Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen.

PURPOSE: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic-pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. METHODS: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m(2); 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. RESULTS: The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m(2) and 211 l/m(2), respectively. The intrapatient variability (22-28%) was far lower than the interindividual variability (33-88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. CONCLUSIONS: All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant.

Inter- and intra-individual variability in transdermal fentanyl absorption in cancer pain patients.

A transdermal therapeutic system (TTS) is recommended for use in chronic cancer pain, particularly in the advanced stages. The aim of this trial was to study intra- and interindividual variabilities in fentanyl transdermal absorption and investigate physiological and clinical parameters that can influence the absorption in patients treated using a TTS for moderate to severe cancer pain. The study group consisted of 108 patients (71 men and 37 women; mean age, 61.3 years) with chronic cancer pain. A total of 507 patches were analysed. The TTSs used to administer fentanyl were removed after a 72-h period. The amount of fentanyl remaining in the patches was determined using a high-performance liquid chromatography method with ultraviolet detection. Depending on the analgesic requirements of the patient, the dose of fentanyl administered by TTS ranged from 25 to 500 microg/h. The study period was 6 months. Large interindividual variability in the amount of remaining fentanyl in the patches occurred. For 58.1% of patches, absorption was 60 to 84%; for 33.2% of them, it was lower; and for 8.8%, it was higher than this range. The intra-individual variability ranged from 2.8 to 75.1%. The bioavailability of fentanyl was statistically different according to patient age. Patients >75 years of age absorbed 50% of the fentanyl during the selected 72-h period, whereas patients <65 years absorbed 66%. Moreover, there is a significant difference in the percentage of absorbed fentanyl according to the type of cancer. The absorption was higher in patients with breast or digestive cancer than in those with lung cancer. Hyperhidrosis, hypertrichosis and the localization of patches on the skin did not influence bioavailability. For the entire group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients.

Population pharmacokinetics of melphalan, infused over a 24-hour period, in patients with advanced malignancies.

PURPOSE: The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies. METHODS: Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3+/-4.5 l/h per m2) than in female patients (12.3+/-4.5 l/h per m2). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m2). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels. CONCLUSION: The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.

Sensitive HPLC-fluorescence method for irinotecan and four major metabolites in human plasma and saliva: application to pharmacokinetic studies.

BACKGROUND: We developed gradient HPLC methods for quantification of the antimitotic drug irinotecan (CPT-11) and its four metabolites, SN-38, SN-38 G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4amino-1-piperidino]-carbonyloxycamptothecin (NPC), as the sum of the lactone and carboxylate forms, in human plasma and saliva. Camptothecin was used as internal standard. METHODS: The sample pretreatment involved protein precipitation with methanol-acetonitrile (50:50 by volume) followed by acidification with hydrochloric acid to convert the lactone ring-opened form into its lactone form, quantitatively. HPLC separation was performed on a Xterra RP18 column. The excitation wavelength was 370 nm, and the emission wavelength was set at 470 nm for the first 24 min and then at 534 nm for the next 4 min. The stabilities of irinotecan and its four metabolites in plasma, saliva, and acidic extracts were also investigated under various conditions. RESULTS: Assays were linear in the tested range of 0.5-1000 micro g/L. For the five analytes, limits of quantification were 0.5 micro g/L in both matrices. The interassay imprecision (as relative standard deviation) was 3.2-14% in plasma and 2.6-5.6% in saliva. Assay recoveries ranged from 92.8% to 111.2% for plasma and 100.1% to 104.1% for saliva. Mean extraction recovery from plasma or saliva was 90%. CONCLUSION: The developed assay can be used to determine pharmacokinetic parameters for CPT-11, SN-38, SN-38 G, APC, and NPC in plasma and saliva from patients with metastatic colorectal cancer.

Modeling plasma and saliva topotecan concentration time course using a population approach.

The purpose of this study was to develop a pharmacokinetic model simultaneously accounting for topotecan concentrations in plasma and saliva. Thirteen patients with metastatic epithelial ovarian cancer received topotecan. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Data were analyzed using the nonlinear mixed-effect model program. The saliva concentrations were associated to a peripheral compartment while the central compartment described the plasma concentration time course. Thus, a three-compartment model was used; the basic parameters were: total clearance (CL), initial volume of distribution (V1), transfer rate constants (k12/k21 and k13/k31). The interoccasion variability was taken into account in the model. Data analysis was performed using a three-step approach; in step 2, a close relationship was found between creatinine CL and topotecan CL. The inclusion of this second stage model significantly improved the fit. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 10.4 to 23 L/h) while interoccasion variability was limited (6%). Seven additional courses were used for model validation. A limited sampling strategy using Bayesian estimation based on two sampling times (saliva at 25 min and plasma plus saliva at 8.5 h after the start of infusion) was developed. This study shows that salivary concentrations can be effectively used for drug monitoring.

Stability of dacarbazine in amber glass vials and polyvinyl chloride bags.

The stability of dacarbazine in commercial glass vials and polyvinyl chloride (PVC) bags in various storage conditions and the emergence of 2-azahypoxanthine, a major degradation product possibly linked with some adverse effects, were studied. Triplicate samples of reconstituted (11 mg/mL) and diluted (1.40 mg/mL) dacarbazine admixtures were prepared and stored at 4 degrees C or at 25 degrees C in daylight, fluorescent light, or the dark. The effect of several light-protective measures (amber glass vials, aluminum foil wrapping, and opaque tubing) on dacarbazine stability in a simulated i.v. infusion system was also evaluated. Dacarbazine quantification and main degradation product determination were performed by high-performance liquid chromatography. Stability was defined as conservation of 90-105% of initial dacarbazine concentration without major variations in clarity, color, or pH and without precipitate formation. Reconstituted dacarbazine solutions were stable for 24 hours at room temperature and during light exposure and stable for at least 96 hours at 2-6 degrees C when stored in the dark. After dilution in PVC bags, stability time increased from 2 hours in daylight to 24 hours in fluorescent light and to 72 hours when covered with aluminum foil. After two hours of simulated infusion, dacarbazine remained stable. Diluted dacarbazine solutions stored at 2-6 degrees C were stable for at least 168 hours. The only degradation product found was 2-azahypoxanthine, which was detected in every sample. The storage and handling of dacarbazine should take into account both the loss of the drug and the production of its potentially toxic degradation product. Dacarbazine must be carefully protected from light, administered using opaque infusion tubing, and, if necessary, refrigerated before administration to reduce 2-azahypoxanthine formation.

A limited-sampling strategy to estimate individual pharmacokinetic parameters of vinorelbine in elderly patients with advanced metastatic cancer.

The aim of this study was to characterize the population pharmacokinetic of vinorelbine in elderly patients and to propose a limited-sampling strategy to estimate individual pharmacokinetic parameters. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20-30 mg/m2. The population parameters were computed, using a three-compartment model, from an initial group of 27 patients. Twelve additional courses were used for model validation and evaluation of eight different limited-sampling strategies. The inter-individual variability of CL was explained by a linear dependency with age. The population average parameters and the interindividual variabilities (CV%) were: CL=47.1 l/h (31.7%), V=16.6 l (64%), k21=0.776 h-1 (20%), k31=0.0346 h-1 (15.2%), alpha=0.431 h-1 (6.84%) and beta=0.0167 h-1 (25%). Bayesian estimation with three measured levels (end of infusion, and 6 and 48 h) can be selected, because it allows adequate estimation of CL, elimination half-life and vinorelbine concentrations with a non-significant bias. Moreover, the choice of these three sampling times presents practicality advantages for the patient's comfort. Vinorelbine clearance decreasing with age and AUC being a good predictor of several toxicity end points during vinorelbine treatment, the limited-sampling strategy developed in this paper may be clinically relevant.

In vitro schedule-dependent interaction between irinotecan and vinorelbine in NCI H460 non-small cell lung cancer cell line.

Despite recent developments, treatment outcome in advanced non-small cell lung cancer (NSCLC) remains far from satisfactory. Vinorelbine and irinotecan have shown good single-agent activity against NSCLC. These two anticancer agents target different phases of the cell cycle: the cytotoxicity of camptothecin occurs mainly in the S-phase while the cytotoxicity of vinca alkaloids occurs mainly in the M-phase. Thus, it seemed interesting to study the combined activity of these two drugs against human NSCLC cell lines in vitro. In this study, the cytotoxic interaction between vinorelbine and SN 38 (the active metabolite of irinotecan), administered at various schedules, was assessed against a human NSCLC cell line, NCI H460. Cell growth inhibition was determined by the MTT assay. The effects of drug combinations were analysed by the isobologram method. The mean IC50 was 2.06 x 10(-6) mg/ml or vinorelbine, 2.72 x x 10(-3) mg/ml for irinotecan and 2.76 x 10(-6) for SN 38. On simultaneous exposure to these two drugs, additive effects were observed, while antagonistic effects were observed on sequential exposure to vinorelbine followed by SN 38. On sequential exposure to SN 38 first followed by vinorelbine, a slight antagonistic effect was observed at the isoeffect 50%; at the isoeffect 70%, additive effects were observed. These findings suggested that simultaneous exposure to vinorelbine and SN 38 may be the optimum schedule for this combination, while sequential administrations may be less cytotoxic and inadequate. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and SN 38 with regard to both anti-tumor activity and toxicity.

Blood and plasma pharmacokinetics of vinorelbine in elderly patients with advanced metastatic cancer.

PURPOSE: As vinorelbine is 78% bound to platelets, it seems interesting to investigate the pharmacokinetic profile of this drug from blood and to compare it to that determined from plasma. Thus, in this study, the comparative blood/plasma pharmacokinetics of vinorelbine were investigated in 15 elderly patients with advanced metastatic cancer. METHODS: The drug was given as a short (10 min) peripheral intravenous infusion; the administered dose ranged from 20 to 30 mg/m2 depending on the patient. Chemotherapy was repeated weekly. During the first and the fifth courses, each patient underwent pharmacokinetic evaluation. Toxicity evaluation was performed after each course of chemotherapy; a total of 109 courses was studied. Plasma and blood vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorimetric detection. Individual pharmacokinetic parameters were estimated with an empirical Bayes methodology. An open three-compartment pharmacokinetic model was used to describe the kinetics of vinorelbine. RESULTS: The half-lives of the terminal part of the curves, determined from blood and plasma data, were of the same order of magnitude: 31-35 h. Mean total clearances were about 0.71 l/h/kg from plasma and 0.45 l/h/kg from blood. Except during the first 15-20 min following the end of infusion, vinorelbine concentrations were 1.9 times higher in blood than in plasma. The ratio AUC(B)/AUC(P) (AUC(B) and AUC(P) are the area under the concentration-time curve from blood and plasma data, respectively) averaged 1.7; it was comparable to the blood/plasma ratio of 1.6 that remained constant over the 72 h of the study. There was substantial intra- and interpatient variability in vinorelbine pharmacokinetic parameters. This variability is similar within and between patients, and between pharmacokinetic parameters computed from blood and plasma. The elimination half-life is the parameter with the lowest intra- and interindividual variability (10-14%), while the AUC is the parameter presenting the highest variability (20-65%). The main haematological toxicity was anaemia (12 patients) and neutropenia (10 patients). Thrombocytopenia occurred in only one patient. At the first cycle, significant correlations were found between AUC(B) and AUC(P) and the decrease in neutrophil count (P < 0.05). The highest haematological toxicities encountered in this study occurred in patients presenting the lowest platelet count. AUC computed from plasma data decreased significantly with the increase of platelet count (P = 0.03). CONCLUSION: From the results of this study, blood did not appear to be a better predictor of haematological toxicity than plasma, but the decrease of platelet count seems to be a good predictor of this toxicity. Indeed, changes in platelet count are likely to produce strong variations in the unbound fraction of vinorelbine; this exposes the patient to a high risk of toxicity.

Oxidant-antioxidant status in relation to survival among breast cancer patients.

The role of plasma oxidant-antioxidant status in survival after breast cancer surgery was investigated in a cohort of patients (n = 363) hospitalized in Southern France between 1989 and 1992. The median follow-up was 8 years after surgery for histologically confirmed breast cancer. Plasma analyses were performed after diagnosis and before surgery and adjuvant therapy. We found an inverse relationship between plasma lipoperoxides (MDA) and tumor size at diagnosis, together with higher lipoperoxide levels in node-negative tumors than in node-positive ones (TNM). The longitudinal approach revealed an increased risk of recurrence for patients with plasma lipoperoxides in the highest tertile of the sample (RR = 2.1, 95% CI 1.1-4.0). In addition, the risk of recurrence increased (RR = 1.7, 95%CI 1.0-3.0), after adjustment for the known prognostic factors (TNM), for patients with plasma lipid-adjusted vitamin E levels of over 22 micromol/l. The risk of breast cancer death was twice as great for patients with plasma lipid-adjusted vitamin E levels above this value. Excesses of plasma lipoperoxides and vitamin E appear to be factors in poor prognosis for breast cancer-specific survival (OVS) and disease-free survival (DFS), respectively, independent of tumor characteristics at diagnosis. Several hypotheses are advanced to explain the possible role of plasma vitamin E as a factor in poor prognosis for survival.

Influência do preparo per-operatório do cólon com polivinilpirrolidona-iodo na cicatrizaçäo da anastomose primária do cólon esquerdo obstruido: estudo em ratos / The influence of per-operative lavage solution with 5

O tratamento da obstruçäo aguda do cólon esquerdo é controverso. Recentemente tem sido utilizado o preparo per-operatório do cólon obstruido na tentativa de se realizar uma ressecçäo e anastomose primária com segurança, num único tempo cirúrgico. O objetivo deste estudo foi o de verificar a influência do preparo per-operatório do cólon com polivinilpirrolidona-iodo (PVPI) diluído a 5% em soluçäo fisiológica na cicatrizaçäo da anastomose primária nessas situaçöes de obstruçäo. Trinta e seis ratos Wistar foram submetidos a uma obstruçäo experimental do cólon esquerdo e 48 h após, randomizados para dois grupos: Controle (n=17), submetidos a ressecçäo seguida de anastomose primária, e Povidine (n=17), submetidos ao mesmo tipo de ressecçäo, porém, antes da realizaçäo da anstomose, o cólon desses animais foi lavado com soluçäo fisiológica + PVPI a 5%. Comparativamente, no 4§ dia de PO houve uma maior percentagem de aderências intensas (p < 0,05) e verificaram-se aos exames, macro e microscópico, grandes ulceraçöes na linha de sutura (p < 0,05), nos animais controles. Näo houve diferença estatística quanto à resistência das anastomoses verificada pelo teste de pressäo (p > 0,05). Conclui-se que a utilizaçäo do preparo per-operatório do cólon, com PVPI a 5%, determina uma cicatrizaçäo menos retardada e menos adversa na anastomose primária do cólon esquerdo obstruído