Evaluation of real-time data obtained from gravimetric preparation of antineoplastic agents shows medication errors with possible critical therapeutic impact: Results of a large-scale, multicentre, multinational, retrospective study.

WHAT IS KNOWN AND OBJECTIVE: Medication errors are a significant cause of morbidity and mortality especially with antineoplastic drugs, owing to their narrow therapeutic index. Gravimetric workflow software systems have the potential to reduce volumetric errors during intravenous antineoplastic drug preparation which may occur when verification is reliant on visual inspection. Our aim was to detect medication errors with possible critical therapeutic impact as determined by the rate of prevented medication errors in chemotherapy compounding after implementation of gravimetric measurement. DESIGN: A large-scale, retrospective analysis of data was carried out, related to medication errors identified during preparation of antineoplastic drugs in 10 pharmacy services ("centres") in five European countries following the introduction of an intravenous workflow software gravimetric system. Errors were defined as errors in dose volumes outside tolerance levels, identified during weighing stages of preparation of chemotherapy solutions which would not otherwise have been detected by conventional visual inspection. KEY RESULTS: The gravimetric system detected that 7.89% of the 759 060 doses of antineoplastic drugs prepared at participating centres between July 2011 and October 2015 had error levels outside the accepted tolerance range set by individual centres, and prevented these doses from reaching patients. The proportion of antineoplastic preparations with deviations >10% ranged from 0.49% to 5.04% across sites, with a mean of 2.25%. The proportion of preparations with deviations >20% ranged from 0.21% to 1.27% across sites, with a mean of 0.71%. There was considerable variation in error levels for different antineoplastic agents. WHAT IS NEW AND CONCLUSION: Introduction of a gravimetric preparation system for antineoplastic agents detected and prevented dosing errors which would not have been recognized with traditional methods and could have resulted in toxicity or suboptimal therapeutic outcomes for patients undergoing anticancer treatment.

Disposition of Erlotinib and Its Metabolite OSI420 in a Patient with High Bilirubin Levels.

Erlotinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for the treatment of non-small cell lung cancer and when combined with gemcitabine for pancreatic cancer. Dose reduction of erlotinib in patients with severe hepatic impairment has been established. We present the case of a male patient suffering from an adenocarcinoma of the pancreas with metastases in the liver and lung, whose disease progression led to highly elevated bilirubin levels of >14 mg/dl accompanied by icterus and pruritus. Despite the known contraindication, the patient agreed to be treated with 150 mg erlotinib p.o. per day. We performed therapeutic drug monitoring of erlotinib on day 1 after the first ingestion of erlotinib and then over a period of 19 days. One-compartment pharmacokinetics on day 1 were calculated, and, based on these data, a pharmacokinetic simulation for the following 19 days was run. On day 1 after the first erlotinib ingestion, plasma concentrations were identical to those described in the literature. On the following days, erlotinib plasma concentrations remained at a similar order of magnitude after daily ingestion. Compared with published data, OSI420 plasma concentrations were clearly higher from day 1 to 16. Due to disease progression, the last intake of erlotinib was on day 16, but plasma concentrations of the drug and metabolite increased excessively thereafter. The data give evidence that total bilirubin levels up to 14 mg/dl do not necessarily cause elevated plasma concentrations of erlotinib when given in doses of 150 mg per day.

Metabolic activation of irinotecan during intra-arterial chemotherapy of metastatic colorectal cancer.

Biotransformation of irinotecan (CPT-11) into its pharmacologic active metabolite SN-38 was investigated in patients treated for advanced colorectal cancer. A dose of 180 mg/m(2) CPT-11 was administered to 6 patients by 60 min hepatic intra-arterial infusion (HAI) via a surgically implanted Port-a-Cath® system. Blood samples were collected from 0 to 360 min after start of HAI, and CPT-11 plus metabolites were analysed by a selective reversed phase HPLC method. The objective of this study was to evaluate the extent to which SN-38 is generated after HAI of irinotecan given at a low dose of 180 mg/m(2). In a second investigation, CPT-11 was administered via conventional intravenous infusion (dose 180 mg/m(2), 60 min infusion time, 11 patients) and CPT-11 plus metabolites were quantified using identical analytical procedure. Compared to i.v. infusion, the pharmacokinetics of CPT-11 and SN-38 were altered by HAI. The mean c(max) of CPT-11 after HAI was reduced by 37%, whereas the mean c(max) of SN-38 increased by 60%. HAI resulted in a desired, increased metabolic conversion of CPT-11 into SN-38 and might improve the regional availability of the pharmacologic active metabolite SN-38 at the site of tumor. Plasma concentrations of the metabolites SN-38 glucuronide and APC remained unaffected by the route of administration.

Disposition of paclitaxel (Taxol) and its metabolites in patients with advanced breast cancer (ABC) when combined with trastuzumab (Hercpetin).

Monoclonal antibodies are capable of modulating drug metabolising enzymes resulting in unexpected plasma concentrations of a drug when given concomitantly. Therefore plasma concentration of paclitaxel (PTX) and its metabolites has been monitored in 10 patients with advanced breast cancer during treatment with PTX alone or combined with trastuzumab (TMAB, paired cross over design). Compared to the MONO regimen PTX peak plasma concentrations were about 25% lower in the TMAB schedule: cmax = 3294 +/- 1174 ng/ml (MONO: 4368 +/- 1887 ng/ml). TMAB also caused lower peak plasma concentration of the main metabolite 6-hydroxy PTX (248 +/- 89 ng/ml) compared to the MONO schedule (194 +/- 82 ng/ml). Cmax of the minor metabolites was distinctly below 100 ng/ml and consequently differed negligible in both schedules. The similar apparent formation rate of the metabolites in both schedules (range from 30 to 50 min) as well as identical tmax values (range 170-190 min) suggested that TMAB had no influence on PTX metabolism. In accordance to plasma concentrations, AUClast of PTX was lower in the MONO schedule (733 +/- 197 microg/ml*min, AUClast = 669 +/- 248 microg/ml*min for TMAB) but without significance. In summary no indices for an altered plasma disposition of PTX and its metabolites could be found when TMAB was given concomitantly.

Long-term pharmacokinetics of doxorubicin HCl stealth liposomes in patients after polychemotherapy with vinorelbine, cyclophosphamide and prednisone (CCVP).

The concentration-time profiles of Doxorubicin (DOXO) from day 0 to day 21 after i.v. infusion of 25 or 30 mg/m2 doxorubicin HCI stealth liposomes (Caelyx) were investigated in 9 patients receiving combination polychemotherapy with cyclophosphamide, vinorelbine and prednisone. Peak serum concentrations occurred from 0.04 to 4.0 days after infusion (mean tmax = 1.79 +/- 1.55 d) with a mean cmax of 4,595 +/- 2,849 ng/ml. A total amount of 12.84 +/- 2.47 mg liposomal DOXO in the plasma volume (Vp = 2,794 + 537 ml) could be estimated at tmax (= 27 % of the mean dose of 47.6 mg). Stealth liposomes were eliminated slowly from the blood with a mean t 1/2el of 1.9 + 0.5 days (MRT was 4.6 + 2.5 days). AUClast values ranged from 8,070 to 33,446 ng/ml*d (mean 10,987 +/- 9,339 ng/ml*d). The low plasma clearance (Cltot = 4,681 +/- 2,835 ml/day) and the small volume of distribution (Vz = 11.7 +/- 6.31) suggested that stealth-liposomes were stable in the blood at least for 14 days. Polychemotherapy with Hyper-CCVP schedule did not alter the stability of stealth liposomes, but peak levels of DOXO seemed to be somewhat lower compared to regression analysis of literature data (cmax versus dosage range from 20 to 60 mg/m2). Due to clast occurring between day 12 to 18, no indices for an accumulation of the drug in the blood could be found, when liposomes were given every four weeks.

Clinical pharmacokinetics and metabolism of paclitaxel after polychemotherapy with the cytoprotective agent amifostine.

BACKGROUND: Cytoprotection of healthy cells represents a new approach in cancer chemotherapy, but a pharmacokinetic drug interaction between the cytostatic and the cytoprotectant is undesired. METHODS: The purpose was to evaluate the clinical pharmacokinetics (PHK) of paclitaxel (PACLI) and its metabolites under cytoprotection in patients suffering from breast cancer. PACLI was administered alone and in a second cycle in combination with amifostine (AMI) as a paired cross over. RESULTS: In both treatment schedules the steady state of PACLI occurred after 3 hours, the tmax of metabolites between 3 and 4 hours. The mean steady-state concentration was cmax = 5432 +/- 1238 ng/ml in the control group and cmax = 5140 +/- 2407 ng/ml in the AMI group. For the serum metabolites, the findings were very similar: 6-OH-PACLI: cmax 413 +/- 153 ng/ml versus 432 +/- 304 ng/ml, 3"-OH-PACLI: cmax 99 +/- 103 ng/ml versus 123 +/- 98 ng/ml, 3",6-DiOH-PACLI: cmax 43 +/- 55 ng/ml versus 75 +/- 85 ng/ml. AUC values of metabolites were slightly higher in the AMI group, but PHK seemed equal. CONCLUSION: The results gave evidence, that cytoprotection with AMI has no clinical consequences on PACLI pharmacokinetics and biotransformation.

Clinical significance of pharmacokinetic drug interactions between interferon-alpha and antineoplastic drugs.

The major problems in chemotherapy are occasional low response rates in patients despite favourable in vitro action, the development of drug resistance and long or short term adverse effects. Therefore, in the past decade efforts have been made to circumvent these problems by combining antineoplastic drugs with biomodulating or cytoprotective agents. Most of the clinically useful drug regimens consist of a cocktail of drugs with different mechanisms of action, and hence different toxicity profiles. Dose-limiting factors in regard to toxicity and therapeutic efficacy predominate, and it is therefore clinically essential to know whether or not a pharmacokinetic drug interaction occurs. The introduction of interferon-alpha (IFNalpha) in chemotherapy is an alternative investigational approach to amplify the cytotoxicity of an antineoplastic drug in order to increase tumour response. Most of the clinical studies reported with IFNalpha provide useful information and identify major pharmacodynamic interactions, but only a few focus on and report potential pharmacokinetic interactions between antineoplastic drugs and IFNalpha in patients. The broad spectrum of antineoplastic drugs whose activity can be enhanced by IFNalpha argues for multiple levels of drug-drug interactions: protein binding (cisplatin), alteration in cellular uptake, modulation of drug target enzymes (dihydropyrimidine hydrogenase) and changes in biotransformation (tretinoin) or excretion. Pharmacokinetic and/or pharmacodynamic interactions may be beneficial (fluorouracil) or sometimes detrimental and coincidental (doxorubicin). This article focuses on observed pharmacokinetic drug interactions between IFNalpha and antineoplastic drugs and discusses possible mechanisms of action.

[Binding of epirubicin to human plasma protein and erythrocytes: interaction with the cytoprotective amifostine]. / In vitro-Untersuchungen zur Bindung von Epirubicin an humane Plasmaproteine und Erythrozyten: Interaktion mit dem Zytoprotektivum Amifostin.

The in vitro binding rate of epirubicin (EPR) to different plasma proteins, control serum, red blood cells and whole blood was investigated without and with the cytoprotective agent amifostine. The binding rate of EPR to plasma proteins fractions and red blood cells dependend on the concentration of the matrix components. EPR was bound more than 90% to human serum alpha-globulin (alpha-HSG), to human serum albumine (HSA) and human serum beta-globuline (beta-HSG) at 80 to 90%, in the case of human serum gamma-globulin (gamma-HSG) the binding rate amounted 75%. The binding rate of EPR to RBCs in whole blood samples reached 38%. Within the observed concentration range of proteins (1-40 micrograms/ml, depending on the protein concentration) AMI caused a reduction of the protein-bound amount of EPR in the range from 2 to 19% of HSA, 4 to 20 in the case of beta-HSG, 2 to 32% in the case of alpha-HSG and 17 to 21% for gamma-HSG. In the whole blood samples the binding of EPR to proteins dropped from 45 to 32% and RBC-partitioning from 38 to 32%. Two compounds with free thiol groups, cystein and glutathione, were compared with AMI in regard to lowering the binding rate of EPR to HSA: the effect was exactly in the same order of magnitude: -17% for AMI, -21.0% for cystein and -20.8% for glutahion (p < 0.002). For a negative control, cystin and phenylalanin were tested, too: both compounds showed no influence on the protein binding of EPR: 63.8% binding rate in the control group, 65.2% in the presence of cystin and 64.6% in the presence of phenylalanin (statistically not significant). The present results indicate, that binding of EPR to serum proteins is reduced in the presence of AMI by interaction of the thiol-group with the protein and that the thiophosphoric ester bond in the test solution must cleave rapidly.

Disposition of 5-formyl- and 5-methyltetrahydrofolic acid in serum after i.v. bolus of calcium folinate: pharmacokinetic drug interaction with preadministered interferon-alpha-2b.

The influence of interferon (IFN) coadministered subcutaneously with the biomodulating agent folinic acid on the blood serum levels of 5-formyl-tetrahydrofolic acid (CHO-THFA) and the biotransformation into its main metabolite in the blood 5-methyltetrahydrofolic acid (CH3-THFA) was studied in patients receiving a chemotherapy with 5-fluorouracil. IFN causes a clear decrease of the serum concentrations of CHO-THFA and a statistically significant decrease of CH3-THFA concentrations (P < 0.01). The effect on serum concentrations could be observed in each patient, but in a different order of magnitude. As a consequence, the preadministration of IFN leads to a significant change in the basic pharmacokinetic parameters of both compounds: the mean area under the concentration-time curve is decreased at 27.4% for CHO-THFA (P < 0.025) and at 22.4% for CH3-THFA (P < 0.025), respectively. The total body clearance is elevated at 45.4% for CHO-THFA (P < 0.05) and at 23.4% for CH3-THFA (P < 0.05). The mean volume of distribution is increased by IFN at 38.2% for CHO-THFA (P < 0.025) and at 22.3% for CH3-THFA (P < 0.05). The nearly identical mean residence time in both groups indicates that CHO-THFA elimination is not affected by IFN. But the results prove a certain interaction between IFN and CHO-THFA. IFN accelerates the distribution of CHO-THFA as well as of its main metabolite from the blood into the tissue or activates the biotransformation of CHO-THFA into CH3-THFA inside the cells of the tissue. The extent of biotransformation of CHO-THFA into CH3-THFA, which takes place in the blood, is not influenced by IFN because percentage AUC-ratios CHO-THFA:CH3-THFA were 89.5:10.5% for the control group and 88.8:11.2% for the IFN group.

Pharmacokinetic interaction between 4'-epidoxorubicin and the multidrug resistance reverting agent quinine.

The serum and red blood cell (RBCs) disposition of epirubicin (EPR) after intravenous bolus injection without and with coadministered quinine ( QUI) was investigated in patients undergoing a cyclic chemotherapy with EPR. QUI possesses a statistical significant influence on the EPR serum concentrations and, as a consequence, on the pharmacokinetic parameters for the initial distribution phase of EPR. Within the first 15 min after administration, EPR was distributed from the central compartment distinctly faster in compare to the control, when QUI was preadministered (t(1/2) = 6 min for the control group and t(1/2) = 3 min with QUI; -46%, p < 0.05). Yet, in the beta-phase when drug-elimination predominates, no statistical significant influence of QUI in regard to EPR serum and RBC concentrations could be observed. Half-life of elimination was 0.5 h for the control group and 8.6 h for the QUI group (-10%). The mean initial serum concentration (co) was reduced significantly by QUI from 7359 +/- 506 ng/ml to 4351 +/- 1682 ng/ml (-42%, p < 0.005). Furthermore, QUI caused a reduction of the serum bioavailability of EPR (expressed as AUC(o-24)-values) from 3404 +/- 1008 ng/ml x h to 2359 +/- 1073 ng/ml x h (-31%, p < 0.05). Vd and Vdbeta were increased at about 90% and the mean total body clearance was accelerated from 45.3 to 1487 ml/min, but due to the large standard deviations the calculated difference for these parameters was not statistically significant. In the observed time interval of 24 h, the red blood cell coefficient of distribution k(rbc) of EPR was lower if QUI was coadministered (k(rbc) = 1.25 +/- 0.12 for the control group k(rbc) = 1.15 +/- 0.13 under QUI; p < 0.04). The results point out that QUI induces an accelerated distribution of EPR from the blood into the tissue and that QUI additionally may have influence on the red-blood cell partitioning of EPR.

[Drug interactions between interferon alpha 2b and 5-fluorouracil during continuous intravenous 5FU infusion]. / Arzneistoff-Interaktion zwischen Interferon-alpha-2b und 5-Fluorouracil während fünftägiger intravenöser 5FU-Infusion.

The concentration-time profile of 5-fluorouracil (5FU) in serum of patients during continuous infusion of 5FU for five days was investigated. The coadministration of each of 5 million units interferon-alpha-2b (IFN) on day 2 and 4 of the infusion causes an accumulation of 5FU in the serum at about 120% on day 3 in compare to the control (day 1 of infusion without IFN). On day 5 of the infusion the mean 5FU serum concentrations are about 170% higher than on day 1 with a level of probability ranging from p < 0.0003 to p < 0.043. Mean AUC-values increase from 5454 ng/ml.h (day 1) to 12069 ng/ml.h (day 3, p < 0.05) and subsequently to 14919 ng/ml.h on day 5 (p < 0.005). IFN causes an decrease of the total body clearance from 2949 ml/h (day 1) to 1959 ml/h on day 3 and to 1258 ml/h on day 5 (p < 0.008), respectively. There might exist a linear correlation between the order of magnitude of the 5FU serum concentrations and its pharmacokinetic parameters on day 1, 3 and 5 and the administration of IFN, because a close correlation ranging from R = 0.972 to R = 0.999 have been found in regression analysis.

Pharmacokinetic interaction of 5-fluorouracil and interferon alpha-2b with or without folinic acid.

The purpose of this study was to evaluate a potential pharmacokinetic (PK) interaction between fluorouracil (5-FU) and the biomodulating agent interferon alpha (IFN-alpha) in patients with metastatic colorectal carcinoma. 5-FU was applied as an intravenous bolus injection of 750 mg m-2 weekly and IFN-alpha 2b (IFN) 5 MU was injected 3 times weekly (TIW) subcutaneously. In the first study, 13 patients were treated by this schedule, 5-FU plasma levels were determined by HPLC on day (d) one as baseline before starting IFN; the analysis was repeated at the second or third cycle of 5-FU administration 1 hour after the last IFN injection respectively. In the second study, 10 patients additionally received folinic acid (FA) 200 mg m-2 as a short time infusion immediately before 5-FU, and a third analysis of FU kinetics was performed in order to compare the influence of a double modulation of IFN and FA to IFN alone. Combination of 5-FU and IFN resulted in a significant increase of the AUC of 5-FU (80%) and the fictive initial concentration (C0, 65%) obviously caused by a reduction of 5-FU clearance by 50%. However, when FA was added to this schedule, no significant changes of FU kinetics compared to 5-FU alone could be documented. Finally, in two pilot patients 5-FU 750 mg was given as a continuous infusion (CI) over 5 days and IFN 5 x 10(6) u was added daily from d2 to d5.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic drug interaction between epirubicin and interferon-alpha-2b in serum and red blood cells.

The influence of interferon-alpha-2b (CAS 99210-65-8, IFN) on the pharmacokinetics of epirubicin (CAS 56420-45-2, EPR) was investigated in 10 patients (4 male, 6 female). EPR was injected as an i.v. bolus over 2 min in a dose of 60 mg/m2 IFN was pre-administered 3 times a week in a dose of 5 x 10(6) IU as a s.c. injection. The comparison of the pharmacokinetics after injection of EPR and EPR+IFN did not show remarkable differences. A statistical significant influence in regard to the terminal elimination half-life (gamma-HL) and the total clearance (CLtot) was found, indicating a reduction of gamma-HL from 18.18 +/- 16.7 for EPR to 8.47 +/- 8.67 h for EPR+IFN and a reduction of the total clearance from 72.33 +/- 55.4 ml/min for EPR to 48.41 +/- 12.7 ml/min for EPR+IFN. The area under the concentration-time curve (AUC, according to the 3-compartment model) increases under the influence of IFN from 2004 +/- 1105 ng/ml.h for EPR up to 2582 +/- 1024 ng/ml.h for EPR+IFN. However, this increase is statistically irrelevant due to the high deviation ranges. Besides, the influence of IFN on the interactions of EPR with red blood cells (RBCs) was investigated in 6 patients under the above conditions. The percental concentration of EPR in RBCs is reduced from 35.4% to 34.7% after administration of IFN. Two metabolites, 13-dihydroepirubicin (M I) and 7-deoxydoxorubicinone (M II), were detected both in serum and RBCs, whereas IFN showed no significant interference with the metabolism or with the binding of the metabolites to RBCs.

In vitro and in vivo binding of epirubicin to red blood cells and human plasma proteins.

In this study, the in vitro interaction of epirubicin (EPR), a cytostatic antibiotic, with plasma proteins (PP), namely alpha-HSA, gamma-HSG, alpha+beta-HSG and with isolated human red blood cells (RBCs) was investigated and further correlated with the in vivo pharmacokinetics and binding of EPR and two of its metabolites, 13-dihydroepirubicin and 7-deoxydoxorubicinone to RBCs. The in vitro encapsulation rate in isolated erythrocytes amounts to 52.9 +/- 2.8% and remains constant within the range of studied concentrations (2.5-20 micrograms/ml). EPR was found to bind differently to the various PP in vitro. Binding to alpha-HSA amounted up to 51.0 +/- 7.10%, to alpha+beta-HSG 79.45 +/- 2.7%, to gamma-HSG 57.1 +/- 2.8%. The in vivo-binding rate of EPR, dihydroepirubicin and deoxydoxorubicinone to RBCs after 5 min of injection was 32 +/- 6.96%, 11.6 +/- 3.1% and 10.05 +/- 3.5% respectively, their availability in serum was 42.6 +/- 11.8%, 2.4 +/- 0.4% and 1.2 +/- 0.67% respectively.

Influence of different doses of interferon-alpha-2b on the blood plasma levels of 5-fluorouracil.

The blood plasma levels of 5-fluorouracil (5FU) after i.v. administration have been determined without and under the influence of 1, 5 or 9 million units (MU) preadministered interferon (IFN) in patients with gastrointestinal carcinoma. The co-administration of 9 MU IFN causes a doubled increase of the 5FU serum concentrations combined with a statistically significant change of the pharmacokinetics of 5FU for c0, AUC, Vd and Cltot (P < 0.005). A similar effect with distinctly increased serum concentrations could be observed for the preadministration of 5 mU IFN whereby c0 and AUC were elevated significantly (P < 0.05), but not Vd, Cltot and cd. The preadministration of 1 MU IFN also leads to higher plasma levels, but no changes in the pharmacokinetics of 5FU could be calculated (P > 0.05). A linear correlation between the IFN dose and the pharmacokinetic parameters c0 (R = 0.958), AUC0-120 (R = 0.948), Vd (R = 0.941) and Cltot (R = 0.963) of 5FU could be found (P < 0.05), but not for the coefficient of distribution and t1/2el. The results indicate that the pharmacokinetics of 5FU might be influenced by the preadministered IFN dose.

Pharmacokinetic interaction between epirubicin and the multidrug resistance reverting agent D-verapamil.

The potential for a pharmacokinetic interaction between epirubicin and the second-generation multidrug resistance modulating agent D-verapamil (DVPM) has been investigated in six patients with advanced colorectal cancer. Our results indicate that a significant interaction takes place. Enhanced distribution of epirubicin from the serum and altered disposition might, in fact, explain the increased level of myelotoxicity in this pilot as well as in other clinical phase II studies involving DVPM.

Clinical pharmacokinetics of 5-fluorouracil. Influence of the biomodulating agents interferon, dipyridamole and folinic acid alone and in combination.

The pharmacokinetics of the antimetabolite 5-fluorouracil (5FU, CAS 51-21-8) were investigated under the influence of the biomodulating agents folinic acid (FA), FA combined with dipyridamole (DPM), DPM, interferon-alpha-2b (IFN), and IFN combined with DPM. IFN as well as IFN/DPM cause an enormous increase of the 5FU plasma concentrations resulting in a statistically significant change of the pharmacokinetics. The mean initial plasma concentrations of 5FU are increased at about 143% under the influence of IFN and at 162% under the influence of IFN/DPM. Accordingly, the mean area under the concentration-time curve is elevated at 114% for IFN and at 184% for IFN/DPM. The volume of distribution (IFN - 39%, IFN/DPM - 38%) as well as the total body clearance (IFN - 30%, IFN/IFN - 44%) are lowered distinctly. In contrary, the coadministration of either FA or DPM or FA/DPM to 5FU does not lead to a significant change in the pharmacokinetic profile of 5FU, but also causes higher plasma concentrations. The present results indicate that the coadministration of biomodulators can lead to distinct changes of the 5FU kinetics, but must not be useful in each case.