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The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.

Background: Irinotecan is an effective treatment for metastatic colorectal cancer. However, its use may be associated with troublesome adverse effects such as delayed diarrhoea, acute cholinergic syndrome and neutropenic infection. The manufacturer decided to release irinotecan for compassionate use in The Netherlands prior to its regulatory approval (June 1998) and first introduction for second-line treatment of metastatic colorectal cancer. In view of the drug's adverse effect profile this was done in a carefully controlled manner., Methods: Irinotecan was made available to patients with colorectal cancer with elaborate precautions. Treating physicians requesting irinotecan for compassionate use received a protocol, providing recommendations for the proper use and the prevention/management of potentially troublesome adverse events. Limited demographic, toxicity and efficacy data were collected., Results: Between June 1997 and September 1998, 112 patients were registered for this programme, 103 of whom actually received irinotecan. The percentage of patients experiencing grade 3-4 adverse effects was relatively low: delayed diarrhoea in 17%, nausea and vomiting 17%, acute cholinergic syndrome 6%, febrile neutropenia 4% and neutropenic infection 2%. Five partial tumour responses and a high proportion of patients with 'no change' were noted., Conclusions: The carefully controlled release of irinotecan for compassionate use with a very detailed protocol for guidance and advice on safety precautions seems to have contributed to the relatively safe use of the drug outside the setting of a formal clinical trial.

Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m(-2) day(-1). Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m(-2) day(-1) and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1-3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4-5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting.

The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel

The objective of this study was to evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the oral absorption of paclitaxel. Patients received oral paclitaxel in doses of 60-360 mg/m(2) in combination with a dose of oral CsA of 15 mg/kg. Dose escalation of paclitaxel from 60 to 300 mg/m(2) resulted in a significant decrease in the area under the concentration-time curve (AUC) of CsA from 24.4+/-9.9 to 17.6+/-2.8 mg/l.h (p=0.03) (n=28). In conclusion, increases in the paclitaxel dose resulted in a decrease in the AUC of CsA. This observation may be explained by the increase in the co-solvent Cremophor EL of paclitaxel causing reduced absorption of CsA.

Purpose: To investigate dose escalation of bi-daily (b.i.d.) oral paclitaxel in combination with cyclosporin A in order to improve and prolong the systemic exposure to paclitaxel and to explore the maximum tolerated dose and dose limiting toxicity (DLT) of this combination., Patients and Methods: A total of 15 patients received during course 1 two doses of oral paclitaxel (2 x 60, 2 x 90, 2 x 120, or 2 x 160 mg/m2) 7 h apart in combination with 15 mg/kg of cyclosporin A, co-administered to enhance the absorption of paclitaxel. During subsequent courses, patients received 3-weekly intravenous paclitaxel at a dose of 175 mg/m2 as a 3-h infusion., Results: Toxicities observed following b.i.d. dosing of oral paclitaxel were generally mild and included toxicities common to paclitaxel administration and mild gastrointestinal toxicities such as nausea, vomiting, and diarrhea, which occurred more often at the higher dose levels. Dose escalation of b.i.d. oral paclitaxel from 2 x 60 to 2 x 160 mg/m2 did not result in a significant increase in the area under the plasma concentration-time curve (AUC) of paclitaxel. The AUC after doses of 2 x 60, 90, 120, and 160 mg/m2 were 3.77 +/- 2.70, 4.57 +/- 2.43, 3.62 +/- 1.58, and 8.58 +/- 7.87 microM.h, respectively. The AUC achieved after intravenous administration of paclitaxel 175 mg/m2 was 17.95 +/- 3.94 microM.h., Conclusion: Dose increment of paclitaxel did not result in a significant additional increase in the AUC values of the drug. Dose escalation of the b.i.d. dosing regimen was therefore not continued up to DLT. As b.i.d. dosing appeared to result in higher AUC values compared with single-dose administration (data which we have published previously), we recommend b.i.d. dosing of oral paclitaxel for future studies. Although pharmacokinetic data are difficult to interpret, due to the limited number of patients at each dose level and the large interpatient variability, we recommend the dose level of 2 x 90 mg/m2 for further investigation, as this dose level showed the highest systemic exposure to paclitaxel combined with good safety.

Oral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m(2)in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m(2)as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration-time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 +/- 1.67 microM x h. In our previously performed study of 120 mg/m(2)oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 +/- 2.29 microM x h. After i.v. administration of paclitaxel the mean AUC was 15.92( )+/- 2.46 microM x h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel., (Copyright 2001 Cancer Research Campaign.)

The aims of this study were to evaluate the efficacy and safety of docetaxel (Taxotere) in patients with progressive locally advanced or metastatic breast cancer, previously treated with at least one chemotherapy regimen, and the effect of the number of previous chemotherapy lines on response rate, progression-free survival and overall survival. Two-hundred and fifty-three patients from 10 hospitals in The Netherlands received docetaxel as part of a compassionate use program. The majority had received prior anthracycline-containing chemotherapy (84.2%). The recommended starting dose was 100 mg/m2 i.v. every 3 weeks. All patients received corticosteroid premedication. Two-hundred and thirty patients were evaluable for response. The overall response rates (ORR) to docetaxel when used as second-, third- or fourth-line treatment were, respectively, 40.2, 26.0 and 34.6% (p value 0.30). The median progression-free survival for this population was 4.9 months and the median overall survival of the whole group was 8.5 months, and both were not related to the number of previous chemotherapy regimens (p value, respectively, 0.71 and 0.16). The toxicity of docetaxel was manageable and neutropenia was the most frequently noted toxicity. This study confirms that docetaxel is an active cytotoxic agent in pretreated patients with progressive locally advanced or metastatic breast cancer and is still active when used as third- or fourth-line treatment.

Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m(2) with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 +/- 0.9 h. mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5-30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid retention (grade 2-3) after two to five courses.

i.v. paclitaxel is inconvenient and associated with significant and poorly predictable side effects largely due to the pharmaceutical vehicle Cremophor EL. Oral administration may be attractive because it may circumvent the use of Cremophor EL. However, paclitaxel, as well as many other commonly applied drugs, has poor bioavailability caused by high affinity for the mdrl P-glycoprotein drug efflux pump, which is abundantly present in the gastrointestinal tract. Consequently, inhibition of P-glycoprotein by oral cyclosporin A (CsA) should increase systemic exposure of oral paclitaxel to therapeutic levels. A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral paclitaxel of 60 mg/m2 with or without 15 mg/kg CsA and with i.v. paclitaxel in subsequent courses. The pharmacokinetics of paclitaxel and its major metabolites were determined during the first two courses. In addition, levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral paclitaxel in combination with CsA was 8-fold higher than after oral paclitaxel alone (P<0.001). Therapeutic concentrations were achieved on average during 7.4 h, which is comparable with an equivalent i.v. dose. The oral combination was well tolerated and did not induce gastrointestinal toxicity or myelosuppression. Cremophor EL plasma levels after oral drug administration were undetectable. In conclusion, coadministration of oral CsA increased the systemic exposure of oral paclitaxel from negligible to therapeutic levels. The combination enables treatment with oral paclitaxel. Undetectable Cremophor EL levels after oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel.

Aim: To investigate the pharmacokinetics of paclitaxel (Paxene) administered to patients with advanced breast or ovarian cancer and to document safety and anti-tumour activity in this study population., Patients and Methods: Patients with advanced breast or ovarian cancer were accrued to two clinical studies. Paclitaxel (Paxene) was administered as a 3-h 175 mg m-2 or as a 96-h 140 mg m-2(105 mg m-2 in the presence of liver metastases) infusion. Patients not responding to the 3-h schedule were permitted to cross-over to the 96-h schedule. The data were compared to those of five patients who were previously treated with paclitaxel administered as Taxol (140 mg m-296-h infusion) at our Institute., Results: Fourteen patients with breast cancer and five ovarian cancer patients were entered into this study. Seven patients received the 3-h regimen, and 12 were assigned to the 96-h schedule. Five patients originally treated with the 3-h schedule, crossed over to the 96-h arm. For the 3-h 175 mg m-2 dose, the area under the plasma concentration vs time curve (AUC) was (mean+/-SD) 16.9+/-4.8 h x micromol x l-1, whereas the AUCs were 5.5+/-1.2 and 4.3+/-0.9 h x micromol x l-1 for the 96-h 140 mg m-2 and 105 mg m-2 doses, respectively. The clearance of paclitaxel was independent of the dose in the 96-h group, indicating linear pharmacokinetics. Pharmacokinetics of Paxene (96-h 140 mg m-2) were not significantly different from the kinetics after Taxol (96-h 140 mg m-2) administration., (Copyright 1999 Academic Press.)

Purpose: To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days., Patients and Methods: Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m(2)/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling., Results: Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m(2)/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m(2)/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% +/- 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer., Conclusion: The recommended dosage is 10 mg/m(2)/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.

The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.

In this review the clinical pharmacokinetics of camptothecin topoisomerase I inhibitors, an important new class of anticancer drugs, is discussed. Two prototypes, topotecan and irinotecan, are currently marketed in many European countries and the USA for the treatment of patients with ovarian and colorectal cancer, respectively. Other camptothecin derivatives, including lurtotecan, 9-aminocamptothecin (9-AC) and 9-nitrocamptothecin (9-NC), are at different stages of clinical development. The common property of camptothecin analogues is their action against DNA topoisomerase I, but beyond this similarity the compounds differ widely in terms of antitumour efficacy, pharmacology, pharmacokinetics and metabolism. We review chemistry, mechanism of action, stability and bioanalysis of the camptothecins. Dosage and administration, status of clinical application, pharmacokinetics, pharmacodynamics and drug interactions are discussed.

A semi-automated reversed-phase high-performance liquid chromatography (HPLC) method has been developed and validated for the quantification of the novel anticancer drug docetaxel in human plasma. The chromatographic system also separated putative hydroxylated metabolites. A limited validation was performed for the assay of the metabolites while these reference compounds were not available in large quantities. The sample pretreatment of the plasma samples involves a solid-phase extraction (SPE) on Cyano end-capped columns. 2'-Methylpaclitaxel was used as internal standard. An APEX-octyl column (150 x 4.6 mm I.D.; particle size 5 microns) was used with acetonitrile-0.02 M ammonium acetate buffer pH 5 mixture as the mobile phase. UV detection was performed at 227 nm. In patient samples hydroxylated docetaxel metabolites were detected and quantified by using the docetaxel calibration curve. The accuracies and precisions of the assay fall within +/- 15% for all quality control samples and within +/- 20% for the lower limit of quantitation, which was 10 ng/ml using 1.00 ml of sample for both the parent drug and its metabolites. The overall recovery of the sample pretreatment procedure for docetaxel was 78.0% +/- 5.8% anc 84.8% +/- 3.1% for the internal standard 2'-methylpaclitaxel. Docetaxel was found to be stable in human plasma at -30 degrees C for at least 6 months. At ambient temperature docetaxel was stable for at most 15 h in human plasma.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be an active anticancer agent, including in platinum-refractory ovarian cancer. The pharmacokinetics of paclitaxel have been extensively described. It displays nonlinear pharmacokinetics in humans, especially when administered in shorter infusion times and at higher doses. Several relationships have been established between pharmacokinetics and pharmacodynamics. In both animal and human studies, hepatic metabolism and biliary excretion have been identified as the main elimination pathways of paclitaxel. It thus can be expected that hepatic dysfunction will have a major impact on the pharmacokinetics of paclitaxel and its main metabolite 6alpha-hydroxypaclitaxel and, thus, on pharmacodynamic outcome (toxicities and responses). Because patients with an altered hepatic function were excluded from most phase I and II studies conducted thus far, little is known about the pharmacokinetics and pharmacodynamics in this group of patients. This report summarizes paclitaxel's metabolism and clinical observations concerning its pharmacokinetics and pharmacodynamics in patients with altered hepatic function. It has been shown that hepatic impairment has a great influence on the systemic exposure of paclitaxel and metabolites with pharmacodynamic consequences. A decrease of biliary elimination is probably the major mechanistic effect that influences paclitaxel metabolism and elimination. Specific dosing guidelines in the treatment of patients with altered hepatic function are required.

Background: Changes in serum CA 125 from baseline do not reflect response to paclitaxel in relapsed ovarian carcinoma patients. Our study aimed to determine whether CA 125 changes relate to tumor response and overall survival during paclitaxel salvage treatment., Methods: Response data and CA 125 values of 77 platinum pretreated ovarian carcinoma patients were included in the study. Patients received 496 courses of paclitaxel in total (median 6; range: 2-18 courses)., Results: Response group numbers on the basis of World Health Organization (WHO) criteria were: 7 partial response, 22 stable disease, and 48 progressive disease. CA 125 values at the moment of clinical response allocation, the median survival duration, and the 3-year survival rate did not differ among WHO defined response groups. For both the stable disease group and the responders, the slopes of the exponential CA 125 regression curves during paclitaxel treatment were negative. Response groups, as defined by CA 125 changes, i.e., halving or doubling of baseline values, after 4 courses were concordant with WHO defined response groups in only 27%, but predicted survival far better., Conclusions: This study confirms that CA 125 changes in patients receiving paclitaxel treatment do not correlate with response allocations according to WHO criteria. In particular, patients with clinically and radiologically defined progression will often not show an increase in CA 125 concentrations from baseline. Those patients who do show doubling of CA 125 values, however, have a very poor prognosis. The CA 125 ratio, as determined after 4 courses of paclitaxel treatment, may be a better indicator of response than WHO defined response status.

Objective: To report a hypersensitivity reaction to etoposide occurring in a patient after 2 months of drug therapy., Case Summary: A 20-year-old man with a diagnosis of testicular carcinoma was treated with bleomycin, etoposide, and cisplatin (BEP regimen). After dose 20 of etoposide, an exanthema was noted, which was attributed to etoposide. The patient had received 19 doses of etoposide during the previous 2 months without any sign of an allergic reaction. Rechallenging the patient with etoposide from another batch resulted in recurrence of the exanthema., Discussion: Both etoposide and its excipient (polysorbate 80) are suspected of causing hypersensitivity reactions. Although the exact mechanism of the hypersensitivity reaction is not known, it is believed to be of nonimmunogenic origin., Conclusions: With a lower rate of infusion of etoposide and/or by premedication with antihistamines and/or corticosteroids, hypersensitivity reactions to etoposide might be prevented in patients with a history of hypersensitivity to this drug.

Background: Hepatic metabolism and biliary clearance play pivotal roles in the disposition of the anticancer drug paclitaxel. 6-alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6-alpha,3'-p-dihydroxypaclitaxel were the major metabolic products of paclitaxel found in human bile. Recently, these metabolic products were detected in human plasma. The pharmacokinetics of paclitaxel and its metabolites were investigated in anthracycline-resistant breast cancer patients treated with high-dose paclitaxel and granulocyte colony-stimulating factor (G-CSF) support., Patients and Methods: Nine patients were entered into this study in which paclitaxel was administered at the relatively high dose of 250 mg/m2 during a 3-hour infusion. G-CSF was administered daily subcutaneously (s.c.)on days 2 to 19 following chemotherapy. Analysis of paclitaxel and metabolite concentrations was performed by a new highly sensitive reversed-phase high performance liquid chromatographic (HPLC) assay., Results: The dose-limiting toxicity in this study was cumulative neurotoxicity. One patient had a partial response and 2 patients had mixed responses of their skin metastases. Relatively low peak plasma concentration (Cmax), with mean values of 6.91 micromol/L (range 3.08 to 8.98) and area under the plasma concentration time curve (AUC), with mean values of 27.04 micromol/L.h (range 14.88 to 40.57), were observed. The total body clearance was 16.99 L/h (range, 10.25 to 27.39). The pharmacokinetic parameter for the prediction of leuko-neutropenia, the duration of the plasma concentration above the threshold of 0.1 micromol/L.h (T > or = 0.1 microM), was 19.72 h (range 10.54 to 26.31). The three major metabolites detected in human plasma were identified as 6-alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and 6-alpha,3'-p-dihydroxypaclitaxel. Cmax and AUC values of these metabolites are reported., Conclusions: The three main metabolic products of paclitaxel in human plasma are 6-alpha-hydroxypaclitaxel, 3'-p-hydroxypaclitaxel and the dihydroxymetabolite 6-alpha,3'-p-dihydroxypaclitaxel. Two patients with liver function disturbances showed a tendency to higher paclitaxel and 6-alpha-hydroxypaclitaxel AUC levels, with more pronounced neuropathy.

Taxanes belong to a new group of antineoplastic agents with a novel mechanism of action for a cytotoxic drug. They promote microtubule assembly and stabilize the microtubules. Paclitaxel, the first agent in this group to become available, was isolated from the Pacific yew, Taxus brevifolia, in 1971. In preclinical and clinical studies, paclitaxel and its semisynthetic analog docetaxel exhibit significant antitumor activity. This review deals with the physicochemical properties, pharmacology, and results of preclinical and clinical trials of the taxanes.

Docetaxel (Taxotere), a new semisynthetic taxoid, is a potentially important chemotherapeutic agent for the treatment of cancer. Forty patients with bidimensionally measurable advanced adenocarcinoma of the colon were treated with docetaxel 100 mg m-2 every 3 weeks as a 1 h infusion without routine premedication. Thirty-nine patients were eligible: 23 males and 16 females. Median age was 60 years (range 41-75) and WHO performance status 1 (0-2). Prior adjuvant chemotherapy was performed in four patients and prior radiotherapy in nine patients. Bidimensionally measurable disease sites included: liver in 26 patients, lymph nodes and abdominal/peritoneal masses in 13, lung/mediastinal masses in ten and subcutaneous nodes in four. The median number of cycles given was 2 (range 1-15). Thirty-three patients were evaluable for response. One patient (3%) achieved a complete response and two (6%) (95% confidence limits 0-14%) a partial response. Side-effects were similar to those observed in other studies. Docetaxel, given at this dosage and schedule, has minimal activity in the treatment of colorectal carcinoma.

Background: Docetaxel, a semisynthetic analog of paclitaxel, made for the needles of the European yew, Taxus baccata, is a potentially important chemotherapeutic agent for the treatment of cancer., Patients and Methods: In a phase II study patients with advanced and/or metastatic breast cancer and bidimensionally measurable disease, were treated with docetaxel 100 mg/m2 every 3 weeks as a 1 hour infusion without any premedication. Treatment was evaluated after 2 courses and every 2 subsequent courses., Results: Thirty-nine patients were entered, 32 were eligible. The eligible patients had a median age of 51 years (range 30-73) and a performance status WHO 1 median, (range 0-2). Twenty-eight patients had been treated with surgery, 24 with radiation. Hormonal treatment was previously given in 23, chemotherapy in 32. Of 24 patients treated as second line strategy, 13 achieved a partial remission, 1 a complete remission (overall response rate 58% (95% CI 37%-78%)). Eight patients treated as first line: 2 PR's, 1 CR. The median overall response duration was 38 weeks. The main toxicity consisted of transient grade 4 neutropenia in 149 of 167 evaluable courses (89%). However, the related infection rate was low. Re-treatment at 3 weeks, as scheduled, was nearly always possible. Other toxicities consisted of skin reactions (81%) and nail changes (41%), neurosensory toxicity (59%) and occasionally hypersensitivity reactions (16%). Fluid retention was a toxicity of major concern, observed in 59% of patients., Conclusion: Docetaxel is a very active drug against breast cancer. Further studies are required to alleviate the non-hematological toxicities.