Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer.

PURPOSE: Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin. PATIENTS AND METHODS: Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61. RESULTS: During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC(0-infinity)) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t(1/2); 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance. CONCLUSION: There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly.

Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist.

The purpose of the study was to investigate the effect of food intake on the pharmacokinetics and metabolism as well as the relative bioavailability of bosentan. Sixteen healthy male subjects were treated in a randomized, four-way, crossover design with single oral doses of 125 mg bosentan, given as one tablet (with or without food), two tablets of 62.5 mg (with food), and a suspension (without food). The pharmacokinetic parameters of bosentan (and also three of its metabolites) were very similar after the four treatments: geometric means for Cmax and AUC0-infinity, ranged from 1.3 to 1.6 microg/ml and from 7.8 to 8.9 microg x h/ml, respectively, and median t(max) from 3.0 to 4.0 hours. The bioavailability of the 125 mg tablet relative to that of the suspension, both given fasted, was 102%. In the presence of food, Cmax and AUC0-max increased by 22% and 10%, respectively, whereas the two 62.5 mg tablets were bioequivalent to the 125mg tablet, both under fed conditions. The pharmacokinetics of the metabolites was independent of the treatment administered. In conclusion, bosentan bioavailability from the newly developed 125 mg tablet formulation is similar to that of the suspension, and food intake does not influence its pharmacokinetics to a clinically relevant extent.

Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients.

PURPOSE: The primary objective of this study was to investigate the influence of renal impairment on the pharmacokinetics of capecitabine and its metabolites in cancer patients. Capecitabine (Xeloda) is an orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), which is preferentially activated to 5-fluorouracil (5-FU) in tumors. METHODS: A total of 27 patients were enrolled, of whom 24 were evaluable for pharmacokinetics (6 with normal renal function, 8 with mild, 6 with moderate, and 4 with severe renal impairment at baseline). Patients received capecitabine orally at the standard dosing regimen (1250 mg/m(2) capecitabine twice daily for 2 weeks followed by a 1-week rest period). On study days 1 and 14, blood samples were collected to evaluate the pharmacokinetics of capecitabine and its metabolites. The relationship between the area under the plasma concentration-time curve (AUC) and creatinine clearance (CL(CR)) was assessed by log-linear regression analysis. RESULTS: The primary pharmacokinetic parameter with respect to the effect of renal dysfunction was systemic exposure to 5'-DFUR, 5-FU and FBAL determined on study day 14. Renal impairment led to an increase in the systemic exposure to 5'-DFUR and FBAL (23% and 109% increase in AUC, respectively) for a 50% reduction in CL(CR). By contrast, renal impairment may lead to decreased exposure to 5'-DFCR. There was no evidence for an effect of renal impairment on systemic exposure to 5-FU or capecitabine. Renal impairment did not have a major effect on peak concentration (C(max)) or elimination half-life (t(1/2)) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU. However, in the case of FBAL, moderate or severe renal impairment caused up to a twofold increase in C(max) and prolongation of t(1/2). All patients with severe renal impairment (four patients) had drug-related grade 3 or 4 adverse-events (AEs) and serious AEs. Patients with moderate renal impairment experienced a similar number of grade 3 or 4 AEs (six of nine patients) but had a higher incidence of serious AEs (three of nine patients) when compared with those with normal renal function (four of six patients and one of six patients, respectively). A similar effect was seen in patients with mild renal dysfunction (grade 3 or 4 AEs in four of eight patients; serious AEs in three of eight patients). The relationship between systemic exposure to capecitabine or its metabolites and safety was investigated using logistic regression. This exploratory analysis showed a strong positive relationship between AUC of 5'-DFUR and treatment-related grade 3 or 4 AEs, whereas there was no relationship with exposure to capecitabine, 5'-DFCR, 5-FU or FBAL. CONCLUSIONS: Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5'-DFUR and FBAL. However, only the AUC of 5'-DFUR is correlated with safety. Based on the safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results from the present study support the recommendation that patients with moderate renal impairment should be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable to that in patients with normal renal function.

Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancer.

BACKGROUND: Capecitabine (Xeloda) is a novel, oral fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue via a three-step enzymatic cascade. PURPOSE: The objective of this study was to compare the pharmacokinetics of capecitabine and its metabolites in Japanese and Caucasian cancer patients. METHODS: The study included 20 Japanese and 24 Caucasian patients with breast cancer. All patients received oral capecitabine 825 mg/m(2) twice daily for 14 days, except for study day 1 when only the morning dose was administered. On study days 1 and 14, blood and urine samples were collected after administration of the first dose and at steady state for the evaluation of the pharmacokinetics of capecitabine and its metabolites. The primary pharmacokinetic parameter was AUC(0-infinity ) of 5'-deoxy-5-fluorouridine (5'-DFUR) on day 14. The pharmacokinetic parameters in Japanese and Caucasian patients were compared using an ANOVA with calculation of the 90% confidence interval (CI) for the ratio of the geometric means. RESULTS: Statistical analysis showed equivalence in the AUC of 5'-DFUR on day 14 with a ratio of 1.01 (90% CI 0.85-1.21). Similarly, no relevant influence of race on the pharmacokinetics of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), or 5-FU was observed. Systemic exposure to alpha-fluoro-beta-alanine (FBAL) was higher in Caucasian than in Japanese patients. On study day 14, both the AUC and the maximum plasma concentration (C(max)) of FBAL were increased by 47% and 33% in Caucasian patients and Japanese patients, respectively. CONCLUSIONS: No clinically relevant differences in the pharmacokinetics of capecitabine and its key metabolites 5'-DFUR, 5'-DFCR, and 5-FU were found between Japanese and Caucasian patients. Plasma concentrations of FBAL were higher in Caucasian than in Japanese patients but this difference is not clinically relevant as FBAL has no antiproliferative activity and systemic exposure to FBAL does not correlate with the tolerability of capecitabine.

Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers.

BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.5 to 3 h after p.o. drug intake or at the end of the 1-h infusion. After both routes of administration, values for maximum drug concentration observed in plasma and area under the concentration-time curve increased slightly more than proportionally to the administered dose. Mean elimination half-lives were particularly long (56 to 77 h after p.o. administration and 76 to 104 h after i.v. administration). The volume of distribution was large (155 to 292 liters after p.o. administration and 304 to 494 liters after i.v. administration) and systemic clearance was low (1.9 to 2.8 liter/h after p.o. administration and 2.8 to 5.0 liter/h after i.v. administration). Urinary recovery of BAL4815 was less than 0.4% of the infused dose. Based on the exposure data, oral bioavailability of BAL4815 is assumed to be very high. The pharmacokinetics of BAL4815 are well suited to maintaining concentrations of BAL4815 for a long period of time in the body and to enabling an effective treatment of systemic mycoses.

Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers.

BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (C(max)) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study, C(max) values of 2.56 and 2.55 microg/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-beta-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50- or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.

Single-dose pharmacokinetics and safety of a novel broad-spectrum cephalosporin (BAL5788) in healthy volunteers.

BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. We investigated the safety and pharmacokinetics of BAL5788 in a double-blind, single-ascending-dose study with 40 healthy male subjects. The subjects were randomized to receive placebo (n = 2 subjects per dose) or BAL5788 (n = 6 subjects per dose) as a 200-ml intravenous infusion over 30 min. The BAL5788 doses used were 125, 250, 500, 750, and 1,000 mg (BAL9141 equivalents). All doses were well tolerated, with no severe or serious adverse events (AEs). The most frequent AE was taste disturbance. No electrocardiographic abnormalities and no trends or clinically significant changes in laboratory parameters or vital signs were observed. The maximum concentration of drug in serum and the area under the concentration-time curve for BAL9141 were dose proportional over the dosing range. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment, and the rate of renal clearance of free drug corresponded to the normal glomerular filtration rate for adults. More than 70% of the administered dose was excreted as BAL9141 in the urine, and almost no prodrug was detected. After the infusion of 750 mg, the mean plasma BAL9141 concentrations exceeded the MIC at which 100% of MRSA isolates are inhibited (4 microg/ml) for approximately 7 h, or 58% of a 12-h dosing interval. These results indicate that infusions of 750 mg twice a day should be adequate for the treatment of infections caused by MRSA.

Multiple-dose pharmacokinetics and safety of a novel broad-spectrum cephalosporin (BAL5788) in healthy volunteers.

BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. Safety and pharmacokinetic data from a multiple-dose study with 16 healthy male volunteers are reported. Subjects were randomized to receive BAL5788 at 500 or 750 mg (as BAL9141 equivalents; n = 6 subjects per dose) or placebo (n = 2 subjects per dose). The doses were given as 200-ml infusions over 30 min once daily on days 1 and 8 and twice daily on days 2 to 7. BAL5788 was well tolerated, with no severe or serious adverse events (AEs) or dosing-related changes in laboratory parameters, electrocardiographic findings, or vital signs. Drug accumulation in plasma was negligible during the dosing period. The results of pharmacokinetic analyses agreed well with data reported from a previous single-ascending-dose study. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment. BAL9141 was predominantly eliminated in urine, and renal clearance of the free drug corresponded to the normal glomerular filtration rate in adults. After multiple infusions of 750 mg, the mean concentrations of BAL9141 in plasma exceeded the MIC at which 100% of MRSA isolates are inhibited (4 microg/ml) for approximately 7 to 9 h, corresponding to 58 to 75% of a 12-h dosing interval.