PubMed Health⌕ Search

Biomedical subjects

J H Schellens

Publications and source records attributed to J H Schellens.

At least 73 records · Page 4Linked to original sources
PubMed1999

A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen.

PURPOSE: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. METHODS: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model). in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin-thiotepa-cyclophosphamide combination). RESULTS: The measured mean AUC in our population was 4.1 min x mg/ml (median 3.9, range 1.9 6.3, SD 1.0 min x mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min x mg/ml (median 4.2, range 2.4-8.4, SD 1.2 min x mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. CONCLUSION: Although easy and attractive to use, the Ghazal-Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations.

Adolescent↗
PubMed1999

Pharmacokinetics of paclitaxel administered in combination with cisplatin, etoposide and bleomycin in patients with advanced solid tumours.

PURPOSE: To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours. METHODS: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m(2)) were administered in combination with etoposide 100 or 120 mg/m(2), and fixed dose of cisplatin 20 mg/m(2) and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II-V. RESULTS: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m(2) dose level (II) was 7.0 +/- 3.6 h micromol(-1) l(-1), for the 175-mg/m(2) dose level (III) 10.6 +/- 2. 8 h micromol(-1) l(-1), for the 200-mg/m(2) dose level (IV) it was 16.0 +/- 5.0 h micromol(-1) l(-1), and for the 175-mg/m(2) dose level (V) it was 12.5 +/- 6.1 h micromol(-1) l(-1). The mean peak plasma concentration (C(max)) values for dose levels II-V were 1.9 +/- 1.1 micromol/l, 3.4 +/- 1.2 micromol/l, 4.3 +/- 1.0 micromol/l and 3.8 +/- 1.2 h micromol/l, respectively. CONCLUSION: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C(max) and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-micromol/l threshold concentration (t > 0.1 microM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded.

Adenocarcinoma↗
PubMed1999

A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel.

PURPOSE: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. METHODS: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. RESULTS: The following single-point model was selected as optimal: AUC carboplatin (min mg(-1) ml(-1)) = 418. c(2.5 h)(mg/ml) + 0.43 (min mg(-1) ml(-1)), where c(2.5 h) is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 +/- 1.6%) and precise (root mean square error = 10.1 +/- 1.5%). CONCLUSIONS: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualize treatment.

Aged↗
PubMed1999

The accumulation of topotecan in 9L glioma and in brain parenchyma with and without dexamethasone administration.

The accumulation of the topoisomerase I inhibitor topotecan in brain tumor as well as in brain around tumor (BAT) and normal brain following an intravenous bolus of topotecan of 0.5 mg/kg was investigated in rats bearing a 9L glioma. Also the influence of dexamethasone (Dex) on the uptake of topotecan was examined. Tumor, BAT and brain tissue as well as whole blood were collected at 1 h after an i.v. bolus of topotecan. Concentrations of total topotecan in tumor, BAT and brain were quantified with high-performance liquid chromatography (HPLC) and compared with concentrations in plasma of total topotecan. In brain tumor tissue the mean total topotecan concentration was 96 +/- 33 ng/g which was 20-fold higher than the accumulation of topotecan in normal brain tissue. In BAT intermediate concentrations of 13 +/- 4.9 ng/g were reached. Mean total topotecan concentration in plasma was 100 +/- 25 ng/ml. We did not find an influence of Dex on the uptake of topotecan in either tissue. We conclude that high tissue concentrations of topotecan can be reached in experimental brain tumors in rats. This observation may be useful in the design of clinical studies with topotecan.

Animals↗
PubMed1999

Oral topotecan: bioavailablity and effect of food co-administration.

The aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m(-2) day(-1) of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m(-2) day(-1)) or i.v. (1.5 mg m(-3) day). They crossed over to receive the alternate regimen on day 2. On days 3-5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93+/-0.23 (90% confidence interval (CI) 0.83-1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6+/-4.4 ng ml(-1)) or without food (9.2+/-4.1 ng ml(-1)) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8-6.1) compared to fasted conditions (2.0 h, range 1.1-8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42+/-13% (90% CI 37-47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9+/-1.0 h) than after i.v. administration (2.7+/-0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption.

Administration, Oral↗
PubMed1999

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients.

The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175-3 h = 42.8+/-24.9 ml h(-1) m(-2); CI175-24 h = 79.7+/-24.3; P = 0.035 and Cl135-3 h = 44.1+/-21.8 ml h(-1) m(-1); Cl140-96 h = 211.8+/-32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics-pharmacodynamics relationships.

Area Under Curve↗
PubMed1999

Clinical pharmacology of anticancer agents in relation to formulations and administration routes.

In the past years, alternative administration routes and pharmaceutical formulations of anticancer agents have been investigated in order to improve conventional chemotherapy treatment. The impact of these adjustments on the pharmacokinetics and pharmacodynamics is discussed. A review of the literature shows many examples of alternative administration forms of anticancer agents with improved pharmacokinetics. Local administration routes have been investigated in order to reduce the systemic toxicity and to enhance the local efficacy of conventional chemotherapy. Oral administration of anticancer agents is preferred by patients for its convenience and its potential for outpatient treatment. In addition, oral administration facilitates a prolonged exposure to the cytotoxic agent. However, poor bioavailability and substantial interpatient variability are noted as limitations for oral chemotherapy. Increased tumour selectivity can also be achieved by the use of specific pharmaceutical formulations, such as liposomes and macromolecular drug conjugates. The composition of these formulations often determine the pharmacokinetic behaviour of the formulated drug. In conclusion, several alternative administration forms of anticancer agents have been designed in the past years, with the potential for improvement of conventional chemotherapy, however, more extensive clinical evaluation of these novel strategies is warranted to prove their real clinical value.

Administration, Oral↗
PubMed1999

In vitro antagonistic cytotoxic interactions between platinum drugs and taxanes on bone marrow progenitor cell CFU-GM.

We have designed and used an in vitro bone marrow cell culturing system for investigating pharmacodynamic interactions between platinum anti-cancer drugs and taxanes. With this system, in which the bone marrow progenitor cell CFU-GM is proliferating and differentiating into granulocytes and monocytes, we could show a strong antagonistic cytotoxicity of the combination carboplatin and Taxotere, in three different schedules, and of the combination cisplatin and Taxol, in two out of the three schedules tested. Modulation of intracellular platinum drug accumulation in granulocytes and monocytes does not seem to be a plausible explanation for the observed antagonism. In vitro co-incubation of granulocytes/monocytes with the combination carboplatin and Taxotere did not reveal an effect of Taxotere on intracellular platinum accumulation. Although Taxol reduced intracellular cisplatin levels by 12%, this effect was not significantly different from the co-incubation of cisplatin with Cremophor EL, the solvent for paclitaxel in Taxol. The toxicity data obtained in this study seem to be in accordance with recent clinical trials where combination therapies with platinum drugs and taxanes resulted in marked reductions in myelosuppression in patients. Therefore, these types of assays could be useful as to the assessment of bone marrow toxicities of clinically important drug combinations.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Phase I and pharmacologic study of the arotinoid Ro 40-8757 in combination with cisplatin and etoposide in patients with non-small cell lung cancer.

This phase I study was performed to assess the feasibility of combining cisplatin/etoposide (VP-16) with the arotinoid Ro 40-8757 and to determine the dose-limiting toxicity (DLT) of Ro 40-8757 in this combination. Patients with non-small cell lung cancer were eligible. Treatment consisted of Ro 40-8757 p.o. day 1-21, cisplatin 100 mg/m2 i.v. on day 2 and VP-16 100 mg/m2 i.v. on day 2-4, repeated every 3 weeks. Eighteen patients were evaluable for toxicity and response. The doses of Ro 40-8757 ranged from 84 mg/m2 once daily to 42 mg/m2 thrice daily (tid). DLT consisting of delayed nausea/vomiting was reached at 42 mg/m2 tid. Consequently, the maximum tolerated dose was set at one dose level below the DLT, i.e. 28 mg/m2 tid. Skin toxicity occurred but was well manageable. Pharmacological analyses showed a small increase in the volume of distribution of cisplatin and VP-16 between the first and third course. However, no relationship with side effects was found. A response was achieved in 50% of patients. The combination of cisplatin/VP-16 with Ro 40-8757 appears to be feasible at a dose schedule of 28 mg/m2 tid. The response rate was at the upper rate of what can be expected with cisplatin and VP-16.

Adult↗
PubMed1999

Phase I and pharmacologic study of BMS-181174 given as a 6 h infusion every 4 weeks to patients with advanced solid tumors.

BMS-181174, a new mitomycin C (MMC) analog, showed more activity than the parent compound in tumor xenografts. In a phase I study with a 5-30 min slow bolus administration, hematologic and vascular toxicity were observed as major side effects. A prolonged infusion was suggested to circumvent the vascular toxicity. In this phase I study BMS-181174 was administered as a 6 h infusion every 4 weeks; the doses studied were 3.2, 6.4, 11.5, 19.0, 32.0, 50.0, 75.0 and 100 mg/m2. Twenty-eight patients were enrolled in the study, the majority with colorectal cancer. Hematologic side effects consisted of thrombocytopenia, and mild leuko- and granulocytopenia. The most distressing non-hematologic side effect was vascular toxicity consisting of phlebosclerosis and phlebitis, becoming dose limiting at 100 mg/m2. One patient developed a hemolytic uremic syndrome at a cumulative dose of 350 mg/m2. Pharmacokinetic data are available for 24 patients. The AUC ranged from 3.35 to 41.49 (microg x h/ml) and was highly correlated with the dose administered (r = 0.83). The kinetics appeared to be linear. One patient with metastatic colon cancer had a partial response of liver metastases. BMS-181174 is a MMC analog with a toxicity profile comparable to that of the parent compound. As doses above 50 mg/m2 are complicated by vascular toxicity precluding multiple administrations, further exploration of BMS-181174 will not be performed.

Adult↗
PubMed1999

Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Adult↗
PubMed1999

Phase I and pharmacokinetic study of irinotecan administered as a low-dose, continuous intravenous infusion over 14 days in patients with malignant solid tumors.

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.

Adult↗
PubMed1999

Phase I and pharmacokinetic study of a daily times 5 short intravenous infusion schedule of 9-aminocamptothecin in a colloidal dispersion formulation in patients with advanced solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m(2)/d. The MTD was assessed on the first cycle and was defined as the dose at which > or = two of three patients or > or = two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography. RESULTS: Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m(2)/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m(2)/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal E(max) models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION: 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1. 1 mg/m(2)/d.

Adult↗
PubMed1999

UFT and oral calcium folinate as first-line chemotherapy for metastatic gastric cancer.

Locally advanced or metastatic adenocarcinoma of the stomach still carries a poor prognosis, with 5-year survival rates of < 15%. Palliative chemotherapeutic regimens for this disease are largely 5-FU-based. We have investigated the clinical activity of an oral combination of uracil and tegafur (UFT) with calcium folinate (Orzel), in patients with measurable metastatic disease. Thirty-six patients received a total of 94 courses of daily UFT 300 mg/m2 plus calcium folinate 90 mg for 28 consecutive days followed by a 7-day rest. Planned treatment doses were maintained in 83% of all evaluable courses. Main toxicities included diarrhea (21 patients) and nausea and vomiting (20 patients). Other side effects were asthenia, malaise, stomatitis, and myelosuppression. At present, 26 patients are evaluable for response. Of these, one achieved a complete response and three achieved partial remissions. In addition, six patients reached stable disease, yielding an overall response rate of 27%. We conclude that the combination of UFT and calcium folinate is a feasible outpatient regimen that warrants further clinical evaluation.

Adenocarcinoma↗
PubMed1999

Coadministration of oral cyclosporin A enables oral therapy with paclitaxel.

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.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin)

Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Totals of 109, 48, 64, and 59 courses were given, respectively. Dose-limiting toxicity consisted of granulocytopenia for the o.d. x 5-day dosage, a combination of myelosuppression and diarrhea in both of the 10-day schedules, and only diarrhea in the 21-day schedule. Pharmacokinetics revealed a substantial variation of the area under curve (AUC) of topotecan lactone in all of the dose schedules with a mean intrapatient variation of 25.4 +/- 31.0% (o.d. x 5), 34.5 +/- 25.0% (o.d. x 10), 96.5 +/- 70.1% (b.i.d. x 10), and 59.5 +/- 51.0% (b.i.d. x 21). Significant correlations were observed between myelotoxicity parameters and AUC(t) day 1 and AUC(t) per course of topotecan lactone. In all of the studies, similar sigmoidal relationships could be established between AUC(t) per course and the percentage decrease of WBCs. At maximum-tolerated dose level, no significant difference in AUC(t) per course was found [AUC(t) per course was 107.4 +/- 33.7 ng x h/ml (o.d. x 5), 145.3 +/- 23.8 ng x h/ml (o.d. x 10), 100.0 +/- 41.5 ng x h/ml (b.i.d. x 10), and 164.9 +/- 92.2 ng x h/ml (b.i.d. x 21), respectively.] For oral topotecan, the schedule rather than the AUC(t)-per-course seemed to be related to the type of toxicity. Prolonged oral administration resulted in intestinal side effects as a dose-limiting toxicity, and short-term administration resulted in granulocytopenia. On the basis of this pharmacokinetic study, no schedule preference could be expressed, but based on patient convenience, administration once daily for 5 days could be favored.

Administration, Oral↗
PubMed1998

Clinical research on antiangiogenic therapy.

A promising novel target for anti-cancer therapy is the tumour vasculature. Both primary tumour growth and the formation of metastasis depend on the establishment of new blood vessels from preexisting ones, a process called angiogenesis. Inhibition of angiogenesis and targeting of the tumour vasculature are highly effective in controlling tumour growth. Several natural and synthetic compounds have been developed and are currently tested in pre-clinical and clinical studies. This review intends to provide an overview of agents with antiangiogenic activity and the early clinical experience with these drugs.

Antibodies↗