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.     

A pharmacokinetic and pharmacodynamic study of the new anthracycline pirarubicin in breast cancer patients

Summary We evaluated the pharmacokinetics of pirarubicin during 16 courses of therapy in 4 patients suffering from breast cancer who were treated with an association of pirarubicin (30–60 mg/m² according to the hematologic tolerance to the previous course, the first course being given at a dose of 40 mg/m²) and continuous infusions of 5-fluorouracil (750 mg/m² daily for 5 days). Pirarubicin's pharmacokinetics and metabolism were linear within this dose range; the metabolites identified were pirarubicinol, doxorubicin and doxorubicinol (AUC ratios of metabolite/pirarubicin were 0.6, 0.64 and 0.57 respectively). Pirarubicin's decay from plasma followed a twocompartmental pattern, showing half-lives of 15.6 min and 16.6 h: the total plasma clearance of the drug was 140 l/h^–1/m^–2, and the total volume of distribution was 2,830 l/m². A relationship was observed between some pharmacokinetic parameters and the toxic effects of the drug: the percentage of survival of granulocytes was significantly correlated with the AUC values for doxorubicin and doxorubicinol, whereas that of platelets was significantly correlated with the AUC values for pirarubicin and pirarubicinol. This is the first study to demonstrate a pharmacokinetic/pharmacodynamic relationship for pirarubicin.     

Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit

Summary Doxorubicin is metabolized extensively to doxorubicinol by the ubiquitous aldoketoreductase enzymes. The extent of conversion to this alcohol metabolite is important since doxorubicinol may be the major contributor to cardiotoxicity. Aldoketoreductases are inhibited in vitro by phenytoin. The present study was conducted to examine the effect of phenytoin on doxorubicin pharmacokinetics. Doxorubicin single-dose pharmacokinetic studies were performed in 10 New Zealand White rabbits after pretreatment with phenytoin or phenytoin vehicle (control) infusions in crossover fashion with 4–6 weeks between studies. Infusions were commenced 16 h before and during the course of the doxorubicin pharmacokinetic studies. Phenytoin infusion was guided by plasma phenytoin estimation to maintain total plasma concentrations between 20 and 30 g/ml. Following doxorubicin 5 mg/kg by i.v. bolus, blood samples were obtained at intervals over 32 h. Plasma doxorubicin and doxorubicinol concentrations were measured by HPLC. The mean plasma phenytoin concentrations ranged from 17.4 to 33.9 g/ml. Phenytoin infusion did not alter doxorubicin pharmacokinetics. The elimination half-life and volume of distribution were almost identical to control. Clearance of doxorubicin during phenytoin administration (60.9±5.8 ml/min per kg, mean±SE) was similar to that during vehicle infusion (67.5±5.4 ml/min per kg). Phenytoin administration was associated with a significant decrease in doxorubicinol elimination half-life from 41.0±4.8 to 25.6±2.8 h. The area under the plasma concentration/time curve (AUC) for doxorubicinol decreased significantly from 666.8±100.4 to 491.5±65.7 n.h.ml^-1. These data suggest that phenytoin at clinically relevant concentrations does not alter the conversion of doxorubicin to doxorubicinol in the rabbit. The reduction in the AUC for doxorubicinol caused by phenytoin appears to be due to an increased rate of doxorubicinol elimination. Phenytoin or similar agents may have the effect of modifying doxorubicinol plasma concentrations by induction of doxorubicinol metabolism rather than by inhibition of aldoketoreductase enzymes.     

Bayesian estimation of doxorubicin pharmacokinetic parameters

Summary Doxorubicin was given by brief i.v. infusion (doses ranging from 25 to 72 mg/m²) to 28 patients for 2–7 successive courses of chemotherapy (68 courses studied in all). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of doxorubicin. Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 19 patients and a total of 30 courses, which, when combined with 4 individual plasma concentrations of drug, led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 38 courses. The estimated parameters for the elimination phase (A₃/V₁ andt1/2 elimination) and the residual plasma level at 48 h as computed by Bayesian estimation on this reduced sub-optimal sampling protocol were compared with a maximal likelihood estimation of these parameters. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean errors were –0.0315×10^–4 l^–1 for A₃/V₁, 0.0839 h fort1/2 elimination, and –0.22 ng/ml forc _{(48 h)}. The precision of the prediction of these three parameters (0.304×10^–5 l^–1, 3.34 h, and 0.659 ng/ml, respectively) remained lower than the interindividual standard deviation (1.42×10^–4 l^–1, 14.9 h, and 4.54 ng/ml, respectively). This procedure enables the estimation of individual pharmacokinetic parameters for doxorubicin at minimal cost and minimal disturbance of the patient.     

Clinical and pharmacokinetic study of 96-h infusions of doxorubicin in advanced cancer patients

A phase I and a pharmacokinetic study of 96-h infusions of doxorubicin were performed in order to evaluate the maximum tolerated dose with this schedule of administration. Seventeen patients suffering from a digestive carcinoma were included in the study and a total of 71 courses of treatment were performed. The starting dose was 15 mg/m²/day and was increased in 2.5 mg/m²/day increments. The main toxicities observed were neutropenia and mucositis, which became limiting from 22.5 mg/m²/day (90 mg/m² over a 96-h period); this dose was therefore defined as the maximal tolerated dose. No objective response to treatment was observed. For further studies, the recommended dose should not exceed 20 mg/m²/day.A plasma plateau concentration of doxorubicin was reached within 24 h. Despite a constant infusion rate, the plasma concentration of doxorubicin showed transient variations in several patients. However, an average plasma concentration could be evaluated for 33 courses of treatment, and this was linearly related to the dose. Doxorubicinol was the only detected metabolite of doxorubicin and its plasma concentration progressively increased throughout infusion. A detailed pharmacokinetic study was performed in 13 courses of treatment. The mean plasma clearance of doxorubicin was 25.2 l/h/m² and the mean terminal half-lives of doxorubicin and doxorubicinol were respectively 43.6 and 66.2 h. Urinary excretion of doxorubicin plus metabolite was regular from the 24th to the 96th hour of infusion; however, the proportion of doxorubicinol progressively increased in urine. The protracted half-life of this metabolite probably explains its accumulation during infusion.     

Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years

Purpose

The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.

Methods

Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively. In total, the combined dataset contained 934 doxorubicin and 935 doxorubicinol plasma concentrations from 82 patients [64 adults and 18 children (<18 years)]. With this combined dataset, a population pharmacokinetic model was developed, using NONMEM^® 7.2 and a predefined model-building strategy. Different structural models, error models and estimation methods were tested, and the inter-individual and the inter-occasion variability (variability between separate (two or three) doxorubicin infusions) were tested. Using a subset of 52 patients, the influence of different covariates on the pharmacokinetic parameters was investigated. The pharmacokinetic parameter estimates obtained from doxorubicin concentrations with the best model were fixed, and an additional compartment for doxorubicinol was added to the model. With the final model for both substances, a potential age dependency and body mass index dependency of the clearance of doxorubicin and doxorubicinol as well as of the volumes of distribution of the central and the metabolite compartment were evaluated.

Results

A four-compartment model best described the doxorubicin and doxorubicinol data of the combined dataset. This model included a proportional residual error model and an inter-individual variability on the clearance of doxorubicin, on the inter-compartmental clearances of the peripheral compartments, on the clearance of doxorubicinol and on the volumes of distribution of the central, one peripheral and the metabolite compartment. Furthermore, the body surface area as covariate on all pharmacokinetic parameters and an inter-occasion variability for the clearance of doxorubicin and the volume of distribution of the central compartment were incorporated in the model. For a patient with the body surface area of 1.8 m², the clearance of doxorubicin was 53.3 L/h (inter-individual variability 31 %, inter-occasion variability 13 %) and the volume of distribution of the central compartment was 17.7 L (inter-individual variability 19 %, inter-occasion variability 21 %), respectively. The residual variability of the model was 22 % for doxorubicin and 26 % for doxorubicinol. The clearance of doxorubicinol was estimated at 44 L/h (inter-individual variability 50 %) and the volume of distribution of the metabolite compartment at 1,150 L (inter-individual variability 57 %). The evaluation of a possible age dependency and body mass index dependency showed a trend to a smaller volume of distribution of the central compartment (normalised to the body surface area) and a higher volume of distribution of the metabolite compartment (normalised to the body weight) in younger patients.

Conclusions

A four-compartment NONMEM^® model for doxorubicin and doxorubicinol adequately described the plasma concentrations in adults and children (>3 years). No pronounced effects of age on the clearance of doxorubicin or doxorubicinol were found, and the analysis did not support the modification of the dosing strategies presently used in children and adults.     

Comparative pharmacokinetics of doxorubicin given by three different schedules with equal dose intensity in patients with breast cancer

Summary The pharmacokinetics of doxorubicin given according to three different schedules with a similar dosetime intensity have been studied and compared in 16 women with metastatic breast cancer. Six patients were treated with doxorubicin 75 mg/m² by i.v. bolus repeated every 3 weeks; 5 patients received doxorubicin by 4-day continuous infusion every 3 weeks (4 at 75 mg/m² and 1 at 60 mg/m²); 5 patients received 25 mg/m² by i.v. bolus given weekly. Timed blood samples were collected and plasma levels of doxorubicin and its metabolite doxorubicinol were measured by high-performance liquid chromatography with fluorescence detection. Peak plasma concentrations were measured, and areas under the concentration-time curves calculated. Peak plasma levels of doxorubicin were significantly lower with the 4-day infusion than with either of the bolus injections. The 4-day infusion, however, gave significantly greater total exposure to doxorubicin and doxorubicinol, as indicated by area under the concentration-time curve, than weekly or 3-weekly bolus treatment. A single bolus injection of doxorubicin 25 mg/m² yielded a total exposure to doxorubicin approximately half that achieved with a 75 mg/m² bolus injection. Over a 3-week period, therefore, total exposure to doxorubicin would be greater with the weekly low-dose schedule than with the 3-weekly administration. We conclude that drug scheduling has significant effects on doxorubicin pharmacokinetics.     

Effect of a low-protein diet on doxorubicin pharmacokinetics in the rabbit

Summary Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enchanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low- protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8–12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1,n=15; group 2,n=14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48±3 vs 59±4 ml min^–1 kg^–1;P<0.05), prolonged the terminal climination half-life (28±2 vs 22±2 h;P<0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722±122 vs 1405±71 ng h ml^–1;P<0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-portein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52±5 vs 40±2 h;P<0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.Supported by the Department of Veterans Affairs and the American Heart Foundation     

Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry

We studied the variability in doxorubicin pharmacokinetics in 27 patients, all of whom had normal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography (HPLC). The relationship of doxorubicin clearance (dose/AUC) with biochemical tests (AST, bilirubin, alkaline phosphatase, albumin, creatinine) and physical characteristics (age, gender, height, weight, tumour type) was investigated. The 6 men had a significantly higher doxorubicin clearance than did the 21 women (median values, 59 and 27 lh^–1 m^–2, respectively;P=0.002). Doxorubicin clearance was significantly lower in patients with breast cancer than in those with other tumours (median values, 26 and 53 lh^–1 m^–2, respectively;P=0.0008). The other biochemical and physical parameters did not correlate with doxorubicin clearance. However, in multivariate analysis, gender was the only factor predicting doxorubicin clearance (r ²=40%). The ratio of the AUCs for doxorubicinol and doxorubicin (R) was higher in the men than in the women (median values, 0.62 and 0.36, respectively;P=0.03). We conclude that gender may be an important determinant of doxorubicin clearance in patients with normal liver biochemistry.     

Influence of the cardioprotective agent dexrazoxane on doxorubicin pharmacokinetics in the dog

Summary The influence of dexrazoxane on doxorubicin pharmacokinetics was investigated in four dogs using the two treatment sequences of saline/doxorubicin or dexrazoxane/doxorubicin. Intravenous doses of 1.5 mg/kg doxorubicin and 30 mg/kg (the 20-fold multiple) dexrazoxane were given separately, with doxorubicin being injected within 1 min of the dexrazoxane dose. Both doxorubicin and its 13-dihydro metabolite doxorubicinol were quantified in plasma and urine using a validated high-performance liquid chromatographic (HPLC) fluorescence assay. The doxorubicin plasma concentration versus time data were adequately fit by a three-compartment model. The mean half-lives calculated for the fast and slow distributive and terminal elimination phases in the saline/doxorubicin group were 3.0±0.5 and 32.2±12.8 min and 30.0±4.0 h, respectively. The model-predicted plasma concentrations were virtually identical for the saline and dexrazoxane treatment groups. Analysis of variance of the area under the plasma concentration-time curve (AUC_0–), terminal elimination rate (_Z), systemic clearance (CL _s), and renal clearance (CL _r) for the parent drug showed no statistically significant difference (P<0.05) between the two treatments. Furthermore, the doxorubicinol plasma AUC_0– value and the doxorubicinol-to-doxorubicin AUC_0– ratio showed no significant difference, demonstrating that dexrazoxane had no effect on the metabolic capacity for formation of the 13-dihydro metabolite. The total urinary excretion measured as parent drug plus doxorubicinol and the metabolite-to-parent ratio in urine were also unaffected by the presence of dexrazoxane. The myelosuppressive effects of doxorubicin as determined by WBC monitoring revealed no apparent difference between the two treatments. In conclusion, these results show that drug exposure was similar for the two treatment arms. No kinetic interaction with dexrazoxane suggests that its coadministration is unlikely to modify the safety and/or efficacy of doxorubicin.     

Paclitaxel by 24-hour infusion with doxorubicin by 48-hour infusion as initial therapy for metastatic breast cancer: Phase I results

Purpose: We and others have demonstrated the antineoplastic efficacy of paclitaxel as a single agent in metastatic breast cancer. We performed this phase I trial to evaluate the combination of paclitaxel with doxorubicin.Patients and methods: Eligible patients had measurable or evaluable metastatic breast cancer for which this was the initial cytotoxic treatment. They may have received adjuvant chemotherapy with other drugs. The study had four parts. In part 1, the patients received paclitaxel by 24-hour infusion followed by doxorubicin by 48-hour infusion. The paclitaxel dose was to be escalated from a starting dose of 125 mg/m2, and the doxorubicin dose was to remain constant at 60 mg/m2 with treatment repeated every three weeks. The results of part 1 prompted part 2 which was a study of the reverse sequence. Part 3 was a formal study of pharmacology and has been reported (J Clin Oncol 14: 2713–21, 1996). In part 4, patients received doxorubicin 50 mg/m2 by bolus followed by paclitaxel 150 mg/m2 by 24-hour infusion for courses 1 and 2. In all subsequent courses doxorubicin was administered by 48-hour infusion. All patients in all four parts of the study had baseline cardiac scans. All patients received standard premedication for paclitaxel.Results: Forty-eight patients were treated in all four parts of the study. In part 1 (10 patients), the maximum tolerated dose (MTD) was paclitaxel 125 mg/m2/24 hours followed by doxorubicin 48 mg/m2/48 hours as defined by dose-limiting mucositis and neutropenic fever which occurred at the starting dose. For part 2 (21 patients), the MTD was doxorubicin 60 mg/m2/48 hours followed by paclitaxel 160 mg/m2/24 hours. In part 4 (seven patients), the MTD was doxorubicin 50 mg/m2/bolus followed by paclitaxel 135 mg/m2/24 hours. In parts 2 and 4, the dose-limiting toxic effect was neutropenia. Of the entire cohort of 48 patients, seven (15%) had a complete response (one persists at five years without intervening therapy), 26 (54%) had a partial response for an objective response rate of 69% (95% confidence interval (95% CI): 54%–81%). The median follow-up of all living patients is 38+ months (range 20+ to 62+); the median response duration is seven months (range 2–33.7+); the median overall survival is 20.5 months (range 5–54+). The median time to progression is 9.6 months (range 1–33.7+ months). Two patients developed congestive heart failure, one at 24 months after her final dose of doxorubicin which amounted to a cumulative lifetime total doxorubicin dose of 870 mg/m2, one after a total of 660 mg/m2. In both, cardiac symptoms were controlled with medications.Conclusions: The combination of paclitaxel/24 hours with doxorubicin/48 hours is an effective antineoplastic treatment for metastatic breast cancer. However, the incidence of complete response, the median overall survival, and time to progression were not greater than for standard doxorubicin-based combinations. Additionally, a sequence-dependent interaction between paclitaxel and doxorubicin, given in the schedule described here, was defined. Other strategies and schedules should be evaluated to maximize the antineoplastic efficacy of these two potent agents.     

Doxorubicin clearance in the obese

A study was carried out to examine the effect, if any, of obesity on doxorubicin pharmacokinetics. Body weight was found to be significantly related to doxorubicin clearance (r = -.75; P less than .001) and elimination half-life (r = .62; P = .003). Thus, the contribution of obesity on pharmacokinetics of antineoplastic agents should be taken into consideration in the analysis of clinical data with respect to toxicity and tumor response. Twenty-one patients were studied with their first course of doxorubicin (50 to 70 mg/m2) administered as a 60-minute intravenous (IV) infusion. Patients were divided into three groups on the basis of percentage of ideal body weight (IBW): normal (less than 115% IBW), mildly obese (115% to 130% IBW), and obese (greater than 130% IBW). Blood samples were collected up to 48 hours after the infusion and analyzed for doxorubicin and its metabolite, doxorubicinol, by high performance liquid chromatography. Doxorubicin area under the curve (AUC) was greater in obese than in normal patients (2,209 v 1,190 ng h/mL; P less than .05), yielding correspondingly reduced systemic clearance of the agent in obese patients (891 v 1,569 mL/min; P less than .001). The mean elimination half-life (T1/2) was 20.4 hours in the obese patients and 13.0 hours in the normal patients. The apparent volume of distribution (Vss) was not significantly different among the three groups of patients, indicating that the prolonged T1/2 in the obese patients is due to the reduction in clearance. The AUC and T1/2 of doxorubicinol were similar among all patient groups.     

Doxorubicin and doxorubicinol plasma concentrations and excretion in parotid saliva

Summary The pharmacokinetics of doxorubicin (DOX) and doxorubicinol (DOXol) was studied in six patients with various advanced neoplastic diseases who received 28–72 mg/m² DOX (nine courses). Plasma and parotid saliva were collected over a 48-h period, and DOX and DOXol were quantified by high-performance liquid chromatography with fluorescence detection. As reported previously, a wide range of plasma levels were found among our patients. It appears that in addition to being quickly cleared from the plasma, both DOX and DOXol are excreted in detectable amounts in parotid saliva, a route of elimination that has been given little attention, if any. Excretion in the saliva exposes the mucosa of the upper gastroinfestinal tract to drug and may play a role in causing stomatitis in patients receiving DOX by the i.v. route. Since huge interindividual and pronounced intraindividual differences were found in S/P ratios that mostly were not systematically related to the plasma drug concentration, the concentration in parotid saliva was not useful in predicting the level of free DOX and DOXol in plasma. For the parent drug and its metabolite, the S/P ratios increased significantly with time during the 48-h period after dosing.This work was supported by a grant from the Association pour la Recherche sur le Cancer (Villejuif, France)     

Ifosfamide,vincristine, doxorubicin and dacarbazine in adult patients with advanced soft-tissue sarcoma

Summary A total of 37 adult patients with locally advanced or metastatic soft-tissue sarcoma (STS) entered a pilot study of combination chemotherapy based on the CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine) regimen, in which cyclophosphamide was replaced by ifosfamide and mesna (1 g/m² ifosfamide given daily on days 1–5 as 2-h infusions, 1.5 mg/m² vincristine given on day 1 as a bolus injection, 50 mg/m² doxorubicin given on day 1 as a 5-min infusion, and 250 mg/m² dacarbazine given daily on days 1–5 as 30-min infusions). The overall response rate in 24 patients who were evaluable for response was 46% [95% confidence interval (CI), 25%–67%] and that in subjects who had not undergone prior chemotherapy was 50% (CI, 27%–73%). In all, 4 patients achieved a complete response (17%; CI, 5%–37%) and 2 remain in remission; 3 additional subjects were surgically rendered disease-free after they had shown a partial response. Overall, 31 patients were evaluable for toxicity. Toxicity was mainly hematological; in 3 patients the nadir WBC was <0.5×10⁹/l, and in 2 cases the nadir platelet count was <50×10⁹/l. During neutropenia, infections requiring intravenous antibiotics occurred in 8 patients (26%) and in 14 of 190 cycles (7.5%); 1 of these was fatal. We conclude that this new regimen offers promise for the treatment of advanced STS, producing acceptable toxicity.This study was supported in part by grants from Finska Läkaresällskapet (Finnish Medical Society)     

Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study

Purpose  We studied the relationship between doxorubicin pharmacokinetics and body composition in children with cancer. Patients and methods  Children between 1 and 21 years of age, receiving doxorubicin as an infusion of any duration <24 h on either a 1-day or 2-day schedule were eligible if they had no significant abnormality of liver function tests, their dose of doxorubicin was not based on ideal body weight or otherwise “capped,” and they weighed ≥12 kg. Body composition was measured by dual-energy X-ray absorptiometry. Doxorubicin and doxorubicinol concentration in plasma were measured by high pressure liquid chromatography. NONMEM was used to perform pharmacokinetic model fitting and S-PLUS was used to perform a post hoc analysis to examine the effect of body composition on pharmacokinetic parameters. Results  Twenty-two subjects (16 male; 10 Hispanic, 10 Caucasian, 2 Asian) completed the study. The median age was 15.0 years (range 3.3–21.5), median weight was 51.5 kg (range 12.4–80), median BMI was 19.7 (range 13.2–30.0), and median body fat was 25% (range 15–36). The population mean clearance of doxorubicin was 420 ml/min/m². Doxorubicinol but not doxorubicin clearance was lower in patients with body fat greater than 30%. Conclusions  Doxorubicinol clearance is decreased in children with >30% body fat. This finding is potentially important clinically, because doxorubicinol may contribute significantly to cardiac toxicity after doxorubicin administration. Further study of the body composition on doxorubicin and doxorubicinol pharmacokinetics and on clinical outcomes is warranted.     

Effect of the paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice.

The effect of the paclitaxel vehicle Cremophor on the pharmacokinetics of doxorubicin and doxorubicinol was studied in two groups of mice given intravenously either 2.5 ml kg-1 Cremophor or saline followed 5 min later by 10 mg kg-1 doxorubicin. In each group three mice were sacrificed at ten time points and doxorubicin and doxorubicinol were measured in plasma by high-performance liquid chromatography (HPLC). With Cremophor present, doxorubicin AUC increased from 1420+/-440 to 2770+/-660 ng h ml(-1) (P<0.05) and doxorubicinol AUC increased from 130+/-76 to 320+/-88 ng h ml(-1) (p<0.05). Neither the terminal elimination half-lives nor the doxorubicinol-doxorubicin AUC ratio changed in the presence of Cremophor, suggesting a lack of a direct effect on drug metabolism. The possibility exists the Cremophor may change the pharmacokinetics of both paclitaxel and other drugs given concurrently.     

Phase I and pharmacokinetic trial of liposome-encapsulated doxorubicin

A total of 21 patients with advanced cancer were entered into a phase I study to determine the maximum tolerable dose (MTD) of liposome-encapsulated doxorubicin (LED) given weekly for 3 consecutive weeks at doses of 20, 30, or 37.5 mg/m² per week. For a comparison of the pharmacokinetic behavior of LED with that of standard-formulation doxorubicin, 13 patients received a dose of standard-formulation doxorubicin 2 weeks prior to the first dose of LED. All doses were given by 1-h infusion through a central vein. Toxicity was evaluated in 22 courses delivered to 17 patients. The MTD with this schedule was 30 mg/m² per week×3. The single patient treated at 37.5 mg/m² weekly could not complete the entire course due to myelosuppression. At the dose of 30 mg/m² per week, three of eight patients had grade 3 leukopenia. Other toxicities included mild to moderate thrombocytopenia, nausea, vomiting, fever, alopecia, diarrhea, fatigue, stomatitis, and infection. At the dose of 30 mg/m² per week, the total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 8.75±8.80 M h (mean±SD) and 3.07±1.45 M, respectively, after LED administration. The total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 3.92±2.47 M h and 2.75±2.70 M, respectively, after the infusion of standard-formulation doxorubicin. The total body clearance of doxorubicin was 18.42±11.23 l/h after the infusion of LED and 31.21±15.48 l/h after the infusion of standard-formulation doxorubicin. The mean elimination half-lives of doxorubicin were similar: 8.65±5.16 h for LED and 7.46±5.16 h for standard-formulation doxorubicin. Interpatient variability in pharmacokinetic parameters as demonstrated by the percentage of coefficients of variation was 33%–105%. There was no relationship between the percentage of WBC decrease or the duration of WBC suppression and the total doxorubicin or doxorubicinol AUC. There was no correlation between the duration of leukopenia and drug exposure as reflected by the AUC of liposome-associated doxorubicin. LED can be given in doses similar to those of standard-formulation doxorubicin and produces acute toxicities similar to those caused by standard doxorubicin.Abbreviations MTD maximum tolerable dose - LED liposome-encapsulated doxorubicin - AUC area under the plasma concentration x time curve - WBC white blood cell count - PLT platelet count - ECOG Eastern Cooperative Oncology Group - EKG electrocardiogram - MUGA multigated nuclide scan - CLTB total body clearance - PC phosphatidylcholine: PG, phosphatidylglycerol - PEG-DSPE polyethylene glycol conjugated to distearoyl phosphatidylethanolamine - HSPC hydrogenated soy phosphatidylcholine - chol cholesterol This work was supported by DHHS, NCl NO-l-CM 07 303 and by a Career Development Award from the American Cancer Society (to B. A. C.)     

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein.

To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(-/-) and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg(-1). Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration-time curve of doxorubicin in mdr1a(-/-) mice were 1.6- and 1.2-fold higher respectively. The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(-/-) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(-/-) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of doxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(-/-) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin.     

Combination chemotherapy for advanced adenocarcinoma of the lung

Summary Combination chemotherapy has been used widely in the treatment of inoperable adenocarcinoma of the lung (ACL), but without uniform success. This review summarizes current knowledge of combination chemotherapy in ACL, with the aim of establishing critical background material for future studies. Not all the numerous combinations applied in non-randomized studies have produced response rates above 20% when evaluated in randomized trials. This holds true for the following regimens: cyclophosphamide+lomustine+methotrexate (response rates 14%–38%), hexamethylmelamine+doxorubicin+ methotrexate (13%–32%), methotrexate+doxorubicin+ cyclophosphamide+lomustine (13%–24%), cyclophosphamide +doxorubicin+cisplatin (0–36%), cyclophosphamide +bleomycin+cisplatin (20%), mitomycin C+vinblastine+cisplatin (26%–33%), cyclophosphamide +doxorubicin+etoposide+cisplatin (29%) and vindesine+cisplatin (33%). None of these combinations has been shown to be clearly superior to single-agent treatment. Nor has any specific regimen been shown to have clear advantages over other active combination chemotherapy regimens or over the sequential administration of either single agents or combined treatments. The prognosis for patients with inoperable ACL remains dismal. None of the studies considered in this review revealed median survival times exceeding 47 weeks. High priority should therefore be given to the identification of new compounds with significant activity against ACL.Supported by Grants from the Danish Cancer Society     

Theoretically required urinary flow during high-dose methotrexate infusion

Summary The renal excretion of methotrexate (MTX) and its major metabolite 7-hydroxymethotrexate (7-OH-MTX) was analysed in 12 children with malignancies during 52 courses of high-dose methotrexate (H-D-MTX) infusion at dosages ranging from 0.7 to 8.4 g/m².The peak concentrations of both MTX and 7-OH-MTX exceeded the aqueous solubilities of these compounds at low pH (6.0). The cumulative MTX excretion in urine was 75%–98% of the administered amount of MTX, and the cumulative 7-OH-MTX excretion in the urine was 3%–15%. The theoretically required urinary flow (TRUF) was estimated as the minimum urine volume needed for complete resolution of MTX and its metabolites in urine. TRUF during MTX infusion from 0 to 6 h and from 6 to 12 h was correlated with the dosage of MTX, and these values were 0.1–1.8 ml/min/m² at pH 7.0, 0.5–11.1 ml/min/m² at pH 6.0, and 1.9–42.2 ml/min/m² at pH 5.0 with dosages of 0.7 to 8.4 g/m². The value of the theoretically required urinary flow is important to ensure adequate hydration and the optimum alkalinization schedule for massive MTX infusion.