited sampling method for estimation of the carboplatin area under the curve (AUC) from one or two plasma concentration determination is presented. The model was conceived and developed using 43 pharmacokinetic studies in 15 patients with ovarian cancer (model data set) who received carboplatin in combination with cyclophosphamide. Linear regression analyses comparing the AUC and the drug concentration at a single time point (0.25–10 h after the end of the infusion) as calculated from the fitted exponential equations gave correlation coefficients as high as 0.97, with maximal correlations falling within the interval of 2–3.25 h. The model was validated prospectively in 9 patients with ovarian cancer (validation data set) who received the same treatment as did the model data set (21 pharmacokinetic studies), testing the equation AUC=0.52×C_2.75h+0.92. Observed and estimated AUCs were correlated in the validation data set (r=0.91). The mean predictive error (MPE%±SE) was –4.4%±3.1% and the root mean squared error (RMSE%) was 13.9%. Multiple regression analysis revealed that adding a second sample drawn at 0.25 h (AUC=0.053×C_0.25h+0.401×C_2.75h+0.628) improved the MPE% to –2.2%±2.1% and the RMSE% to 9.4% (r=0.96). We conclude that the carboplatin AUC can be estimated from a single plasma sample at 2.75 h or, more precisely, from two plasma samples at 0.25 and 2.75 h. The methods described may prove to be a handy tool for the calculation of approximate AUCs in trials of a size that would discourage detailed pharmacokinetic studies.This work was supported by grants from the Lundbeck Foundation and the Danish Cancer Society     

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion

Summary A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m² per day for 5 days and repeated every 21–28 days. The patient population had a median age of 55 years (range 38–76) and a median Karnofsky performance status of 80 (range 60–100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/l (range 100–4800) in 8 heavily pretreated patients treated at 350 mg/m² per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m² and had WBC nadirs of 800/l and 600l. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m² per day, nadir 85000/l). Neither hyponatremia nor symptomatic hypoosmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m² per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09–6.79 g/ml. Steady state was achieved in 14.5±5.9 h (mean ±SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t^1/2 of 5.3±3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543±150 g/ml h and reflected a cyclophosphamide total-body clearance (CL_TB) of 103±31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6–4.3 g/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3%±7.6% and 15.1%±2.0% of the administered daily dose, respectively. The t^1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m² as an i.v. bolus. The AUC of alkylating activity associated with the 5-day continuous infusion of cyclophosphamide is about three times greater than the AUC of alkylating activity calculated after a 1500-mg/m² bolus dose of cyclophosphamide. Daily urinary excretions of cyclophosphamide and alkylating activity associated with the 5-day continuous infusion schedule are similar to those reported after bolus doses of cyclophosphamide.     

Clinical pharmacokinetics of 3-deazaguanine

Summary 3-Deazaguanine (3DG), an antipurine antimetabolite, has recently completed a phase I clinical trial at this Institute. The drug was given on a dailyx5 schedule by i.v. infusion over 0.25–2.16 h. The pharmacokinetics of 3DG during 16 courses were studied in 12 patients at doses of 200–800 mg/m². 3DG in plasma was measured by an isocratic reverse-phase high-performance liquid chromatographic (HPLC) procedure carried out on IBM phenyl columns at 40° C using 10mM phosphate buffer (pH 7) as the mobile phase and detection at 300 nm. Plasma decay of 3DG was biexponential in all patients. The AUC correlated linearly with dose at 200–600 mg/m² but deviated from linearity at doses>600 mg/m². The drug was cleared rapidly from plasma; at doses of 200–600 mg/m², the mean plasma clearance was 61.64±9.97 l/h and the mean terminal-phase elimination half-life was 1.6±0.6 h. The steady-state volume of distribution (98.8±29.1 l) and distribution coefficient (1.24±0.39 l/kg) indicated extensive tissue distribution for the drug. No statistically significant difference was observed between the pharmacokinetics of 3DG on day 1 and that on day 4 as evaluated in three patients for whom complete plasma data were available on both days.