Biomedical subjects

A Sparreboom

Publications and source records attributed to A Sparreboom.

At least 19 recordsLinked to original sources

PubMed2002

Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38.

We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.

Adult↗

PubMed2002

The use of oral cytotoxic and cytostatic drugs in cancer treatment.

Although with a few exceptions, most new anticancer agents are initially developed for intravenous use, oral treatment with anticancer agents is, if feasible, to be preferred, as this route of administration is convenient to patients, reduces administration costs and facilitates the use of more chronic treatment regimens. Recent studies have identified various physiological barriers limiting the oral absorption of anticancer drugs. Presently, several strategies are explored to alter the low and variable oral bioavailability of several important anticancer agents by taking advantage of an intentional interaction between anticancer agents and drugs that modulate active intestinal drug transporters or (intestinal) enzymes.

Administration, Oral↗

PubMed2002

Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies.

The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.17 ml/kg, intravenous (i.v.)) given in combination with cisplatin (10 mg/kg, intraperitoneal (i.p.)) did not change the pharmacokinetics of cisplatin. Cisplatin-induced haematological toxicity, expressed as white blood cells (WBC) at nadir, was significantly reduced by CrEL from 5.05+/-0.95 to 6.50+/-1.31 x 10(9)/l (P=0.0009). Data obtained from cancer patients treated with cisplatin (70 mg/m(2), 3-h i.v.) and topotecan (0.45 or 0.60 mg/m(2)/day x 2) preceded by CrEL (12 ml, 3-h i.v.) (n=6) or without CrEL (n=10) similarly indicated significant differences in the percent decrease in WBC between the groups (46.5+/-18.7 versus 67.2+/-15.0%; P=0.029). Likewise, the percent decrease in platelet count was significantly greater in the absence of CrEL (23.9+/-5.38 versus 73.3+/-15.5%; P=0.0003). Pharmacokinetic parameters of unbound and total cisplatin and of topotecan lactone and total drug were not significantly different from historic control values (P>or=0.245). Overall, this study provides further evidence on the important role of CrEL in the pharmacological and toxicological profile of cisplatin, and implies that reformulation of cisplatin with CrEL for systemic treatment might achieve an improvement of its therapeutic index, particularly in the setting of a weekly dose-dense concept.

Animals↗

PubMed2002

Phase I pharmacokinetic and sequence finding study of the combination of docetaxel and methotrexate in patients with solid tumours.

This phase I study was performed to assess the feasibility and possible enhanced antitumour activity of the sequential administration of methotrexate (MTX) and docetaxel (D) in patients with solid tumours. Pharmacokinetic analysis was performed to investigate the pharmacokinetic interaction of the two agents. A total of 22 patients were enrolled, a total of six dose levels were investigated. MTX (days 1+15) 30, 40 and 50 mg/m(2)+D (day 2 or day 1) 75 and 85 mg/m(2) with supportive care measures. Both haematological and non-haematological toxicities were significant, preventing dose escalation above MTX 40 mg/m(2)+D 75 mg/m(2). Four partial responses were documented, three in patients with breast cancer, one in a patient with urothelial cell cancer. Pharmacokinetic data did not give an explanation for the significant toxicity as they revealed no interaction of D and MTX kinetics. Methotrexate and 7-OH MTX kinetics seemed to be independent of the administration of D and the moment of D administration appeared not to influence MTX kinetics. The sequential administration of MTX and D results in significant toxicity without any evidence of a clinical benefit.

Adult↗

PubMed2002

Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933.

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.v.) administered R101933, and determined the disposition of docetaxel with and without the P-gp inhibitor. Patients received i.v. R101933 alone at a dose escalated from 250 to 500 mg on day 1 (cycle 0), docetaxel 100 mg/m(2) as a 1-h infusion on day 8 (cycle 1) and the combination every 3 weeks thereafter (cycle 2 and further cycles). 12 patients were entered into the study, of whom 9 received the combination treatment. Single treatment with i.v. R101933 was associated with minimal toxicity consisting of temporary drowsiness and somnolence. Dose-limiting toxicity consisting of neutropenic fever was seen in cycles 1 and 2 or in further cycles at both dose levels. The plasma pharmacokinetics of docetaxel were not changed by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 22.5+/-6.2 l/h/m(2) and 24.2+/-7.4 l/h/m(2) (P=0.38) in cycles 1 and 2, respectively. However, the faecal excretion of unchanged docetaxel decreased significantly after the combination treatment from 2.5+/-2.1% to less than 1% of the administered dose of docetaxel, most likely due to inhibition of the intestinal P-gp by R101933. Plasma concentrations of R101933 were not different in cycles 0 or 2 and the concentrations achieved in the first 12-h period after i.v. infusion were capable of inhibiting P-gp in an ex vivo assay. We conclude that the combination of 100 mg/m(2) i.v. docetaxel and 500 mg i.v. R101933 is feasible, lacks pharmacokinetic interaction in plasma, and shows evidence of P-gp inhibition both in an ex vivo assay and in vivo as indicated by the inhibition of intestinal P-gp.

Adult↗

PubMed2002

Dosing strategies for anticancer drugs: the good, the bad and body-surface area.

Most anticancer drugs are characterised by a narrow therapeutic window; hence, a small change in dose can lead to poor antitumour effects or an unacceptable degree of toxicity. The rationale for using body surface area (BSA) to dose antineoplastic agents is to normalise the effects of drugs, and accordingly, it has been routinely employed as the only independent variable. In the last 10 years, however, several studies have shown a poor relationship of BSA for predicting drug exposure, and an irrelevant correlation between this variable and pharmacokinetic (PK) parameters. In this paper, the results of this relationship for various commonly used antineoplastic agents are reviewed, and the influence of BSA to decrease the total variability in clearance among patients is underlined. As reported, BSA failed to individualise the effects of the majority of the agents explored. The criteria that can predict a clinically meaningful relationship between BSA and drug clearance are discussed, and some alternative strategies to dose agents when BSA has proven to be useless are proposed.

Antineoplastic Agents↗

PubMed2002

Dose-dense cisplatin/paclitaxel. a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer.

A randomised phase I/II trial with weekly cisplatin 70 mg/m(2) (days 1, 8, 15, 29, 36, 43) in combination with escalating doses of paclitaxel either 4-weekly or weekly was conducted in 49 patients with ovarian cancer; patients were chemotherapy-nai;ve or had a first relapse after platinum-based chemotherapy. Paclitaxel could be safely escalated to 225 mg/m(2) 4-weekly or 100 mg/m(2) weekly, with fatigue as the major adverse event. Myelosuppression, renal toxicity and neurotoxicity were mild to moderate. Pharmacokinetic analysis showed an approximately 2-fold reduction of DNA-adduct formation in leucocytes compared with cisplatin without paclitaxel. No pharmacokinetic interaction was found between paclitaxel and cisplatin. After (re-)induction, additional chemotherapy consisted of conventional paclitaxel/cisplatin, paclitaxel/carboplatin, paclitaxel single agent or carboplatin/cyclophosphamide. The overall response rate was 94% in 17 evaluable chemotherapy-nai;ve patients and 84% in 25 patients with recurrent disease. Median progression-free survival (PFS) was 17 months (chemotherapy-nai;ve: 23 months, recurrent: 11 months) and median overall survival was 41 months (chemotherapy-nai;ve: 48 months, recurrent: 24 months). In conclusion, both cisplatin/paclitaxel regimens showed excellent activity with manageable toxicity in patients with advanced ovarian cancer.

Adult↗

PubMed2001

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer.

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m(-2) d(-1) on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m(-2) d(-1), experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m(-2) d(-1)) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m(-2) d(-1)). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m(-2)d(-1) in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.

Administration, Oral↗

PubMed2001

Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy.

In view of the similarity in chemical structure of the available 5HT(3)-receptor antagonists it is assumed, whilst these agents all act at the same receptor, that failure to one agent would predict subsequent failure to all 5HT(3)-receptor antagonists. We conducted a randomized double blind trial of granisetron 3 mg plus dexamethasone 10 mg versus continued treatment with ondansetron 8 mg plus dexamethasone 10 mg in patients with protection failure on ondansetron 8 mg plus dexamethasone 10 mg during the first 24 hours following highly emetogenic chemotherapy. Of 40 eligible patients, 21 received ondansetron + dexamethasone and 19 received granisetron + dexamethasone. We found a significant benefit from crossing-over to granisetron after failure on ondansetron. Of the 19 patients who crossed over to granisetron, 9 patients obtained complete protection, whereas this was observed in 1 of the 21 patients continuing ondansetron, P = 0.005. These results indicate that there is no complete cross-resistance between 5HT(3)-receptor antagonists, and that patients who have acute protection failure on one 5HT(3)-receptor antagonist should be offered cross-over to another 5HT(3)-receptor antagonist.

Adult↗

PubMed2001

Mechanism-based pharmacokinetic model for paclitaxel.

PURPOSE: To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia. PATIENTS AND METHODS: Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively. RESULTS: The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug. CONCLUSION: Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.

Adult↗

PubMed2001

Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure.

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m(2) (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non-protein-bound cisplatin in plasma by atomic absorption spectrometry. RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL(free)) was 57.1 +/- 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m(2) (mean, 1.86 +/- 0.19 m(2)), with an interpatient variability of 10.4%. When CL(free) was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL(free) and BSA (r = 0.42). Intrapatient variability in CL(free), calculated from 90 patients was 12.1% +/- 7.8% (range, 0.30% to 32.7%). CONCLUSION: In view of the high interpatient variability in CL(free) relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

Adult↗

PubMed2001

Liquid chromatographic determination of ketoconazole, a potent inhibitor of CYP3A4-mediated metabolism.

A high-performance liquid chromatographic assay with UV detection has been developed for the determination of ketoconazole in human plasma. Quantitative extraction was achieved by a single solvent extraction involving a mixture of acetonitrile-n-butyl chloride (1:4, v/v). Ketoconazole and the internal standard (clotrimazole) were separated on a column packed with Inertsil ODS-80A material and a mobile phase composed of water-acetonitrile-tetrahydrofuran-ammonium hydroxide-triethylamine (45:50.2:2.5:0.1:0.1, v/v). The column effluent was monitored at a wavelength of 206 nm with a detector range set at 0.5. The calibration graph was linear in the range of 20-2000 ng/ml, with a lower limit of quantitation of 20.0 ng/ml. The extraction recoveries for ketoconazole and clotrimazole in human plasma were 93+/-9.7% and 83+/-10.0%, respectively. The developed method has been successfully applied to a clinical study to examine the pharmacokinetics of ketoconazole in a cancer patient.

Chromatography, Liquid↗

PubMed2001

Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.

Administration, Oral↗

PubMed2001

Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles.

Nonlinear disposition of paclitaxel (Taxol) in cancer patients has been described in several studies, but the underlying mechanism is still a matter of speculation. Previously, we have shown in vitro that the paclitaxel formulation vehicle, Cremophor EL (CrEL), alters the blood distribution of paclitaxel as a result of entrapment of the compound in circulating CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. Based on these findings, we prospectively re-evaluated the linearity of paclitaxel disposition in patients using whole blood and plasma analysis, and sought to define a new pharmacokinetic model to describe the data. Seven patients with solid tumors were treated with paclitaxel infused over 3 h, each at consecutive 3-weekly dose levels of 225, 175 and 135 mg/m2 (CrEL dose level, 18.8, 14.6, and 11.3 ml/m2, respectively). Patient samples were collected up to 24 h after the start of infusion, and analyzed by high-performance liquid chromatography. Paclitaxel peak levels and areas under the curve in whole blood increased linearly with dose, whereas plasma levels showed substantial deviation from linearity. This was shown to be caused by a CrEL concentration-dependent decrease in paclitaxel uptake in blood cells, as reflected by the blood:plasma concentration ratios which altered significantly from 0.83 +/- 0.11 (at 135 mg/m2) to 0.68 +/- 0.07 (at 225 mg/m2). It is concluded that the nonlinear disposition of paclitaxel is related to paclitaxel dose-related levels of the formulation vehicle CrEL, leading to a disproportionate drug accumulation in the plasma fraction. The pharmacokinetic model developed accurately described the data, and will help guide future development and refinement of clinical protocols, especially in defining the exposure measure best linked to paclitaxel effects and toxicities.

Adult↗

PubMed2001

The (ir)relevance of plasma protein binding of anticancer drugs.

The major purpose of therapeutic drug monitoring is to enable drug dosage individualization for differences among patients in rates of drug metabolism and/or excretion. The standard analytical methods for measuring concentrations of drugs in plasma determine drug bound to plasma proteins as well as free drug dissolved in plasma water. For this reason, the relationship between total drug concentration in plasma and treatment outcome (i.e. toxicity and efficacy) will only be good if the degree of plasma protein binding of the agent is constant, or if so little drug is protein bound that changes in binding make insignificant changes in unbound concentration. A review of available literature data indicates that, in general, protein binding of anticancer drugs is not of principal clinical relevance. However, there are several instances, in which monitoring of unbound concentrations might be useful: (i) agents demonstrating protein-concentration-dependent binding, (ii) agents that bind irreversible or near covalently, (iii) when formulation excipients modulate unbound drug levels, and (iv) metabolically interconvertible agents. While available evidence suggests that for these agents unbound drug levels correlate better with clinical effects than total plasma concentrations, there are insufficient data to justify the recommendation of the routine use of unbound drug concentration monitoring for any of these agents at present.

Antineoplastic Agents↗

PubMed2001

Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation.

Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy. The pharmacokinetic behaviour of CrEL is dose-independent, although its clearance is highly influenced by duration of the infusion. This is particularly important since CrEL can affect the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation. In addition, it has been shown that CrEL, as an integral component of paclitaxel chemotherapy, modifies the toxicity profile of certain anticancer agents given concomitantly, by mechanisms other than kinetic interference. A clear understanding of the biological and pharmacological role of CrEL is essential to help oncologists avoid side-effects associated with the use of paclitaxel or other agents using this vehicle. With the present development of various new anticancer agents, it is recommended that alternative formulation approaches should be pursued to allow a better control of the toxicity of the treatment and the pharmacological interactions related to the use of CrEL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Combination chemotherapy of the taxanes and antimetabolites: its use and limitations.

In an effort to improve response rates of chemotherapy, taxanes have been combined with other cytotoxic agents such as antimetabolites. However, the use of some of these combinations in patients has been restricted by severe toxicity. The significance of the sequence of drug administration in combining methotrexate (MTX) and taxanes was recognised in in vitro studies, showing synergistic effects for the sequence of MTX followed by paclitaxel, and antagonism for exposure in the reverse order. A possible explanation might be an MTX-induced synchronisation of cells in the S phase of the cell cycle, after which cells are more susceptible for the cytotoxic action of taxanes. Clinical studies using this sequence were hampered by severe neutropenia and mucositis at relatively low doses of both drugs. As no pharmacokinetic interactions were observed, the excess of toxicity may have been due to sequence-dependent synergistic actions on bone marrow and mucosa. In contrast, and confusingly, in vitro studies on 5-fluorouracil (5-FU) and taxanes indicate that 5-FU preceeding or simultaneously given to paclitaxel impairs cytotoxicity as compared with paclitaxel monotherapy, while the reverse sequence results in additive or synergistic cytotoxicity. While almost all clinical studies have used the sequence of a taxane followed by 5-FU, various schedules appeared feasible and effective. The combination of a 5-FU analogue, capecitabine and taxanes was supported by in vitro data. A large phase III trial confirmed the feasibility and superior efficacy of this combination in breast cancer patients relapsing after an anthracycline. Conflicting results exist on the benefit of combining gemcitabine and taxanes in tumour cell lines. Although the accumulation of gemcitabine triphosphate (dFdCTP) in mononuclear cells was significantly higher with an increasing dose of paclitaxel, no pharmacokinetic interactions for both agents were noticed. A pharmacokinetic analysis of the gemcitabine-docetaxel combination therapy has not been published in detail. Despite numerous trials, so far no optimum schedule has been established. Regarding data on actually delivered dose intensities, a 2- or 3-weekly cycle seems favourable and feasible. However, possible severe pulmonary toxicity warrants cautious monitoring of patients treated with this combination. Different outcomes of preclinical and clinical studies reveal that combining two chemotherapeutic agents is not simply a matter of putting antitumour activities together. Drug interaction may result in synergism, not only of efficacy but also of toxic side-effects. Adding two drugs may also implicate antagonism in drug efficacy due to unwanted interference in cytotoxicity or pharmacokinetics. For agents acting at a specific phase of the cell cycle, the sequence of administration may determine the efficacy and toxicity of a combination therapy. Because of an observed discrepancy between in vitro data and clinical studies, we would like to emphasise the need for adequate dose-finding clinical trials together with pharmacokinetic data analysis before examining any new combination chemotherapy in more detail in phase II studies.

Antimetabolites, Antineoplastic↗

PubMed2001

Role of formulation vehicles in taxane pharmacology.

The non-ionic surfactants Cremophor EL (CrEL) and Tween 80, both used as formulation vehicles of many (anticancer) agents including paclitaxel and docetaxel, are not physiological inert compounds. We describe their biological properties, especially the toxic side effects, and their pharmacological properties, such as modulation of P-glycoprotein activity. In detail, we discuss their influence on the disposition of the solubilized drugs, with focus on CrEL and paclitaxel, and of concomitantly administered drugs. The ability of the surfactants to form micelles in aqueous solution as well as biological fluids (e.g. plasma) appears to be of great importance with respect to the pharmacokinetic behavior of the formulated drugs. Due to drug entrapment in the micelles, plasma concentrations and clearance of free drug change significant leading to alteration in pharmacodynamic characteristics. We conclude with some perspectives related to further investigation and development of alternative methods of administration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗