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.     

Pharmacokinetically guided dosing of carboplatin in paediatric cancer patients with bilateral nephrectomy

An approach to carboplatin dosing in children with bilateral nephrectomy using a renal function-based dosing formula with a glomerular filtration rate of zero was investigated in the current study. Carboplatin exposure was determined in a total of nine courses of chemotherapy in four patients with Wilms tumour. Carboplatin exposures following initial dosing were less than 50% of the defined target area under the plasma concentration-time curve (AUC) in all four patients studied, with actual AUC values of between 31% and 45% of the target exposures. The use of real-time pharmacokinetic monitoring to guide dosing within a course of carboplatin treatment resulted in exposures within 15% of the target AUC in all patients. Using this information to guide dosing on additional courses of treatment in the same patient resulted in consistent exposures without the need for further monitoring or dose adjustment. These results indicate that real-time pharmacokinetic monitoring of carboplatin treatment plays a key role in ensuring that an appropriate exposure to carboplatin is achieved in children with bilateral nephrectomy. Carboplatin dosing based on patient body weight, or use of a fixed dose of carboplatin, would both be predicted to result in individual patients receiving unsatisfactory drug exposures. Further studies are warranted to further elucidate the relationship between non-renal clearance of carboplatin and patient body weight in this and other patient subpopulations where there remains concern about the optimal way to use this anticancer drug.     

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.     

Adaptive dosing and platinum-DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours

A pharmacokinetic-pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration-time curve (AUC) values of 21 or 20 mg ml(-1).min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum-DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80-126% of target AUC values, as compared to estimated exposures of 65-213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values >25% above the target AUC than those patients attaining AUC values >25% below the target AUC, following renal function-based dosing. Platinum-DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug-target interaction.     

Therapeutic monitoring of carboplatin dosing in a premature infant with retinoblastoma

Introduction  Carboplatin dosing based on renal function and therapeutic monitoring have been previously shown to be beneficial in the treatment of children with cancer. However, the applicability of such approaches to the treatment of premature or newborn infants, where kidney function may change markedly with advancing gestational and postnatal age, is unknown. Diagnosis of retinoblastoma in a preterm infant provided a rare opportunity to carry out adaptive carboplatin dosing in a patient with immature renal function. Case report  A preterm female infant born at a gestational age of 32 weeks was diagnosed with bilateral retinoblastoma at 35 weeks. Carboplatin treatment with real-time pharmacokinetic monitoring was initiated on day 26 of life at an initial dose of 6.6 mg/kg. Plasma samples were obtained at specified time points and carboplatin levels quantified by atomic absorption spectrometry. Additional doses of carboplatin were determined by pharmacokinetic monitoring based on the achievement of carboplatin AUC values of 5.2–7.8 mg/ml min on three courses of treatment. Increased carboplatin doses administered on successive courses of treatment reflected a greater than twofold increase in drug clearance, from 3.4–7.1 ml/min over a 7-week period. Pharmacokinetically-guided carboplatin dosing led to the attainment of AUCs within 10% of target values on each course of treatment. The patient completed five courses of carboplatin with both tumours defined as inactive after this treatment period. Conclusions  Data obtained from studying this patient suggests that adaptive carboplatin monitoring represents a feasible and beneficial clinical approach in preterm infants or neonates.     

Prospective validation of renal function-based carboplatin dosing in children with cancer: A United Kingdom Children's Cancer Study Group Trial.

PURPOSE: Carboplatin dosing in adults with cancer is based on renal function. The purpose of the current study was to validate a previously developed pediatric carboplatin-dosing formula. PATIENTS AND METHODS: Thirty-eight pediatric patients were randomized to receive a carboplatin dose calculated according to surface area or a renal function-based dosing formula. On the next course of therapy, the alternative dosing method was used for each patient. Carboplatin pharmacokinetics (based on free plasma platinum concentrations) were measured after both courses. RESULTS: The mean observed areas under the carboplatin concentration-versus-time curve (AUCs) after renal function- and surface area-based dosing were 98% and 95% of the target AUCs, respectively. The variation in the observed AUC was significantly less after renal function-based dosing (F test, P =.02), such that 74% of courses had an observed AUC within +/- 20% of the target value, versus 49% for courses after dosing according to surface area. Only one of 22 courses at the center with the most experience with renal function-based dosing was associated with an AUC outside +/- 20% of the target value, versus nine of 22 courses after surface area-based dosing in the same center. There was a relationship (r(2) =.71) between carboplatin AUC and thrombocytopenia in 10 neuroblastoma patients treated with a combination of carboplatin, vincristine, etoposide, and cyclophosphamide. CONCLUSION: Renal function-based carboplatin dosing in children results in more consistent drug exposure than surface area-based drug administration.     

A phase I trial of AUC-directed carboplatin with infusional doxorubicin and ifosfamide plus G-CSF in patients with advanced gynecologic malignancies

The effect of the addition of G-CSF to carboplatin, ifosfamide and doxorubicin (CIA) at the maximally tolerated dose (MTD) was studied in a phase I clinical trial. Nine patients with incurable solid tumors were treated: six endometrial and epithelial ovarian cancers, one colon cancer with pelvic masses and two unknown primary cancers. The carboplatin dose was calculated using the Calvert formula and administered in a standard 30-min intravenous infusion. The initial carboplatin dose was AUC 4.0 mg/ml per min. Fixed doses of ifosfamide (1.25 g/m² per day), mesna (1.0 g/m² per day, and doxorubicin (15 mg/m² per day) were combined and given as a 4-day continuous intravenous infusion in an attempt to decrease nonhematologic toxicity. The dose-limiting toxicity of CIA was myelosuppression, mainly neutropenia and thrombocytopenia. Nonhematologic toxicities were hemorrhagic cystitis, weakness, fatigue, and nausea and vomiting. The MTD for CIA was established at the first dose level of carboplatin (4.0 mg/ml per min). Following this, G-CSF was added to the regimen in an unsuccessful effort to escalate the carboplatin dose. Free and total carboplatin pharmacokinetics were determined using flameless atomic absorption spectroscopy. There was one complete response and one partial response among eight evaluable patients. Both responding patients had advanced ovarian cancer. We conclude that carboplatin dose intensification beyond an AUC of 4.0 mg/ml per min is not made feasible by the addition of G-CSF to infusional doxorubicin and ifosfamide in patients with advanced gynecologic cancer. Received: 22 December 1999 / Accepted: 28 April 2000     

Carboplatin therapeutic monitoring in preterm and full-term neonates

IntroductionAdministration of the most appropriate dose of chemotherapy to neonates is particularly challenging and frequently not standardised based on any scientific rationale. We report the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life.MethodsCarboplatin therapeutic monitoring was performed to achieve target drug exposures area under the plasma concentration–time curve (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma treated over an 8 year period. Carboplatin was administered over 3 days with therapeutic drug monitoring utilised to target cumulative AUC values of 5.2–7.8 mg/ml min.ResultsAUC values achieved were within 15% of target values for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on initial mg/kg dosing schedules. Carboplatin clearance determined across three consecutive chemotherapy courses in two patients increased from 3.4 to 7.1 ml/min and from 7.2 to 16.5 ml/min, representing increases of 210–230% over several weeks of treatment. Complete remission was observed in 8/9 patients, with no renal toxicity reported and only one patient experiencing ototoxicity.ConclusionThe study highlights the benefits of utilising therapeutic drug monitoring to achieve target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of marked increases in drug clearance observed over consecutive chemotherapy courses. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform future treatment.     

Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients.

PURPOSE: To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood-derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] x minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison. PATIENTS AND METHODS: Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m(2) plus ifosfamide 6 g/m(2) were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1, 200 mg/m(2), and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) x min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC. RESULTS: Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula. CONCLUSION: Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.     

Individual dosing of carboplatin based on drug monitoring in children receiving high-dose chemotherapy

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3-17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml x min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients' characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from -41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was -11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between -7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children.     

Pentetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy

Summary Platinum distribution was studied in rat peritoneal tumors after i.p. treatment with equimolar doses of carboplatin and cisplatin. Low platinum concentrations (4 ppm) were detected in the periphery of the tumor after carboplatin treatment, whereas no platinum was detected 0.5 mm in from the periphery. In contrast, after cisplatin treatment, high platinum concentrations (29 ppm) were measured in the periphery of the tumor and moderate concentrations (14 ppm) were measured in the center. Only following increased carboplatin doses were low platinum concentrations detectable in the tumor. The total platinum concentration in the tumors was determined after equimolar administration of both drugs. In all, 7 times more platinum was detected after cisplatin treatment than after carboplatin treatment, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumors. When single cells were incubated with equimolar concentrations of carboplatin and cisplatin, 6–7 times more platinum was found in cells treated with cisplatin. However, pharmacokinetic studies favored i.p. administration of carboplatin because the clearance of this compound from the peritoneal cavity, expressed ast _1/2, was lower than that of cisplatin (239 vs 78 min), resulting in an AUC in the peritoneal cavity for both total and ultrafiltered drug that was almost 3 times higher for carboplatin than cisplatin. The AUC for ultrafiltered carboplatin in plasma was 2-fold that for cisplatin (2,801±210 vs 1,334±431 M m). The present study demonstrated that in spite of the pharmacological advantages of carboplatin, its capacity to penetrate into peritoneal tumors and tumor cells is far lower than that of cisplatin.This work was supported by grant NKI 86-5 from the Dutch Cancer Society     

Pharmacokinetics of BW12C and mitomycin C,given in combination in a phase 1 study in patients with advanced gastrointestinal cancer

The effect of combining the oxygen-transport-modifying drug BW12C with mitomycin C was investigated in a phase 1 study of 26 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 60 mg/kg. Dose-limiting toxicity of vomiting was experienced at doses greater than 50 mg/kg. This corresponded to whole blood levels 700 g/ml and to >50% haemoglobin modification. Whole blood concentrations of BW12C and modification of the haemoglobin oxygen saturation curve were linearly dependent on dose. BW12C whole blood pharmacokinetics were best described by a one-compartment model and were clearly dose-dependent. The half-life increased from 2.1 h at a dose of 20 mg/kg to 7.2 h at a dose of 60 mg/kg. The AUC increased in a similar non-linear fashion with increasing dose. Mitomycin C was given at a fixed dose of 20 mg/m² at the end of the BW12C infusion. Mitomycin C plasma pharmacokinetics fitted a two-compartment model, giving a mean beta half-life of 50±7 min and AUC of 1.1±0.08 g/ml h, and were unaffected by the combined treatment. There was no evidence of increased mitomycin C toxicity.     

A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission

Purpose: To prospectively determine the efficacy of repeated high-dose alkylating chemotherapy to salvage patients with germ-cell tumors who relapsed after adequate first-line chemotherapy.Patients and methods: Patients with germ-cell cancers relapsing from a first, second or third complete remission induced by chemotherapy were offered to participate in a Dutch national prospective trial with broad entry criteria. The salvage treatment began with a conventional dose of ifosfamide (4 g/m² on day 1) and etoposide (100 mg/m² on days 1, 2 and 3) followed by daily s.c. administration of G-CSF (10 µg/kg) until peripheral blood progenitor cells had been harvested. Immediately after bone marrow recovery, an intermediate dose chemotherapy course of carboplatin (target AUC: 10 mg · ml^–1 · min on day 1) and etoposide (500 mg/m² on days 1, 3 and 5) was given with G-CSF daily s.c. After bone marrow recovery, two subsequent courses of high-dose CTC chemotherapy were given, each containing cyclophosphamide (6 g/m²), thiotepa (480 mg/m²) and carboplatin (target AUC: 20 mg · ml^–1 · min). The high-dose chemotherapy was administered as 30–60-minute infusions, divided over 4 days and the stem-cell transplants were given 48–72 hours after the last chemotherapy infusion. Whenever possible, residual masses were resected at the end of treatment.Results: Thirty-five patients were treated between January 1994 and October 1997. The toxicity of the treatment was manageable. Second CTC courses were administered in 25 patients and were associated with hemorrhagic cystitis and veno-occlusive disease in 3 and 4 patients, respectively. One patient who had recently undergone a partial hepatectomy, died of veno-occlusive disease. At the time of analysis, the median follow-up of the surviving patients was 37 months (range 12–56 months). The median progression-free survival for all patients was 44 months, and the median overall survival has not been reached. According to the internationally accepted criteria for predicting the outcome of salvage chemotherapy in germ-cell cancer (Beyer et al. J Clin Oncol 1996; 14: 2638–45), 30 patients had good risk criteria. Of these, 29 received high-dose chemotherapy. Of this group, the salvage rate at two years was 65% (95% confidence interval: 49.5%–85.1%).Conclusions: Over half of the germ-cell cancer patients relapsing from a chemotherapy-induced complete remission can be salvaged by a treatment strategy that incorporates high-dose chemotherapy, even when treatment is given in a multi-center setting. These data confirm the international prognostic model proposed by Beyer et al. in a prospectively studied, independent patient group and provide further evidence that high-dose therapy has a role in the salvage setting of patients with germ-cell cancer.     

Systemic and tumor disposition of platinum after administration of cisplatin or STEALTH liposomal-cisplatin formulations (SPI-077 and SPI-077 B103) in a preclinical tumor model of melanoma

Purpose SPI-077 and SPI-077 B103 are formulations of cisplatin encapsulated in pegylated STEALTH liposomes that accumulate in tumors. However, the extent to which active platinum (Pt) is released from the liposome is unknown. Thus, we evaluated the disposition of encapsulated and released Pt in plasma and tumors after administration of STEALTH liposomal and nonliposomal cisplatin.Methods Cisplatin (10 mg/kg), SPI-077 (10 mg/kg), and SPI-077 B103 (5 mg/kg) were administered i.v. to mice bearing B16 murine melanoma tumors. Microdialysis probes were placed into the right and left sides of each tumor, and serial samples were collected from tumor extracellular fluid (ECF) after administration of each agent. After each microdialysis procedure, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (three mice per time point) were obtained. Unbound Pt in tumor ECF and plasma, and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Area under the tumor ECF (AUC_ECF) concentration versus time curves of unbound Pt were calculated. Intrastrand GG (Pt-GG) and AG (Pt-AG) Pt-DNA adducts were measured via ³²P-postlabeling.Results Mean±SD peak concentrations of total Pt in tumor homogenates after administration of cisplatin, SPI-077, and SPI-077 B-103 were 3.2±1.9, 11.9±3.0, and 3.5±0.3 g/g, respectively. After cisplatin, mean±SD AUC_ECF of unbound Pt was 0.72±0.46 g/ml·h. There was no detectable unbound Pt in tumor ECF after SPI-077 or SPI-077 B-103 treatment. Mean±SD peak concentration of Pt-GG DNA adducts after administration of cisplatin, SPI-077, and SPI-077 B-103 were 13.1±3.3, 3.5±1.3, and 2.1±0.3 fmol Pt/g DNA, respectively.Conclusion This study suggests that more SPI-077 and SPI-077 B103 distribute into tumors, but release less Pt into tumor ECF, and form fewer Pt-DNA adducts than does cisplatin.     

Clinical pharmacokinetics of carboplatin in children

The present study was undertaken to evaluate in children the plasma pharmacokinetics of free carboplatin given at different doses and schedules and to evaluate the inter- and intrapatient variability and the possible influence of schedule on drug exposure. A total of 35 children (age range, 1–17 years) with malignant tumors were studied. All patients had normal renal function (creatinine clearance corrected for surface body area, above 70 ml min^–1 m^–2; range, 71–151 ml min^–1 m^–2) and none had renal involvement by malignancy. Carboplatin was given at the following doses and schedules: 175, 400, 500, and 600 mg/m² given as a 1-h infusion; 1,200 mg/m² divided into equal doses and infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m² given as a 5-day continuous infusion. A total of 57 courses were studied. Carboplatin levels in plasma ultrafiltrate (UF) samples were measured both by high-performance liquid chromatography and by atomic absorption spectrophotometry. Following a 1-h infusion, carboplatin free plasma levels decayed biphasically; the disappearance half-lives, total body clearance, and apparent volume of distribution were similar for different doses. In children with normal renal function as defined by creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we found at each dose studied a limited interpatient variability of the peak plasma concentration (C_max) and the area under the concentration-time curve (AUC) and a linear correlation between the dose and both C_max (r=0.95) and AUC (r=0.97). The mean value ± SD for the dose-normalized AUC was 13±2 min m² l^–1 (n=57). The administration schedule does not seem to influence drug exposure, since prolonged i.v. infusion or bolus administration of 1,200 mg/m² achieved a similar AUC (13.78±2.90 and 15.05±1.44 mg ml^–1 min, respectively). In the nine children studied during subsequent courses a limited interpatient variability was observed and no correlation (r=0.035) was found between AUC and subsequent courses by a multivariate analysis of dose, AUC, and course number. The pharmacokinetic parameters were similar to those previously reported in adults; however, a weak correlation (r=0.52,P=0.03) between carboplatin total body clearance and creatinine clearance varying within the normal range was observed. A dosing formula appears unnecessary in children with normal renal function since a generally well-predictable free carboplatin AUC is achieved following a given dose.Supported by the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.)     

Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit

Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg·kg^–1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739±265 vs 100±10 ng·ml^–1) and doxorubicinol (78±3 vs 16±3 ng·ml^–1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92±0.9 vs 3.59±0.72 g·g^–1 tissue;P<0.001) and doxorubicinol (0.24±0.02 vs 0.09±0.01 g·g^–1 tissue;P<0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol.     

Pharmacokinetic and pharmacodynamic studies with 4′-epi-doxorubicin in nasopharyngeal carcinoma patients

Summary The plasma pharmacokinetic profile of 4-epidoxorubicin (epirubicin) was investigated in 28 patients with nasopharyngeal carcinoma (NPC) after single i.v. rapid infusions. All patients had normal liver and renal functions. Plasma concentrations of the parent compound were specifically determined by a high-performance liquid chromatographic (HPLC) method, with UV detection at 254 nm. Plasma levels of the compound were fitted to a three-compartment open model; a triexponential decrease in plasma concentrations with a long terminal plasma halflife (44.8±21.2 h) was observed in 27 patients. The respective mean (±SD) serum concentration at 72 h and the AUC, plasma clearance, and terminal elimination rate constant in complete responders were 7.67±1.98 ng/ml, 4,002±3,080 ng· h/ml, 26.6±12.9 l/h·m², and 0.009±0.007 l/h, whereas those in nonresponders were 4.96±1.8 ng/ml, 1,88±652.8 ng·h/ml, 44.4±15 l/h·m², and 0.017±0.006 l/h, respectively; these differences were significant (P(0.05). Epirubicin produced a 52% response rate, including 6 patients with a complete response, 8 with a partial response, 11 with no change, and 2 with progressive disease. No relationship could be found between the various pharmacokinetic parameters and either leukopenia, age, or sex. These observations strongly suggest that plasma clearance may be one of the determining factors affecting the response or nonresponse of NPC patients to epirubicin, and a dose adjustment according to plasma clearance would probably increase the response rate.     

Phase I and pharmacokinetic study of weekly oral therapy withvinorelbine in patients with advanced breast cancer (ABC)

Background:A phase I dose-escalation study of a newformulation of oral vinorelbine was conducted to determine the maximumtolerated dose (MTD) of a once weekly regimen and preliminarypharmacokinetic profile in patients with advanced breast cancer (ABC).Twenty-six patients were treated at dose levels ranging from 60 to 100mg/m²/week. Pharmacokinetics was assessed during the firstadministration. Patients and methods:All patients hadhistologically confirmed locally advanced or metastatic breast cancerand had received no more than two prior chemotherapy regimens forABC. Results:The MTD was 100 mg/m²/weekdue to the occurrence of dose-limiting neutropenia, nausea/vomitingand constipation in five of six patients. Toxicities at 80mg/m²/week were manageable, neutropenia being the maintoxicity (grade 3–4 seen in 10 of 13 patients). Nausea, vomitingand diarrhoea were common but rarely severe. Vinorelbine was rapidlyabsorbed with maximum blood concentration (C_max) of 103.8± 41.6 ng·ml^–1 observed 1.2 ± 0.8hours (T_max) after administration of 80 mg/m².Pharmacokinetic exposure increased linearly with dose. Area under theconcentration-time curve (AUC) and concentration measured 24 hours afterdrug intake (C_24h) were significantly correlated withdepletion of neutrophils. Objective tumour responses were reported in 6of the 14 evaluable patients treated at doses 80mg/m²/week. Conclusion:The safety profile oforal vinorelbine appears comparable to that of intravenous dosing. Therecommended phase II dose is 80 mg/m²/week and requiresregular monitoring of neutrophil counts.     

Overestimation of carboplatin doses is avoided by radionuclide GFR measurement

Background:

Glomerular filtration rate (GFR) is used in the calculation of carboplatin dose. Glomerular filtration rate is measured using a radioisotope method (radionuclide GFR (rGFR)), however, estimation equations are available (estimated GFR (eGFR)). Our aim was to assess the accuracy of three eGFR equations and the subsequent carboplatin dose in an oncology population.

Patients and methods:

Patients referred for an rGFR over a 3-year period were selected; eGFR was calculated using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault (CG) equations. Carboplatin doses were calculated for those patients who had received carboplatin chemotherapy. Bias, precision and accuracy were examined.

Results:

Two hundred and eighty-eight studies met the inclusion/exclusion criteria. Paired t-tests showed significant differences for all three equations between rGFR and eGFR with biases of 12.3 (MDRD), 13.6 (CKD-EPI) and 7.7 ml min⁻¹ per 1.73 m² (CG). An overestimation in carboplatin dose was seen in 81%, 87% and 66% of studies using the MDRD, CKD-EPI and CG equations, respectively.

Conclusion:

The MDRD and CKD-EPI equations performed poorly compared with the reference standard rGFR; the CG equation showed smaller bias and higher accuracy in our oncology population. On the basis of our results we recommend that the rGFR should be used for accurate carboplatin chemotherapy dosing and where unavailable the use of the CG equation is preferred.     

Pharmacokinetics of carboplatin administered in combination with the bradykinin agonist Cereport (RMP-7) for the treatment of brain tumours

Introduction: Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood–brain barrier (BBB). In order to investigate the pharmacokinetics of carboplatin in combination with Cereport, we performed pharmacological studies in conjunction with early clinical trials. Methods: Pharmacokinetic samples were collected from eight patients in a phase I study (Cereport 100–300 ng/kg) and ten patients in a phase II study (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were compared with respect to the dose of Cereport and with historical controls. Results: Cereport combined with carboplatin was well-tolerated, with mild haematological toxicities consistent with the target area under the concentration–time curve (AUC) of 7 mg/ml*min. Although the clearance of carboplatin was within the range reported for this drug alone, the addition of Cereport resulted in a higher than expected carboplatin AUC. This effect was related to the dose of Cereport in the phase I study (AUC values 104–133% of target, Spearman rank correlation coefficient=0.71, P < 0.001). The higher than expected AUC value was confirmed in the phase II study (AUC values 106–189% of target). Conclusions: Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation. Received: 12 April 1999 / Accepted: 9 September 1999