Erratum to "Evaluation of MoPyC-prosthesis implantation and the use of angular stable plates in the treatment of comminuted radial head fractures" [J. Orthop. 16 (2019) 288-293].

[This corrects the article DOI: 10.1016/j.jor.2019.03.002.].

Evaluation of MoPyC-prosthesis implantation and the use of angular stable plates in the treatment of comminuted radial head fractures.

OBJECTIVE: Comminuted radial head fractures are disproportionately often accompanied by injuries of the bone or ligaments and can be treated in different ways. METHODS: 15 patients with a comminuted radial head fracture were treated with an angular stable plate (=G1) and 8 with a MoPyC-prosthesis (=G2). RESULTS: G1 shows an average Morrey-score of 83,87 points. Complications occurred in 5/15 patients. Within G2 an average Morrey-score of 86 was achieved. Complications could be shown in 2/8 patients. CONCLUSION: Both the treatment provides a clear individual benefit for the patients and predict promising results for the treatment of comminuted radial head fractures.

Evaluation of MoPyC-prosthesis implantation and the use of angular stable plates in the treatment of comminuted radial head fractures.

OBJECTIVE: Comminuted radial head fractures are disproportionately often accompanied by injuries of the bone or ligaments and can be treated in different ways. METHODS: 15 patients with a comminuted radial head fracture were treated with an angular stable plate (=G1) and 8 with a MoPyC-prosthesis (=G2). RESULTS: G1 shows an average Morrey-score of 83,87 points. Complications occurred in 5/15 patients. Within G2 an average Morrey-score of 86 was achieved. Complications could be shown in 2/8 patients. CONCLUSION: Both the treatment provides a clear individual benefit for the patients and predict promising results for the treatment of comminuted radial head fractures.

Options and limits of angle stable plates in the treatment of comminuted radial head fractures.

OBJECTIVE: New angle-stable plates provide more stability and better anatomical fit than previous plates. METHODS: 22 patients treated with an angle-stable plate were included. Postoperative the outcomes were evaluated according to the scoring systems of Morrey, Radin and Riseborough. RESULTS: 3 patients received a score of excellent, 14 good, and 5 satisfactory. We detected 3 cases of implant failure and 2 cases of postoperative neurological damage. 3 patientes received a radial head necrosis. CONCLUSIONS: Our results show that the angle-stable radial head locking plate can only be used in limited cases in the treatment of multi-fragment radial head fractures.

Thorough QT/QTc study of tocilizumab after single-dose administration at therapeutic and supratherapeutic doses in healthy subjects.

OBJECTIVES: The study was intended to determine whether tocilizumab has a threshold pharmacologic effect on cardiac repolarization as detected by QT/QTc prolongation on 12-lead electrocardiograms (ECGs) in healthy subjects. METHODS: This was a multicenter, double-blind, placebo- and active-controlled, parallel group study. Healthy subjects received either an intravenous infusion of tocilizumab 10 mg/kg (n = 30) or 20 mg/kg (n = 31), oral moxifloxacin 400 mg (n = 31), or placebo (n = 29). Triplicate ECGs were obtained at predose, 2 h postdose on Day 1, and on Days 8, 15, and 29. Blood samples for pharmacokinetic analyses were collected at predose and up to 28 days postdose. Adverse events and laboratory safety tests were assessed throughout the study. RESULTS: Estimated mean study-specific, heart rate-corrected QT interval change from time-matched baseline versus placebo was negative at all time points (range -5.4 to -1.0 ms); the associated upper bound of the 1-sided 95% confidence limit was below threshold (10 ms). No clinically significant abnormalities in other electrocardiographic parameters were detected. No electrocardiographic abnormalities constituted an adverse event. After tocilizumab dosing, median time to maximum serum concentration was 2 h postdose; mean apparent terminal half-life was 9.3 ± 1.2 (10 mg/kg) and 12.1 ± 1.5 (20 mg/kg) days. Tocilizumab was well tolerated. Neutrophil counts decreased after tocilizumab administration, reaching a nadir 2 to 5 days after infusion. Mean neutrophil counts returned to baseline in the 10-mg/kg group and were near baseline in the 20-mg/kg group at the follow-up visit (Day 50 ± 2). CONCLUSIONS: There was no QT prolongation effect of clinical concern by tocilizumab at both the therapeutic (10 mg/kg) and the supratherapeutic (20 mg/kg) dose in healthy subjects.

Pharmacokinetics, pharmacodynamics, and tolerability of aleglitazar in patients with type 2 diabetes: results from a randomized, placebo-controlled clinical study.

This multicenter, randomized, double-blind, placebo-controlled, ascending-dose study investigated the pharmacokinetics, pharmacodynamic effects, safety, and tolerability of aleglitazar, a novel peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist. After a 3-week washout period, 71 patients with type 2 diabetes received either a single oral dose of aleglitazar (20, 50, 100, 300, 600, or 900 microg) or placebo, followed by once-daily dosing for 6 weeks. Few adverse events were reported, with no apparent relationship between the rate of incidence or severity of the adverse events and the dose of aleglitazar administered. Aleglitazar exposure increased in a dose-proportional manner both after a single dose and at steady state, with no accumulation. Aleglitazar produced dose-dependent improvements in levels of fasting and postprandial glucose, insulin resistance, and lipid parameters. Dose-dependent decreases from baseline in creatinine clearance exceeded 10% at doses >300 microg. The PPARalpha- and PPARgamma-related effects occurred over similar dose ranges, indicating that aleglitazar is a balanced agonist of the two receptor subtypes.

Assessment of the bioequivalence of two nelfinavir tablet formulations under fed and fasted conditions in healthy subjects.

OBJECTIVES: This study was designed to assess the bioequivalence between the commercial 250 mg nelfinavir tablet and the new 625 mg nelfinavir tablet (Roche) which was developed to reduce the daily pill burden for patients from 10 to 4 tablets in a nelfinavir 1250 mg twice daily regimen. METHODS: A total of 52 healthy male subjects were enrolled in this randomized four-period crossover study to receive single oral doses of 1250 mg nelfinavir administered as five commercial 250 mg tablets (reference formulation) and as two new 625 mg tablets (test formulation). Each of the two formulations were taken after an overnight fast and immediately after intake of a standard breakfast (820 kcal) on separate occasions. Blood samples were collected pre-dose and at appropriate intervals after drug administration. Plasma concentrations of nelfinavir and its main metabolite M8 were assayed by a validated LC-MS/ MS assay and the pharmacokinetics of nelfinavir and M8 were derived using standard non-compartmental analysis. RESULTS: The primary parameters for bioequivalence testing were the logarithmically transformed AUC(0-inf) and C(max) of nelfinavir taken from 50 subjects who completed all four treatments. Bioequivalence was accepted if the 90% confidence interval (CI) was contained entirely in the equivalence region (80%, 125%). In the fed state, this criterion was met for AUC (effect ratio = 95%; CI = 87%, 103%) and Cmax (effect ratio = 101%; CI = 94%, 109%) and bioequivalence of the two treatments could be concluded. In the fasted state, AUC clearly failed to meet the bioequivalence criteria (effect ratio = 73%; CI = 59%, 90%) and Cmax was borderline outside the lower acceptance region (effect ratio = 97%; CI = 79.6%, 118%). Therefore, bioequivalence could not be concluded under fasted condition. Food increased the systemic exposure to nelfinavir (as reflected by comparison of the logarithmically transformed AUC(0-inf) values under fed and fasted conditions) by six- and eight-fold after dosing with the 250 mg and the 625 mg tablet, respectively. CONCLUSIONS: Bioequivalence of the new 625 mg nelfinavir tablet relative to the commercial 250 mg tablet, at a dose of 1250 mg, was confirmed in the fed state but not under fasted conditions. As nelfinavir is recommended to be taken with food, the new tablet is well-suited to decrease the daily pill burden for patients on a nelfinavir twice daily regimen and to enhance patient's compliance and adherence.

Tolerability and pharmacokinetics of the collagenase-selective inhibitor Trocade in patients with rheumatoid arthritis.

OBJECTIVES: The purpose of this study was to assess the tolerability and multiple-dose pharmacokinetics of Trocade in rheumatoid arthritis patients. METHODS: Forty-eight patients entered this double-blind, placebo-controlled, multiple ascending dose study. Patients received Trocade (25, 50, 100 or 150 mg) or placebo once daily for 28 days. Tolerability was assessed daily. Plasma pharmacokinetics was assessed on days 1 and 28. Trough blood samples were collected weekly. RESULTS: Trocade was well tolerated, with no differences in the adverse event profile compared with placebo. There were no relevant changes in laboratory parameters, vital signs or 12-lead ECG recordings. Plasma concentration profiles showed that Trocade was rapidly absorbed and most was eliminated within 24 h. The area under the plasma concentration-time curve and the maximum plasma concentration reached increased with dose, but this increase was not proportional to dose. No relevant accumulation was seen. CONCLUSIONS: Trocade was well tolerated for the 28-day study period. From exposure data, doses of 100 and 150 mg were expected to yield plasma levels associated with efficacy, and from trough concentrations the doses of 25 and 50 mg were also expected to be efficacious.

Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients.

The pharmacokinetics of an orally administered valine ester of ganciclovir (GCV), valganciclovir (VGC), were studied. These were compared to the pharmacokinetics of oral and intravenous GCV. Twenty-eight liver transplant recipients received, in an open-label random order with a 3- to 7-day washout, each of the following: 1 g of oral GCV three times a day; 450 mg of VGC per os (p.o.) once a day (q.d.); 900 mg of VGC p.o. q.d.; and 5 mg of intravenous (i.v.) GCV per kg of body weight q.d., given over 1 h. GCV and VGC concentrations were measured in blood over 24 h. One-sided equivalence testing was performed to test for noninferiority of 450 mg of VGC relative to oral GCV (two-sided 90% confidence interval [CI] > 80%) and nonsuperiority of 900 mg of VGC relative to i.v. GCV (two-sided 90% CI < 125%). The exposure of 450 mg of VGC (20.56 microg. h/ml) was found to be noninferior to that of oral GCV (20.15 microg. h/ml; 90% CI for relative bioavailability of 95 to 109%), and the exposure of 900 mg of VGC (42.69 microg. h/ml) was found to be nonsuperior to that of i.v. GCV (47.61 microg. h/ml; 90% CI = 83 to 97%). Oral VGC delivers systemic GCV exposure equivalent to that of standard oral GCV (at 450 mg) or i.v. GCV (at 900 mg of VGC). VGC has promise for effective CMV prophylaxis or treatment with once-daily oral dosing in transplant recipients.

Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone.

OBJECTIVE: To use pharmacostatistical models to evaluate the overall exposure of patients with Parkinson's disease to levodopa in the presence and absence of tolcapone. METHODS: Four hundred twelve patients with Parkinson's disease with fluctuating and nonfluctuating responses to levodopa participated in three multicentered, parallel, double-blind, placebo-controlled dose-finding studies and received either placebo or tolcapone in addition to levodopa-decarboxylase inhibitor therapy. Sparse blood samples were obtained from 393 patients for levodopa and 3-O-methyldopa assay, and the data were analyzed with use of the NONMEM program. RESULTS: The fraction of levodopa metabolized to 3-O-methyldopa was substantially reduced by the co-administration of tolcapone (by 65%, 74%, and 84% with tolcapone doses of 50, 200, and 400 mg, respectively, in fluctuators, and by 50% and 90% with doses of 200 and 400 mg, respectively, in nonfluctuators). This led to an overall reduction in levodopa clearance (CL) of approximately 15% to 25% in fluctuators and 20% to 30% in nonfluctuators. Because this was partly compensated for by a reduction in levodopa dose in these studies, the total daily exposure of patients to levodopa was only slightly increased (11% to 16%). The peak-trough fluctuations of plasma levodopa (Cmax-Cmin) were reduced in both populations in a dose-dependent fashion. CONCLUSIONS: Tolcapone effectively inhibited the formation of 3-O-methyldopa and resulted in a decrease in levodopa CL. The consequent increase in levodopa bioavailability was mostly offset by reductions in levodopa dose. It is possible that decreased fluctuations in plasma levodopa concentrations rather than increased levodopa exposure may explain the clinical benefits obtained with tolcapone.

Lack of interaction between tolcapone and tolbutamide in healthy volunteers.

To assess the effect of tolcapone (an inhibitor of cytochrome P450 [CYP] 2C9 in vitro) on the pharmacokinetics and hypoglycemic effect of the CYP 2C9 substrate tolbutamide, 12 healthy male volunteers were randomized to receive a single dose of tolbutamide 500 mg plus either placebo or tolcapone 200 mg after an overnight fast and 30 minutes after the start of a 6.5-hour 5% glucose infusion (150 mL/h). The participants crossed over to receive the alternative regimen after a washout period of at least 7 days. Tolcapone had no effect on the pharmacokinetics of tolbutamide or its metabolites and did not influence the effect of tolbutamide on plasma glucose concentrations. No serious adverse events or abnormal laboratory results or vital signs were reported. In conclusion, clinically relevant drug-drug interactions between tolcapone and tolbutamide when given together in clinical practice appear unlikely.

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients.

PURPOSE: [corrected] Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. METHODS: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m2 of capecitabine twice daily p.o. for 5-7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. RESULTS: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P = 0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P = 0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. CONCLUSIONS: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5'-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues.

Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies.

AIMS: To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor. METHODS: Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. RESULTS: The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h. CONCLUSIONS: Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.

Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients.

PURPOSE: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gender, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. METHODS: The study was designed as an open, randomized two-way crossover trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 25 patients with solid tumors. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrations was between 2 and 8 days. After each administration, serial blood and urine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS and in urine by NMRS. RESULTS: Based on the primary pharmacokinetic parameter, AUC(0-infinity) of 5'-DFUR, equivalence was concluded for the two formulations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 80% to 125%. There was no clinically significant difference between the t(max) for the two formulations (median 2.1 versus 2.0 h). The estimate for C(max) was 111% for formulation B compared to formulation A and the 90% confidence interval of 95% to 136% was within the reference region 70% to 143%. Overall, these results suggest no relevant difference between the two formulations regarding the extent to which 5'-DFUR reached the systemic circulation and the rate at which 5'-DFUR appeared in the systemic circulation. The overall urinary excretions were 86.0% and 86.5% of the dose, respectively, and the proportion recovered as each metabolite was similar for the two formulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and multivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokinetic parameters AUC(0-infinity) and C(max) of capecitabine and its metabolites revealed no clinically significant effects. The only statistically significant results were obtained for AUC(0-infinity) and C(max) of intact drug and for C(max) of FBAL, which were higher in females than in males. CONCLUSION: The bioavailability of 5'-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, the two formulations can be regarded as bioequivalent. The variables investigated (age, gender, body surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites.

Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers.

OBJECTIVE: Ganciclovir is commonly used in the treatment of cytomegalovirus (CMV) disease in patients who are immunocompromised and for the prevention of CMV disease in solid organ transplant recipients. Owing to limited bioavailability and saturable absorption, the use of oral ganciclovir in CMV retinitis is restricted to maintenance therapy only. As induction therapy must be given intravenously, an oral formulation which could be used for induction would offer significant benefits. A previous study of valganciclovir, a valyl ester prodrug of ganciclovir showed a 10-fold increase in plasma ganciclovir concentrations compared with the oral formulation. However, before studies can be conducted to confirm the utility of oral valganciclovir for the treatment and prevention of CMV disease, a dose must be selected for use in these studies. This study was designed to investigate the pharmacokinetics of ganciclovir and valganciclovir. DESIGN AND PARTICIPANTS: The study was an open-label, randomised, 4-way crossover, dose-ranging pharmacokinetic study, conducted in 39 patients who were HIV- and CMV-seropositive. The participants were randomised to one of 2 groups: fasted (n = 19) and fed (n = 20). In both groups, participants received 450, 875, 1750 and 2625 mg oral valganciclovir once daily for 3 days in a randomised order. RESULTS: In the 32 participants who completed the study, valganciclovir was rapidly absorbed and converted into ganciclovir (maximum ganciclovir concentrations occurred after 1.0 to 1.75 hours in the fasted group and 1.5 to 2.0 hours in the fed group). Systemic exposure to valganciclovir was low [with an area under the concentration-time curve to 24 hours (AUC24) of 1.3 to 2.5% that of ganciclovir]. The mean plasma concentrations of ganciclovir were dose-related. Peak concentrations of ganciclovir were achieved approximately 30 minutes after those for valganciclovir. In the fed state, the AUC24 of ganciclovir increased proportionally with dose. The mean AUC24 values for ganciclovir were slightly higher following food (24 to 56%) than in the fasted state. Based on linear regression of AUC24 values from the fed group, a dose of valganciclovir of 900 mg/day is expected to produce a daily exposure (AUC24) comparable with an intravenous dose of ganciclovir 5 mg/kg/day. CONCLUSIONS: These results show that once daily oral valganciclovir can produce exposures of ganciclovir (AUC24) exceeding those attained using intravenous ganciclovir 10 mg/kg. This suggests that oral valganciclovir may be suitable in many circumstances currently requiring intravenous ganciclovir, allowing for more convenience in the management of patients with CMV retinitis by utilising a 2 or 4 tablet daily regimen to cover all phases of treatment.

Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin.

To investigate the effects of bosentan (Ro 47-0203), an endothelin receptor antagonist, on the pharmacokinetics and pharmacodynamics of warfarin, a double-blind, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy male volunteers. All subjects received a single oral dose of 26 mg racemic warfarin twice, once in the morning of the 6th day of treatment with 500 mg bosentan twice daily for 10 days and once at the same time point during treatment with placebo twice daily for 10 days. Both treatments were separated by a 2- to 3-week washout period. Blood samples were collected at intervals up to 120 hours following the warfarin dose for the measurement of prothrombin time and factor VII activity and for determination of plasma concentrations of R- and S-warfarin. Bosentan treatment led to a statistically significant reduction of the maximal prothrombin time (PTmax) and the AUC0-120 h of PT and factor VII activity compared to placebo, on average, by 23% to 38%. This reduction could be explained by an increase in the elimination of the pharmacologically more active S-enantiomer whose mean AUC0-infinity was reduced by 29%. The mean AUC0-infinity of R-warfarin was also decreased by 38%. Cmax and tmax of both enantiomers did not change. Close monitoring in patients receiving warfarin is recommended at initiation or discontinuation of treatment with bosentan.

Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites.

Capecitabine (Xeloda) is a rationally designed oral, tumor-selective fluoropyrimidine carbamate aimed at preferential conversion to 5-fluorouracil (5-FU) within the tumor. Because capecitabine is extensively metabolized by the liver, it is important to establish whether liver dysfunction altered the pharmacokinetics of capecitabine and its metabolites. This was investigated in 14 cancer patients with normal liver function and in 13 with mild to moderate disturbance of liver biochemistry due to liver metastases. They received a single oral dose of capecitabine (1255 mg capecitabine/m2) with serial blood and urine samples collected up to 72 h after administration. Concentrations of capecitabine and its metabolites were determined in plasma by high-performance liquid chromatography or liquid chromatography coupled to mass spectrometry and in urine by 19F-nuclear magnetic resonance spectroscopy. Although plasma concentrations of capecitabine, 5'-deoxy-5-fluorouridine, 5-FU, dihydro-5-FU, and alpha-fluoro-beta-alanine were, in general, higher in patients with liver dysfunction, the opposite was found for 5'-deoxy-5-fluorocytidine. These effects were not clinically significant. Total urinary recovery of capecitabine and its metabolites was 71% of the administered dose in patients with normal hepatic function and 77% in patients with hepatic impairment. The absolute bioavailability of 5'-deoxy-5-fluorouridine was estimated as 42% in patients with normal hepatic function and 62% in patients with impaired hepatic function. In summary, mild to moderate hepatic dysfunction had no clinically significant influence on the pharmacokinetic parameters of capecitabine and its metabolites. Although caution should be exercised when capecitabine is administered to patients with mildly to moderately impaired hepatic function, there is no need for, a priori, adjustment of the dose.

The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects.

AIMS: To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects. METHODS: This was an open-label, randomized, two-way crossover study in 18 evaluable young male subjects. They received, on two occasions which were separated by at least 2 weeks washout period, 0.375 mg digoxin once daily for 13 days following a loading dose of 0.375 mg given twice on the day before the once daily dosing regimen started. On one occasion treatment with 500 mg bosentan twice daily was started on the eighth day of digoxin treatment and continued for 1 week. Serum concentrations of digoxin were determined up to 24 h postdose on day 8 (first day of bosentan treatment) and day 14 (last day of bosentan treatment) of the digoxin treatment period. Plasma concentrations of bosentan were measured at two time points after the first bosentan dose and up to 12 h after the last morning dose of bosentan. Safety was assessed by adverse events, clinical laboratory tests, blood pressure and pulse rate measurements and ECG recordings. RESULTS: Steady-state of digoxin was always achieved after 7 days of treatment. Serum concentrations of digoxin were within the usual therapeutic range. Average steady-state Cmax and Ctr were 2-2.1 microg l-1 and 0.65-0.69 microg l-1, respectively, when given alone. Bosentan did not lead to statistically significant changes in Cmax and Ctr of digoxin. AUC (0,24h) of digoxin, however, was slightly reduced after 1 week of treatment with bosentan. The reduction was 12% on average with a narrow 95% confidence interval of 0-23%. Bosentan pharmacokinetic parameters after 1 week of treatment were as expected with a mean Cmax of 3260 microg l-1 and a mean AUC (0, 12h) of 12 600 microg l-1 h. CONCLUSIONS: Treatment with bosentan 500 mg twice daily for 1 week did not show clinically relevant effects on the pharmacokinetics of digoxin in healthy human subjects

Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients.

PURPOSE: In the present study the possible influence of the antacid Maalox on the pharmacokinetics of capecitabine (Xeloda) and its metabolites was investigated in cancer patients. METHODS: A total of 12 patients with solid, predominantly metastatic tumors of various origin received a single oral dose of 1250 mg/m2 of capecitabine (treatment A), a single oral dose of 1250 mg/m2 of capecitabine followed immediately by 20 ml of Maalox (treatment B), and a single oral dose of 1250 mg/m2 of capecitabine followed 2 h later by 20 ml of Maalox (treatment C) in an open, randomized, three-way cross over fashion. Serial blood and urine samples were collected for up to 24 h after each administration. Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chromatography/mass spectrometry and in urine using nuclear magnetic resonance spectroscopy. RESULTS: Administration of Maalox either concomitantly with capecitabine or delayed by 2 h did not influence the time to peak plasma concentrations (Cmax) or the elimination half-lives of capecitabine and its metabolites. Unexpectedly, moderate increases in the Cmax and AUC0-infinity values obtained for capecitabine and 5'-deoxy-5-fluorocytidine were observed when Maalox was given together with capecitabine. However, these increases, which ranged between 10% and 31%, were not statistically significant (P > 0.05) and are not of clinical significance. There was no indication of consistent changes in the plasma concentrations of the other metabolites 5'-deoxy-5'-fluorouridine (5'-DFUR), 5-fluorouracil, and alpha-fluoro-beta-alanine. The Cmax and AUC0-infinity values recorded for these three metabolites increased and decreased in a stochastic manner. The magnitude of these changes was low (<13%) and not statistically significant. The primary statistical analysis of the AUC0-infinity obtained for 5'-DFUR provided a P value of 0.4524 and clearly indicated no significant difference between the treatments. The addition of Maalox had no influence on the overall urinary recovery or the proportion of the dose recovered as capecitabine or its metabolites from urine. CONCLUSION: At the dose used in this study, the effect of concomitantly delivered Maalox on the extent and rate of gastrointestinal absorption of capecitabine is not clinically significant. Therefore, there is no need to adjust the dose or timing of capecitabine administration in patients treated with Maalox.

Mibefradil pharmacokinetic and pharmacodynamic population analysis.

Mibefradil is a new T-channel selective calcium antagonist effective in the treatment of hypertension and chronic stable angina pectoris. In this study steady-state plasma mibefradil concentrations and pharmacodynamic measurements were obtained from American and European clinical studies and analyzed using NONMEM. Doses ranged from 12.5-200 mg orally once-daily. A linear one-compartment pharmacokinetic model with first-order absorption was employed. Best parameter estimates were as follows: absorption rate-constant = 2.7 hours-1, clearance = 5.7 L/hour, volume of distribution = 179 L. The bioavailability of the 25 mg oral dose relative to higher doses was 0.83. Conclusions based on the Emax model equations were that at average plasma concentrations achieved clinically (approximately 300 ng/ml and approximately 600 ng/ml for 50 and 100 mg/day, respectively) the effect on heart rate is near maximum, the effect on blood pressure is about 50% of maximum, and the effect on PQ interval is small. The model also predicts that diastolic blood pressure and heart rate reductions will tend to be greater in patients with higher baseline values and with increasing mibefradil plasma concentrations. The increase in PQ interval is strongly related to plasma mibefradil concentration. The population analysis shows that mibefradil pharmacokinetics and pharmacodynamics were not affected in a clinically relevant manner by demographic characteristics.