Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients.

Oral idarubicin (IDA) is an active drug in metastatic breast cancer, but its role in the management of this tumor is yet not established completely. To investigate a new modality of IDA administration, a dose-finding study was designed with hyperfractionated doses. The purpose was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetics of this schedule. IDA was administered twice daily as outpatient therapy in cycles of 3 weeks followed by a 1-week rest. Thirty-one patients with progressive metastatic breast cancer and pretreated with chemotherapy (including epirubicin and doxorubicin) were enrolled. DLT was defined as G4 hematological toxicity or any other toxicity G3 or higher (Bloom and Richardson grading). Inter- and intrapatient dose increases were studied. Pharmacokinetics of IDA and its metabolite idarubicinol (IDOL) were evaluated. IDA dose was increased from 2 mg/day to 10 mg/day, by steps of 1 mg/day, with the larger dose given in the evening. MTD was reached at 10 mg/day. Overall, the therapy cycles were 69 (median/patient, 2; range, 1-6). DLTs were G4 neutropenia associated with leukopenia and thrombocytopenia in one patient and G3 diarrhea in another of the 5 patients in the 10 mg/day cohort. The two patients developing DLT at the daily dose of 10 mg received a dose normalized for body surface of 6.85 and 5.65 mg/m2/day, respectively. We considered 5.5 mg/m2/day to be the MTD. Other toxicities were nausea, vomiting, neutropenia, and diarrhea, grades G1 to G2. By univariate analysis, significant correlations were observed between absolute neutrophil count at nadir and IDA area under the curve (P = 0.022; r = -0.33), IDA Cmax (P = 0.0067; r = -0.38), IDOL area under the curve (P = 0.0009; r = -0.43), and IDOL Cmax (P = 0.0016; r = -0.41), respectively. By multivariate analysis, IDA Cmax was the strongest determinant for neutropenia (R2 = 0.14; P = 0.01). Among the 21 patients evaluable for response, 3 (14.3%) had partial response (lasting 3, 6, and 8 months, respectively), and 6 (28.6%) had a complete arrest of disease progression (lasting 2-6 months). In conclusion, the MTD of this schedule is 10 mg/day and the DLTs are neutropenia and diarrhea. Tolerance was good, and the treatment is feasible as home therapy. Some objective measurable responses were documented in this group of anthracycline-pretreated patients. IDOL could have a role for the pharmacological effect. Further evaluation of this schedule is warranted to assess the activity and toxicity of prolonged oral IDA administration.

Pharmacokinetics of vinorelbine in patients with liver metastases.

BACKGROUND: The main elimination pathway of vinorelbine is hepatic metabolism, and the clearance of vinorelbine could be reduced in patients with liver metastases. OBJECTIVES: To study the pharmacokinetics of vinorelbine in patients who have advanced breast cancer with or without liver metastases and to study the relationship between hepatic function and vinorelbine clearance. PATIENTS AND METHODS: We studied 29 patients with advanced breast cancer: 19 with liver metastases and 10 control patients with extrahepatic metastases (mean age, 61 years; age range, 38 to 81 years). The vinorelbine dose was 30 mg/m2 as a short intravenous infusion; the dose was reduced by 50% in patients with bilirubin > 2 mg/dl. Patients were classified by ultrasonographic estimation of the liver volume replaced by tumor (%LVRT). Standard liver function tests and a monoethylglycinexylidide test (a quantitative liver function test based on lidocaine metabolite formation) were performed. Vinorelbine was assayed in plasma by HPLC with fluorescence detection. Vinorelbine determination was impossible in two patients with more than 75% LVRT because of interferences. Pharmacokinetic parameters were calculated with a noncompartimental method and compared by means of the Kruskal-Wallis test. RESULTS: A lower vinorelbine clearance rate was observed in the five patients with more than 75% LVRT (22.9 L/hr/m2) compared with the 10 patients with no liver metastases (48.0 L/hr/m2) and the 12 patients with 25% to 75% LVRT (45.3 L/hr/m2). Terminal elimination half-life and apparent volume of distribution were not significantly different among groups. The monoethylglycinexylidide test had a significant correlation with vinorelbine clearance. (r2 = 0.70; p = 10(-4). CONCLUSIONS: These results support vinorelbine dose reduction in patients with severe liver failure but not in patients with moderate secondary liver involvement. The monoethylglycinexylidide test may prove to be useful for vinorelbine dose individualization.

Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer.

25 patients older than 65 years with metastatic breast cancer were treated with vinorelbine 30 mg/m2 i.v. days 1 and 8 every 3 weeks; the pharmacokinetics were studied in 10 of them. Vinorelbine showed a large apparent volume of distribution (mean 23.4 l/kg), a long terminal half-life (mean 26.2 h) and a large systemic clearance rate (mean 1.2 l/kg). These results are similar to those reported in younger patients. No correlation has been found between toxicity, age and drug exposure. We observed 6 partial responses out of 20 evaluable patients despite a relatively low mean dose intensity (67%). Severe neutropenia occurred in 37% of the patients; other side-effects were acceptable. This study does not provide a pharmacokinetic rationale for reducing the dosage of vinorelbine in selected elderly patients.

Paclitaxel as a radiosensitiser: a proposed schedule of administration based on in vitro data and pharmacokinetic calculations.

Paclitaxel is efficacious against many human cancers. Because it blocks cells at the radiosensitive G2-M interface, paclitaxel has been investigated as a radiosensitiser. The results have been equivocal and somewhat contradictory. It is impossible to obtain proper pharmacokinetic calculations, aimed at obtaining maximum cytotoxicity and/or radiosensitisation, without knowing (i) how long the drug must be in contact with the cells, (ii) how long the effect lasts after the drug is removed from the cellular environment, (iii) whether the drug acts as a radiosensitiser even when, like cis-platinum, it is added after the radiation and (iv) what the minimum quantity of drug in the cellular environment is required for both chemotoxicity and radiosensitisation. The present work addresses the above questions. Two radioresistant cell lines of human origin were used, A375 melanoma and S549 lung carcinoma, in a clonogenic assay where only colonies with 50 or more cells were counted. For the irradiation, 6 MV X-rays were used. Any G2-M block was quantified by cell cycle kinetics analysis. From the results, a simulation of pharmacokinetics was conducted to calculate the schedule of administration of paclitaxel most likely to achieve and maintain significant chemotoxocity and radiosensitisation. The minimum concentration of paclitaxel for measurable cytotoxicity was 3 nM for both cell lines, but the drug was more toxic to the A549 cells. The minimum concentration for measurable radiosensitisation was 3 nM for A375 and approximately 0.1 nM for A549, but whereas above 3 nM the radiosensitivity increased in A375, it decreased above 1 nM for A549. A minimum of 18 h incubation with the drug was necessary for measurable effects and the radiosensitising effects were lost soon after its removal. There was no radiosensitisation if paclitaxel was added after the radiation, and, at the minimum effective concentrations, it caused only a minor and transient G2-M block. The pharmacokinetic calculations predict that 15 mg/m2 paclitaxel given as a 1 h infusion 5 days/week for 3 weeks during the radiotherapy should achieve both cytotoxicity and radiosensitisation. The mechanism of radiosensitisation by paclitaxel at the concentrations suggested by our results does not appear to be via a G2-M block and is probably concentration dependent. The results imply that low-dose, daily infusions of paclitaxel for as long as possible during a course of radiotherapy are more likely to result in radiosensitisation and prolonged cytotoxicity than high-dose infusions given once a week.

Cytochrome P450IID subfamily in non-human primates. Catalytical and immunological characterization.

Interindividual variations of debrisoquine metabolism was recently identified in non-human primates tested in vivo. The catalytical and immunological characterization of cytochrome P450IID subfamily was undertaken in hepatic microsomes from extensive metabolizer primates. The NADPH/O2 mediated metabolism of debrisoquine, dextromethorphan and bufuralol was similar to the kinetics reported in humans. The CuOOH mediated metabolism of bufuralol suggested that at least two enzymes are responsible for bufuralol 1'-hydroxylation. Eleven compounds were tested for their capacity to modify P450IID function in vitro. Eight competitive inhibitors of P450IID6 in man were all and exclusively competitive inhibitor of P450IID subfamily in non-human primates. Quinidine, which is the strongest competitive inhibitor in man, exhibited the higher inhibitory potency in monkey (Ki = 0.75 microM). Anti-LKM antibody against P450IID subfamily cross-reacted with two proteins of 49 and 47 kDa, and sera containing anti-LKM antibody against these two proteins inhibited dextrorphan formation in vitro. These data provide evidence for catalytical and immunological similarities between human and monkey microsomes and indicate that the primate system could be a model for enzymatic studies of P450IID.

The effects of cardiac transplantation and cyclosporine therapy on digoxin pharmacokinetics.

Most patients needing cardiac transplantation are treated with digoxin for heart failure. Because of its narrow therapeutic range, even recommended doses of digoxin may cause severe toxicity. Several drugs, including quinidine, amiodarone, verapamil, and propafenone can interact with digoxin, leading to toxic accumulation of the glycoside. The authors have recently reported two cases of severe digitalis toxicity after the initiation of cyclosporine treatment in patients awaiting cardiac transplantation. A preliminary study on two additional patients suggested that cyclosporine reduced the plasma clearance and volume of distribution of digoxin. To assess the mechanism of this interaction, the authors studied digoxin pharmacokinetics in patients awaiting cardiac transplantation and again after the surgery, during chronic cyclosporine therapy. To separate the effects of transplantation and cyclosporine on digoxin pharmacokinetics, pharmacokinetic studies were subsequently performed in dogs to allow controlled experimental conditions for evaluation of the digoxin-cyclosporine interaction.

Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma.

Etoposide dosage in patients with liver dysfunction remains controversial. Since etoposide has a hepatic component to its clearance (CL) and shows a high degree of protein binding, hepatic impairment could affect etoposide disposition. However, the empiric recommendation that the dose of etoposide be decreased in such patients may reduce systemic exposure and be detrimental to its antitumor activity. To address these issues we studied the pharmacokinetics (PK) of etoposide in patients with hepatocellular carcinoma (HCC) and underlying cirrhosis (n = 17) treated with daily oral etoposide. Unbound etoposide was obtained by ultrafiltration. Etoposide concentrations (total and free drug) were measured by high-performance liquid chromatography (HPLC) and analyzed by noncompartmental equations. The patients had mild or moderate liver dysfunction. Albuminemia was in the normal range for all the patients. Creatininemia was normal in all but two patients. PK results (mean and range) showed that etoposide disposition was unchanged in patients with liver dysfunction. We found slightly high etoposide bioavailability [F, 61% (17-95%)] and clearance [CL, 1.1 (0.7-2.3)l h(-1) m(-2)] resulting in a normal degree of systemic exposure (AUC(oral) 27 microg h ml(-1)). Normal protein binding [PB 93.2% (84.4-98.1%)] contributed to a normal level of exposure to free drug (AUC(f, oral) 1.9 microg h ml(-1)). The distribution volume [V(SS) 8.4 (6.1-13.2) l/m2] and the effective half-life [t1/2eff, 5.1 (3.0-9.6) h] were normal. Median CL and protein binding did not differ in the seven patients with total bilirubin value of > 1.2 mg/dl as compared with the ten patients with total bilirubin levels of < or = 1.2 mg/dl (1.3 versus 1.01 h(-1) m(-2) and 92.5% versus 93.4%, respectively). In agreement with this PK finding, we observed no clinical evidence of increased toxicity in patients with hyperbilirubinemia as compared with patients with normal bilirubinemia (mean WBC decrease 38% versus 47%). The only case of severe (grade 4) hematological toxicity was observed in one patient with reduced glomerular filtration. Since the pharmacological effects of etoposide correlate with the level of systemic exposure to the free drug, our data suggest that no dose reduction is needed in patients with HCC. It is even possible to increase the dose intensity in patients with favorable PK parameters under appropriate hematological and therapeutic drug monitoring.

Chronopharmacology of methotrexate pharmacokinetics in childhood leukemia.

Survival has been shown to improve when maintenance therapy for acute lymphocytic leukemia in children is given at night rather during the day. We examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In a crossover study, we determined the pharmacokinetics of intravenous methotrexate at 10:00 and 21:00 h in six children with standard or high-risk leukemia. During the study, children refrained from concomitant drugs (6-mercaptopurine and trimethoprim sulfamethoxazole). There was a significant fall in methotrexate plasma clearance at night (from 5.6 +/- 3 ml/min/kg to 4.7 +/- 2.3 ml/min/kg p < 0.05). Renal clearance of methotrexate tended to decrease at night and unbound renal clearance decreased significantly (from 17.5 +/- 1.7 ml/min/kg to 8.5 +/- 3.6 ml/min/kg p < 0.05). Creatinine clearance did not exhibit diurnal variation, when comparing two 12-h collections, but there was a significant decrease in the nonglomerular clearance of methotrexate (from 14.8 +/- 5.2 to 6 +/- 4 ml/min/kg). Because it is a weak organic acid, the tubular secretion of methotrexate depends on urinary pH. At night urinary pH is more acidic. This may result in more reabsorption and hence reduced renal clearance.

The feasibility of using EMLA (eutectic mixture of local anaesthetics) cream in pediatric outpatient clinics.

EMLA is a eutectic mixture of local anaesthetics, lidocaine and prilocaine, effective in alleviating the pain of venous puncture in children. The lag time of 60 minutes, which is necessary to achieve effective anaesthesia after skin application, may be an important obstacle to the use of EMLA. In this study we recorded the routine practice of six pediatric outpatient clinics which may use EMLA. Our data show a large variability in the feasibility of using EMLA: In the Hematology-Oncology clinics 85% of the patients could benefit from EMLA without prolonging their hospital stay; in the Neurology clinic the mean waiting time is 60.2 +/- 45 minutes, and an additional 15 minutes would be required for only 26 percent of the patients. In four other clinics where the blood work is performed at the phlebotomy station, the waiting time before venous puncture ranges from five to 12 minutes and the use of EMLA would require major changes in the organization of the clinic, or a longer waiting time. In children suffering from chronic diseases, for whom painful medical procedures are a major cause of anxiety, the additional waiting time may be acceptable by both patients and their parents.

[Analgesia-sedation in pediatric resuscitation: indications, modalities]. / L'analgésie-sédation en réanimation pédiatrique: indications, modalités.

Recently in pediatric intensive care, sedative and analgesic drugs are being used more frequently, not only for painful and stressful procedures, but also to improve the techniques of intensive care and the patient's comfort. Benzodiazepines are the most common drugs used for sedation, and narcotics for pain.

The perception of teratogenic risk of cocaine.

While there has been a substantial increase in recreational use of cocaine by young adults, conclusive evidence for cocaine teratogenicity in humans is lacking, and even those believing the drug is teratogenic agree that the rates are quite small. While counseling pregnant women on their teratogenic risk, it was our impression that there is an unrealistically high perception of reproductive risk of cocaine. We wished to quantify the perception of teratogenic risk of cocaine by the public, physicians, and by pregnant women who were counseled following gestational exposure to the drug. Women taking cocaine during the first trimester of pregnancy (n = 54), controls with post secondary education (n = 30), and physicians (n = 30) were asked, using a visual analogue scale, to quantify the teratogenic risk of cocaine and the tendency to terminate/continue the pregnancy after first trimester exposure; in the case of the "public" and physicians this was a hypothetical question. Both physicians and the controls perceived cocaine to be teratogenic (13.4 +/- 11% risk of major malformations by physicians, and 56.5 +/- 22.8% by the "public"). The controls believed cocaine to be as hazardous as thalidomide (57.2 +/- 25.6% risk for thalidomide). Asked whether they would wish to terminate such pregnancy in their family, most physicians (56%) and the controls (70%) had a greater than 50% tendency to terminate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of midazolam in critically ill neonates.

Midazolam is a water soluble benzodiazepine, with a short elimination half-life in adults and children. An IV bolus of midazolam 0.2 mg.kg-1 was administered to 10 critically ill neonates receiving intensive care who required sedation. The plasma clearance was 6.85 ml.min-1 and the elimination half-life was 6.52 h. Midazolam was well tolerated during and after administration. Because of its short half-life compared to diazepam, midazolam could be used during the neonatal period to produce brief rapid sedation.

Morphine excretion in breast milk and resultant exposure of a nursing infant.

We report the case of an infant who was breastfed while his mother was receiving low doses of morphine. Morphine concentration in his serum was in the analgesic range (4 ng/ml), while concentrations in the milk varied substantially in three samples collected within 2 hours (10, 100, 12 ng/ml). The calculated dose that the infant must have received to achieve the observed serum concentration had to be between 0.8 to 12% of maternal dose, based on reference literature values of clearance and bioavailability. The current perception that maternal morphine exposure is safe for the breastfed infant is based on a 50 year old data which were determined by an analytical method 1000 fold less sensitive than the present HPLC, thus leading to a likely erroneous conclusion.

Seizures presenting as apnoea.

Between the ages of 3 and 6 months a baby boy presented with repeated, non-specific episodes of cyanosis, apnoea, bradycardia, and abnormal movements of the limbs. The episodes were severe and required resuscitation and several admissions to hospital. Initial investigations showed only signs of oesophagitis. Despite treatment of the oesophagitis the symptoms recurred, and electroencephalography and polygraphy eventually showed evidence of minor seizures. Severe epilepsy with tonic-clonic seizures developed when he was 6 months old.

Are current pediatric dose recommendations for intravenous theophylline appropriate?

Theophylline, a first-line antiasthma drug, is often associated with severe toxicity even when taken in the recommended schedule. Theophylline toxicity has been associated with upper respiratory tract infections (URTI) due to reduced total-body clearance of theophylline. Some researchers believe this inhibition stems from a direct effect of viruses, but others postulate it is a result of the fever. We examined whether current theophylline dose recommendations are appropriate for children with acute asthma with a concurrent URTI. We also wished to elucidate whether the viral infection or the fever inhibits theophylline clearance. A total of 2254 medical records of asthmatic children admitted to The Hospital for Sick Children in Toronto were reviewed between 1987 and 1990. Clearance rate was calculated as the ratio between the infused dose rate and measured steady-state concentrations. Subsequently, these clearance rates were used to calculate steady-state concentrations that would be achieved by the recommended dose rates of theophylline. Reduced theophylline clearance was associated with the presence of URTI (p = 0.029) but not fever. Age correlated significantly with theophylline clearance (p = 0.027). If these children were to receive the recommended intravenous dose rate of theophylline, two-thirds of them would achieve steady-state serum concentrations above 15 mg/L, and one-third would achieve concentrations above 20 mg/L. Reevaluation of the present recommended theophylline dose rate is needed, as the majority of children requiring intravenous theophylline have a concurrent URTI with compromised total-body clearance. A correction factor of 60% is recommended to adjust the dose rate during an URTI. If utilized by prescribing physicians, it may reduce theophylline toxicity during an URTI episode.

Sensitive high-performance liquid chromatographic method with fluorescence detection for measurement of vinorelbine plasma concentrations.

A high-performance liquid chromatographic (HPLC) method with fluorescence detection for the determination of vinorelbine in plasma is described. The technique was derived from that published by Debal for an assay of vinorelbine in cell culture medium. The modifications concern the preparation procedure for plasma samples (a two-step liquid-liquid extraction from plasma is described), optimization of the mobile phase composition, and use of a single C18 column. These changes resulted in an improved sensitivity and reproducibility of the assay and led to its feasibility for clinical pharmacokinetic studies. The range of the assay is 2 to 1000 ng/ml.

Determination of unbound etoposide concentration in ultrafiltered plasma by high-performance liquid chromatography with fluorimetric detection.

Etoposide is a highly protein bound drug, and monitoring the concentration of free drug could help individualize dosage in oncological patients. The cost and difficulty of the standard techniques (equilibration dialysis) has hampered the monitoring of free drugs. We describe a simple HPLC method for the measurement of free etoposide concentration in plasma. Sample preparation involves the ultrafiltration of plasma by a Centrifree device for 30 min at 2000 g and extraction with chloroform. The isocratic separation is performed with a mu Bondapak phenyl analytical column. Fluorimetric detection is used (288-328 nm excitation and emission wavelengths). Linearity of the calibration curve is excellent between 0.05 and 1 microgram/ml. Accuracy and precision are reported at the concentrations 0.06 and 0.4 microgram/ml: within-run accuracy is 10% and 6.2%, respectively; between-run accuracy is < or = 1%; within-run coefficients of variation (C.V.) are 10.6 and 5.0%; between-run C.V. are 11.6 and 6.8% respectively. The range of the assay is 0.05 to 1 microgram/ml. The feasibility of the technique has been tested in 7 patients treated with oral etoposide for hepatocarcinoma (mean protein binding 91%). We found no interference from endogenous substances, co-administered drugs (alizapride, furosemide, ranitidine) and other antineoplastic agents (doxorubicine, idarubicine, vinblastine, vinorelbine).

Diurnal variation of methotrexate disposition in children with acute leukaemia.

There is recent evidence that survival is improved when maintenance therapy for acute lymphocytic leukaemia in children is given at night. We have examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In 6 children with leukaemia there was a significant fall in methotrexate plasma clearance at night (from 5.6 to 4.7 ml.kg-1.min-1). Renal clearance of methotrexate tended to fall at night and unbound renal clearance fell significantly (from 17.5 to 8.5 ml.min-1.kg-1 P less than 0.05). Creatinine clearance did not exhibit diurnal variation, whereas there was a significant fall in the non-glomerular clearance of methotrexate (from 14.8 to 6 ml.min-1.kg-1). Since methotrexate is a weak organic acid, its tubular secretion depends on urinary pH. At night urinary pH is more acidic, and this may result in more reabsorption and hence reduced renal clearance.

Effect of cyclosporin A on protein binding of teniposide in cancer patients.

We investigated the effect of cyclosporin A (CSA) on protein binding of teniposide (VM26) in 16 patients with metastatic renal cell carcinoma receiving i.v. VM26 alone over 24 h (total dose, 200 mg/m2) and in association with CSA (5 mg/kg/2 h followed by 30 mg/kg/48 h i.v.). CSA was used in an attempt to overcome multidrug resistance. The unbound fraction (%fu) of VM26 was significantly (p=0.04) higher in the cycles with CSA (median 0.8; range 0.4-1.9) than in the cycles with VM26 alone (median 0.5; range 0.1-1.6). Both total VM26 area under curve concentration (AUC0-infinity) and free VM26 AUC0-infinity increased after treatment with CSA, but the median increase in free AUC0-infinity was higher (2.7-fold) than total AUC0-infinity (1.5-fold) (p = 0.04). Bilirubin was significantly (p<0.01) increased after CSA but no association was observed between bilirubin level and %fu of VM26. Albumin was in the normal range after both VM26 alone and VM26 plus CSA. The nadir of absolute neutrophil count (ANC) after VM26 plus CSA (median 700/microl, range <100-2860/microl) was lower than after VM26 alone (median 1900/microl, range 200-6000/microl) (p = 0.0007). The median percentage of ANC compared to the pretreatment value (ANC nadir/ANC pretreatment x 100) was 39.0% (range 3.1-98.8%) in the cycles with VM26 alone and 16.9% (range 1.4-97.9%) (p = 0.007) after VM26 plus CSA. Percentage change of neutrophils significantly correlated with free AUC0-infinity VM26 in the cycles with VM26 alone and VM26 plus CSA (p = 0.04, r = -0.53 and p = 0.04, r = -0.52, respectively). Only a trend which failed to reach significance was observed between total AUC0-infinity VM26 and percentage change of neutrophils in the cycles with VM26 alone and in association with CSA (p = NS, r = -0.33 and p = 0.055, r = -0.49, respectively). In conclusion, patients treated with CSA had higher systemic exposure to unbound VM26.