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  • 1
    Electronic Resource
    Electronic Resource
    Factors Affecting Topotecan Sensitivity in Human Leukemia Samples (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 803 (1996), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1996.tb26382.x
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    Fulltext
  • 2
    Electronic Resource
    Electronic Resource
    Pretreatment H2 receptor antagonists that differ in P450 modulation activity: comparative effects on paclitaxel clearance rates and neutropenia (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 227-232 
    Details
    ISSN: 1432-0843
    Keywords: Key words Paclitaxel ; H2 antagonists ; Cytochromes P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Histamine-2 receptor antagonists (H2RAs) are principal components of the premedication regimen used to prevent major hypersensitivity reactions in patients receiving paclitaxel. Several different H2RAs, including cimetidine, ranitidine and famotidine, have been used in clinical trials of paclitaxel, as well as by clinicians in different geographic regions and hospitals primarily because of differences in the availability of the various H2RAs. However, H2RAs have highly variable cytochrome P450-modulating capabilities, and the P450 system appears to play a major role in paclitaxel metabolism and disposition. Therefore, the use of different H2RAs may result in different pharmacologic, toxicologic and antitumor profiles due to differential effects on paclitaxel metabolism. This study evaluated whether cimetidine and famotidine, which possess disparate P450-modulating capabilities, differentially affect paclitaxel clearance rates and the agent’s principal toxicity, neutropenia. Women with advanced, platinum-refractory ovarian carcinoma received two courses of treatment with 135 mg/m2 paclitaxel over 24  h while participating in the National Cancer Institute’s Treatment Referral Center Protocol. A crossover design was employed in which consecutive patients received either 300 mg cimetidine i.v. or 20 mg famotidine i.v. before their first course of paclitaxel and the alternate H2RA before their second course. In order to evaluate the differential effects of cimetidine and famotidine on pertinent pharmacologic and toxicologic parameters in the same individual, paclitaxel concentrations at steady-state (Css), paclitaxel clearance rates, and absolute neutrophil counts (ANCs) were obtained during both courses. Paclitaxel Css values were not significantly different in individual patients when either cimetidine or famotidine preceded paclitaxel (p=0.16). Mean paclitaxel clearance rates were 271 and 243 ml/min per m2 following cimetidine and famotidine, respectively. These clearance rates were not significantly different in paired analysis (p=0.30). The likelihood of subsequently requiring granulocyte-colony stimulating factor (G-CSF) for severe neutropenia during course 1 did not differ significantly between the two H2RAs (p=0.9). Among patients who did not require G-CSF, mean percentage decreases in ANC were 87.7% and 84.2% after paclitaxel cycles preceded by cimetidine and famotidine, respectively. These measures of neutropenia did not differ significantly in paired analysis (p=0.13). These results show that the H2RAs cimetidine and famotidine do not differentially affect the pharmacologic and toxicity profiles of paclitaxel when used in the premedication regimen to prevent major hypersensitivity reactions, and may be interchanged.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050313
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  • 3
    Electronic Resource
    Electronic Resource
    Pretreatment H2 receptor antagonists that differ in P450 modulation activity: comparative effects on paclitaxel clearance rates and neutropenia (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 227-232 
    Details
    ISSN: 1432-0843
    Keywords: Paclitaxel ; H2 antagonists ; Cytochromes P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Histamine-2 receptor antagonists (H2RAs) are principal components of the premedication regimen used to prevent major hypersensitivity reactions in patients receiving paclitaxel. Several different H2RAs, including cimetidine, ranitidine and famotidine, have been used in clinical trials of paclitaxel, as well as by clinicians in different geographic regions and hospitals primarily because of differences in the availability of the various H2RAs. However, H2RAs have highly variable cytochrome P450-modulating capabilities, and the P450 system appears to play a major role in paclitaxel metabolism and disposition. Therefore, the use of different H2RAs may result in different pharmacologic, toxicologic and antitumor profiles due to differential effects on paclitaxel metabolism. This study evaluated whether cimetidine and famotidine, which possess disparate P450-modulating capabilities, differentially affect paclitaxel clearance rates and the agent's principal toxicity, neutropenia. Women with advanced, platinum-refractory ovarian carcinoma received two courses of treatment with 135 mg/m2 paclitaxel over 24 h while participating in the National Cancer Institute's Treatment Referral Center Protocol. A crossover design was employed in which consecutive patients received either 300 mg cimetidine i.v. or 20 mg famotidine i.v. before their first course of paclitaxel and the alternate H2RA before their second course. In order to evaluate the differential effects of cimetidine and famotidine on pertinent pharmacologic and toxicologic parameters in the same individual, paclitaxel concentrations at steady-state (Css), paclitaxel clearance rates, and absolute neutrophil counts (ANCs) were obtained during both courses. Paclitaxel Css values were not significantly different in individual patients when either cimetidine or famotidine preceded paclitaxel (p=0.16). Mean paclitaxel clearance rates were 271 and 243 ml/min per m2 following cimetidine and famotidine, respectively. These clearance rates were not significantly different in paired analysis (p=0.30). The likelihood of subsequently requiring granulocyte-colony stimulating factor (G-CSF) for severe neutropenia during course 1 did not differ significantly between the two H2RAs (p=0.9). Among patients who did not require G-CSF, mean percentage decreases in ANC were 87.7% and 84.2% after paclitaxel cycles preceded by cimetidine and famotidine, respectively. These measures of neutropenia did not differ significantly in paired analysis (p=0.13). These results show that the H2RAs cimetidine and famotidine do not differentially affect the pharmacologic and toxicity profiles of paclitaxel when used in the premedication regimen to prevent major hypersensitivity reactions, and may be interchanged.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685851
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  • 4
    Electronic Resource
    Electronic Resource
    The effects of food and divided dosing on the bioavailability of oral vinorelbine (1996)
    Springer
    Cancer chemotherapy and pharmacology 39 (1996), S. 9-16 
    Details
    ISSN: 1432-0843
    Keywords: Key words Vinorelbine ; Navelbine ; Oral ; Bioavailability ; Food ; Divided dosing ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22±28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3±1.6 h in the fasting state to 2.5±1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16±51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050532
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  • 5
    Electronic Resource
    Electronic Resource
    Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 493-496 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21–77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (〈65 or 〉65 years) versus dose delivered [〈 the maximum tolerated dose (MTD) vs ≥ the MTD] or toxicity (〈 grade 3 vs ≥ grade 3). Of 344 patients, 81 (23.5%) were 〉65 years old, 34 (9.9%) were ≥70 years old, and 5 (1.5%) were ≥75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged ≥75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686507
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  • 6
    Electronic Resource
    Electronic Resource
    Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data (1994)
    Springer
    Cancer chemotherapy and pharmacology 33 (1994), S. 493-496 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21–77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (〈65 or 〉65 years) versus dose delivered [〈 the maximum tolerated dose (MTD) vs ≥ the MTD] or toxicity (〈 grade 3 vs ≥ grade 3). Of 344 patients, 81 (23.5%) were 〉65 years old, 34 (9.9%) were ≥70 years old, and 5 (1.5%) were ≥75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged ≥75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686507
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  • 7
    Electronic Resource
    Electronic Resource
    Evaluation of weekly escalating doses of dichloromethotrexate in patients with hepatocellular carcinoma and other solid tumors (1982)
    Springer
    Cancer chemotherapy and pharmacology 8 (1982), S. 305-310 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Twenty-one patients with solid tumors were treated with weekly 6-h intravenous infusions of dichloromethotrexate (DCM), with escalating doses every other week. Frequently observed toxicities included leukopenia, thrombocytopenia, and mucositis. Nausea, vomiting, diarrhea, and elevation of hepatic enzymes and bilirubin occurred less often. The toxicity of DCM was dose-dependent; the maximum tolerated dosage excalation plan was 400 mg/m2x2 weeks, 800 mg/m2x2 weeks, and then 1,200 mg/m2 weekly. Plasma concentrations of DCM were measured during 61 infusions and apparent half-lives determined. The plasma elimination of DCM appears to be similar to that of methotrexate. Three objective tumor responses seen in the seven hepatocellular carcinoma patients treated warrant further investigation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00254055
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  • 8
    Electronic Resource
    Electronic Resource
    A phase I trial of trimetrexate glucuronate (NSC 352122) given every 3 weeks: clinical pharmacology and pharmacodynamics (1989)
    Springer
    Cancer chemotherapy and pharmacology 24 (1989), S. 314-320 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Trimetrexate glucuronate (TMTX), a non-classic folate antagonist, has been evaluated clinically on several schedules. We studied TMTX given as an i.v. bolus over 5–30 min every 3 weeks in 44 patients with advanced solid tumors; it was given at doses ranging from 20 to 275 mg/m2. The maximal tolerated dose (MTD) on this schedule is 220 mg/m2, which we also recommend as a starting dose for phase II studies in patients without extensive prior therapy. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for non-toxic patients. The principal dose-limiting toxicity was myelosuppression, although in some patients a flu-like syndrome precluded dose escalation. Significant rash and mucositis also frequently occurred in toxic patients. TMTX plasma concentrations were measured after the first dose and the data were fit by two-or three-compartment mammillary pharmacokinetic models. The TMTX clearance rate was 36.5±21 ml/min per m2 and did not change with dose; non-linearities with increasing dose were apparent in the steady-state volume of distribution (VSS) and in the terminal disposition half-life (t 1/2). The difference between pre-treatment and nadir leucocyte counts was correlated with TMTX dose (r=0.58; P=0.0006) and with the area under the concentration vs time curve (AUC) (r=0.41; P=0.02). Pre-treatment plasma albumin concentrations correlated weakly with the nadir white blood count (r=-0.36; P=0.047). Optimal schedules for the administration of TMTX have not been established and phase II trials using both bolus and daily x5 schedules are under way.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00304765
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  • 9
    Electronic Resource
    Electronic Resource
    Camptothecin analogues: studies from The Johns Hopkins Oncology Center (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. S53 
    Details
    ISSN: 1432-0843
    Keywords: Topoisomerase I ; Camptothecin ; Cancer chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The camptothecin analogues topotecan and irinotecan (CPT-11) are active anticancer drugs. This article reviews the accumulated results of clinical and laboratory studies performed with these agents at The Johns Hopkins Oncology Center. In a phase I clinical and pharmacology trial of topotecan given as a 30-min infusion daily for 5 days every 3 weeks, profound neutropenia precluded dose escalation above 1.5–2.0 mg/m2 per day, the maximum tolerated dose (MTD). The daily ×5 schedule has been developed further with dose escalation using granulocytecolony-stimulating factor support in patients who have kidney or liver dysfunction and given in combination with cisplatin. In addition, a phase I trial of topotecan given as a 5-day continuous intravenous infusion to patients with refractory leukemia has had promising antileukemic responses. A separate series of in vitro studies indicates that a modest degree of resistance to the cytotoxicity of topotecan can be mediated by P-glycoprotein. A phase I and pharmacology study of irinotecan given as a 90-min infusion every 3 weeks has defined an MTD of 240 mg/m2, with dose escalation being limited by several toxicities. These included an acute treatment-related syndrome of flushing, warmth, nausea, vomiting, and diarrhea; a subacute combination of nausea, diarrhea, anorexia, and weight loss; and/or neutropenia. Antitumor activity has been observed with topotecan and irinotecan in patients with a variety of solid tumors and refractory leukemia in our studies, which supports the widespread enthusiasm for this group of compounds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00684864
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  • 10
    Electronic Resource
    Electronic Resource
    Sequence-dependent cytotoxic effects due to combinations of cisplatin and the antimicrotubule agents taxol and vincristine (1993)
    Springer
    Journal of cancer research and clinical oncology 119 (1993), S. 727-733 
    Details
    ISSN: 1432-1335
    Keywords: Sequence dependence ; Vincristine ; Taxol ; Antimicrotubule agents ; Cisplatin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The antineoplastic activity that taxol has demonstrated in advanced ovarian cancer and other neoplasms in which the platinum analogues are among the most active agents has been the impetus for the development of taxol/platinum combination regimens. Since both classes of agents are known to induce cell-cycle-dependent effects and to delay cell-cycle traverse in specific phases of the cycle, an evaluation of drug sequence dependence was incorporated into initial clinical studies of the drug combination. To complement clinical studies, sequence-dependent interactions were assessed in vitro using L1210 leukemia. Cytotoxicity resulting from the combination of taxol and cisplatin was significantly increased over that achieved with cisplatin alone only when cisplatin was administered after taxol. This sequence was significantly superior to both the reverse sequence and to simultaneous drug treatment. Results achieved with sequence iterations of vincristine and cisplatin were nearly identical. In addition, alkaline-elution studies, using the optimal sequence of cisplatin and either taxol or vincristine, demonstrated that these antimicrotubule agents do not increase the formation of cisplatin-induced DNA interstrand and DNA-protein crosslinking over that produced by cisplatin alone. Although the mechanisms for the sequence-dependent cytotoxic interactions between cisplatin and the antimicrotubule agents have not been determined, it is likely that antagonistic interactions occur with the suboptimal sequences, probably because of cell-cycle-dependent phenomena.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01195344
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