A phase I and pharmacokinetic study of gemcitabine given by 24-h hepatic arterial infusion

PurposeThis study was performed to assess the toxicities, the maximum-tolerated dose (MTD), the pharmacokinetics and the anti-tumour activity of gemcitabine given by 24-h hepatic arterial infusion (HAI).Patients and methodsPatients with liver malignancies received gemcitabine by 24-h HAI, weekly × 3, every 4 weeks. On day 1 or day 8 of the first cycle, patients received one administration by 24-h intravenous infusion for pharmacokinetic comparison and to determine hepatic extraction.ResultsThirteen patients received gemcitabine at the dose levels of 75, 135 and 180 mg/m². The MTD was 180 mg/m² with thrombocytopaenia as the dose-limiting toxicity. Pharmacokinetic analysis showed a significantly lower maximum gemcitabine plasma concentration (C_max: HAI, 26, 80 and 128 nM, respectively; IV, 229, 264 and 293 nM, respectively) and area under the plasma-concentration-versus-time curve (AUC_0–24h: HAI, 386, 1247 and 2033 nmol × h/L, respectively; IV, 3526, 4818 and 5363 nmol × h/L, respectively) during HAI, compared with intravenous infusion (both P < 0.001). Additionally, the mean hepatic extraction ratios of gemcitabine at the 75, 135 and 180 mg/m² dose level were 0.89, 0.75 and 0.55, respectively. Hepatic extraction decreased linearly with increasing dose. The C_max and AUC_0–24h of 2′,2′-difluoro-2′-deoxyuridine, the deaminated product of gemcitabine, were similar for HAI and intravenous infusion. Seven patients had stable disease for a median duration of 9 months (range: 2–11 months).ConclusionsGemcitabine given by 24-h HAI was well tolerated and resulted in significantly lower systemic gemcitabine plasma concentrations than intravenous infusion due to a relatively high hepatic extraction.     

The pharmacokinetics of reduced folates after intraperltoneal and intravenous administration of racemic [6S,R]-folinic acid

We investigated the pharmacokinetics of tetrahydrofolates following the administration of [6S,R]-folinic acid and 5-fluorouracil delivered i.v., i.p., and by a combination of both routes in patients with colon cancer. The concentrations of the biologically active tetrahydrofolates ([6S]-folinic acid and 5-methyltetrahydrofolate) and the relatively inert diastereomer [6R]-folinic acid were monitored using a selective on-line coupled achiral-chiral high-performance liquid chromatographic method. In plasma, a target concentration of 5 M active tetrahydrofolates, which is considered necessary for an optimal synergistic effect, could be achieved after i.v. or combined i.v. and i.p. administration but was not reached in a patient receiving i.p. [6S,R]-folinic acid alone. In three patients receiving i.p. [6S,R]-folinic acid a high level of [6S]-folinic acid was observed in ascites, suggesting that the peritoneal cavity may act as a storage site for tetrahydrofolates after i.p. administration. In these patients, only a trace level of the active metabolite 5-methyltetrahydrofolate was detected in ascites, which may indicate that tetrahydrofolate derivatives penetrate only minimally, if at all, into the peritoneal cavity from the central compartment. These data would indicate that a combination of i.p. and i.v. administration may, from the pharmacological point of view, indeed contribute to an improved treatment of minimal residual disease persisting in the peritoneal cavity.     

A phase I clinical and pharmacokinetic study of the dolastatin analogue cemadotin administered as a 5-day continuous intravenous infusion

Purpose: The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibiting microtubule assembly and tubulin polymerization. Cemadotin is a synthetic analogue of dolastatin 15 with potent antiproliferative and preclinical antitumor activity. This report describes a phase I study to evaluate the administration of cemadotin to adult cancer patients by a 5-day continuous intravenous (CIV) infusion. Methods: All patients had histologically confirmed refractory solid tumors. The dose was escalated from an initial level of 2.5 mg/m² (0.5 mg/m² daily) according to a modified Fibonacci algorithm. A minimum of three patients was evaluated at each dose level until the maximum tolerated dose (MTD) was established. Treatment was repeated every 21 days until patients were removed from the study due to toxicity or disease progression. Drug-related toxicities were evaluated and graded by the U.S. National Cancer Institute's Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and its metabolites with an intact N-terminal region of the molecule was used for pharmacokinetic studies. Results: Twenty heavily pretreated patients received a total of 40 courses of cemadotin over five dose levels ranging from 2.5 to 17.5 mg/m². Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m² was established as the MTD. Nonhematologic toxicities attributed to the drug were moderate, and there was no evidence of the cardiovascular toxicity noted in the prior phase I studies of cemadotin given IV as a 5-min injection or 24-h infusion. There were no objective antitumor responses. Time courses of the cemadotin RIA equivalent concentration in whole blood were defined in 14 patients during the first cycle of therapy. The RIA-detectable species exhibited apparent first-order pharmacokinetics across the entire range of doses. The mean ± SD of the observed steady-state blood concentration at the 12.5 mg/m² MTD was 282 ± 7 nM (n=3). Blood levels decayed monoexponentially following the end of the infusion, with a mean half-life of 13.2 ± 4.3 h (n=14) in all patients. Mean values (n=14) of the total blood clearance and apparent volume of distribution at steady state were 0.52 ± 0.09 l/h/m² and 9.9 ± 3.3 l/m², respectively. Conclusions: The cardiotoxic effects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing this compound into disease-oriented efficacy studies is merited. Received: 8 November 1999 / Accepted: 28 April 2000     

多西紫杉醇脂质体的制备及其在家兔体内的药代动力学

背景与目的:多西紫杉醇(Docetaxel,DOC)已在临床应用于非小细胞肺癌、乳腺癌、卵巢癌等的治疗,但其水溶性差,现临床使用的注射剂均采用吐温-80和13%乙醇溶液作为混合溶媒,静脉注射时常引发严重的过敏反应而限制了其临床使用.本课题研究DOC脂质体的制备方法,并考察用聚乙二醇2000(poly ethylene glycol-2000,PEG-2000)修饰前后的两种脂质体在家兔体内的药代动力学.方法:用薄膜蒸发法制备普通和PEG-2000修饰的DOC脂质体,测定其包封率、粒径和表面电位;静脉注射给药后,以地西泮为内标,采用固相萃取-高效液相色谱法测定血浆中药物含量;用3p87程序和SPSS13.0统计软件处理和分析数据,计算有关药代动力学参数.结果:制备的DOC脂质体包封率＞75%,平均粒径在150 nm左右.普通市售多西紫杉醇注射液(market docetaxel,M-DOC)和普通脂质体(docetaxel liposome,L-DOC)及PEG-2000修饰的长循环脂质体(PEG-2000-modified DOC long circulating liposome,PEG-DOC-LCL)的分布相半衰期分别为(0.17±0.04)、(0.31±0.11)和(0.32±0.06)h,消除相半衰期分别为(8.54±1.05)、(11.18±1.33)和(10.51±1.13)h,表观分布容积分别为(13.66±3.62)、(8.65±1.11)和(6.31±0.55)L,0～24 h曲线下面积分别为(13.45±2.44)、(22.83±3.57)和(29.31±5.96)mg·(h·L)-1,零时间至所有原形药物全部消除时间内的曲线下面积分别为(15.07±2.76)、(28.70±4.95)和(36.95±9.13)mg·(h·L)-1,清除率分别为(1.10±0.18)、(0.54±0.08)和(0.42±0.07)L/h.结论:薄膜分散法制备的DOC脂质体包封率较高,粒径较小;两种DOC脂质体均可不同程度地增加DOC的曲线下面积,降低表观分布容积和清除率,从而延长其在血液循环中的时间,并以用PEG修饰的DOC脂质体效果更好.     

A phase I study of thiotepa administered by short-term and protracted continuous intravenous infusion

Forty-five patients received escalating dose rates of continuous infusion thio-triethylene thiophosphoramide (TEPA) for either five (26 patients) or 28 (19 patients) days. Dose rate limiting toxicity for the 5-day infusion was myelosuppression with leukocyte and platelet nadirs on days 21 and 28, respectively. The nadir was influenced by the presence and degree of liver disease. The optimal dose rate for 5-day infusion in the absence of liver disease was 12 mg/m2/d and was reduced to 8 mg/m2/d in patients with major liver disease. Dose rate limiting toxicity for the protracted 28-day infusion was leukopenia. The optimal dose rate for the 28-day infusion was 4 mg/m2/d. Pharmacologic studies included determination of plasma steady state concentrations (CSS) of thio-TEPA and TEPA. Dose rates up to 10 mg/m2/d produced thio-TEPA and TEPA CSS below the levels of detection of available analytical methodology, except in three patients infused at dose rates of 1, 2, and 4 mg/m2/d, respectively.     

A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion

Purpose A phase I pharmacologic study was undertaken to determine the maximum tolerated dose (MTD), to characterize the pharmacokinetic profile, and to evaluate all toxicities of the aqueous colloidal dispersion formulation of 9-aminocampothecin (9-AC).Methods 9-AC was administered as a constant 72-h i.v. infusion every 2 weeks to adult cancer patients at dose rates ranging from 25 to 59 g/m² per hour.Results Twenty patients with refractory solid tumors received a total of 86 courses of 9-AC at four dose levels. Myelosuppression, particularly granulocytopenia, was the most common toxicity. Two of six assessable patients entered at 59 g/m² per hour had dose-limiting toxicity (grade 3 diarrhea or need for a 2-week treatment delay to permit granulocyte recovery), whereas lower doses were well tolerated. At the recommended dose, 47 g/m² per hour, the average steady-state plasma levels (Cpss) and area under the curve (AUC) of 9-AC lactone and total drug were 15 and 75 nM, and 1034 and 4220 nM·h, respectively. A moderate correlation was seen between 9-AC lactone AUC and the percentage decrease in granulocytes.Conclusions The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 g/m² per hour (1.13 mg/m² per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity.     

A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m² per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m², three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m², two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 M. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m² per day.     

A phase I clinical study of Nimorazole as a hypoxic radiosensitizer

Nimorazole, a 5-Nitromidazole compound has been shown in animal studies to have similar radiosensitizing properties to misonidazole at clinically acceptable dose levels. The drug is well absorbed in humans after oral administration with peak plasma levels occurring around 90 min after ingestion (range 35-135 min) and a plasma half life between 2 and 4.8 hours. Total doses of Nimorazole up to 60 grams given in daily doses with conventional radiation therapy have demonstrated a significant lack of side effects, in particular no demonstrable neurotoxicity.     

A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors.

BACKGROUND: This study of GTI-2040, a 20-mer phosphorothioate oligonucleotide complementary to the messenger ribonucleic acid (mRNA) of the R2 subunit of ribonucleotide reductase (RNR), was conducted to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of the agent in patients with advanced solid tumors or lymphoma. Plasma pharmacokinetics of GTI-2040 and suppression of RNR expression in peripheral blood mononuclear cells were also studied. PATIENTS AND METHODS: GTI-2040 was administered as a continuous intravenous infusion for 21 days every 4 weeks. Dose escalation was performed using an accelerated, dose-doubling schedule until any drug related toxicity > or = grade 2 was observed; subsequent dose escalation followed a more conservative dose escalation scheme with three patients/cohort. RESULTS: A total of 49 cycles of therapy were administered to 36 patients at GTI-2040 doses ranging from 18.5 mg/m(2)/day to 222 mg/m(2)/day. GTI-2040 was generally well tolerated. At the highest dose level examined, two patients experienced dose limiting reversible hepatic toxicity. Constitutional toxicities consisting of fatigue and anorexia were the most common toxicities. CONCLUSIONS: The recommended dose of GTI-2040 given on this infusion schedule is 185 mg/m(2)/day. GTI-2040 appears to have a manageable toxicity profile and is generally well tolerated as a single agent.     

A phase I study of human lymphoblastoid interferon administered by continuous intravenous infusion

Summary A phase I study of human lymphoblastoid interferon (IFN-) was undertaken in patients with acute leukaemia and other malignancies. The pharmacokinetics of intravenous IFN- were also investigated.IFN- was administered to two patients by intravenous (IV) bolus injection at a dose of 5×10⁶ U/m²; and to a further 37 patients (40 cycles) by continuous intravenous infusion (IVI) for 5, 7, or 10 days at doses ranging from 5 to 200×10⁶ U/m²/day. Pyrexia, general malaise, anorexia, and rigors were observed at all dose levels; three patients became hypotensive. Myelosuppression occurred in all patients, including seven without bone marrow infiltration. Transient rises in alkaline phosphatase and transaminases (SGOT) were observed in patients receiving daily doses greater than 30×10⁶ U/m². Dose-limiting central nervous system toxicity, hyperkalaemia, and hypocalcaemia were encountered at 200×10⁶ U/m².In six patients with acute leukaemia there was a fall in the number of circulating leukaemic blasts and in one patient with acute myelogenous leukaemia (AML) the degree of bone marrow infiltration decreased from 99% to less than 5% with cellularity returning to normal. Serum levels of IFN above 1,000 U/ml were achieved with daily doses above 30×10⁶ U/m² given by IVI. The maximum safely tolerated daily dose, 100×10⁶ U/m² administered for 7 days, is appreciably higher than that used in most previous studies, although even at this level consideralbe toxicity may be encountered.     

Unchanged pharmacokinetics of etoposide given by intra-arterial hepatic infusion as compared with i.v. infusion

 We investigated the pharmacokinetics of etoposide given to a patient suffering from multifocal liver metastases from an unknown primary tumor. The drug was given either by i.v. infusion or by hepatic arterial infusion (HAI). The calculated pharmacokinetic parameters (mean values ± SD) were similar after i.v. infusion and HAI, viz., 6.4±0.7 versus 6.5±0.2 h for the terminal elimination half-life (t _1/2β), 98.5±1.3 versus 101.3±5.9 mg l^-1 h for the area under the plasma concentration-time curve (AUC), 21.2±0.3 versus 20.6±1.2 ml min^-1 m^-2 for clearance (Cl), 17.7±1.9 versus 18.1±2.6 mg/l for the peak concentration, and 11.7±1.3 versus 11.6±1.0 l/m² for the volume of distribution (V _d ), respectively. We therefore conclude that administration of etoposide by HAI does not result in a significantly higher liver extraction. Hepatic extraction of etoposide is determined by the fraction of non-protein-bound (free) drug present. The lack of a difference between the two administration routes suggests that under in vivo conditions the equilibrium between free and bound drug is established before the drug reaches the hepatic arterioles. Consequently, administration by HAI does not lead to an increased exposure of the tumor in the liver to free (active) etoposide. Furthermore, the overall exposure of the liver to total (bound + free) etoposide is increased only from about 100 to 120 mg l^-1 h. These results do not favor the use of this more complex route of drug administration in the treatment of (metastatic) cancer located in the liver. Received: 5 November 1995/Accepted: 17 January 1996     

A phase I study of intravenous iododeoxyuridine as a clinical radiosensitizer

Twenty-four patients with locally advanced (19 patients) or metastatic (5 patients) tumors were treated in a Phase I study combining constant intravenous infusions of iododeoxyuridine (IUdR) and hyperfractionated radiation therapy. IUdR was given as a constant infusion for 12 hours/day for two separate 14-day infusion periods in most patients. The dose of IUdR was escalated from 250 to 1200 mg/m2/12-hour infusion in this study. The initial tumor volume was treated to 45 Gy/1.5 Gy BID/3 weeks followed by a cone-down boost to 20-25 Gy/1.25 Gy BID/2 weeks after a planned 2-week break. THe IUdR infusion preceded the initial and cone-down irradiation by 1 week. Local acute toxicity (within the radiation volume) was uncommon and few patients required an alteration of the planned treatment schedule. Two patients developed late local toxicity with one patient showing clinical signs of radiation hepatitis and another patient developing a large bowel obstruction that required surgical bypass. Dose-limiting systemic toxicity was confined to the bone marrow with moderate to severe thrombocytopenia developing on Day 10-14 of infusions at 1200 mg/m2/12 hours. Mild stomatitis and partial alopecia occurred in some patients at this dose level. No systemic skin toxicity was seen. Pharmacology studies revealed steady-state arterial plasma levels of IUdR of 1 to 8 X 10(-6) M over the dose range used. In vivo IUdR incorporation into tumors was studied in three patients with high-grade sarcomas using an anti-IUdR monoclonal antibody and immunohistochemistry and demonstrated incorporation in up to 50-70% of tumor cells. The preliminary treatment results, particularly in patients with unresectable sarcomas, are encouraging. In comparison to our previous experience with intravenous bromodeoxyuridine, this Phase I study of IUdR shows less systemic toxicity (especially to skin), higher (2-3X) steady-state arterial levels, and comparable in vivo tumor cell incorporation.     

The effect of P-glycoprotein and cytochrome P450 3a on the oral bioavailability of vinorelbine in mice

Purpose: This study was designed to determine the effects of P-glycoprotein (P-gp) and cytochrome P450 3a metabolism on the oral bioavailability of the vinca alkaloid Vinorelbine (Navelbine; VRL). Methods: Pharmacokinetics of VRL were determined in FVB wild-type and mdr1a/1b (−/−) mice after oral and intravenous administration of 10 mg/kg VRL with or without oral ritonavir (5 mg/kg) prior to VRL. Serial blood samples were drawn for a period of up to 48 hours using mice with a cannulated jugular vein. Feces was collected for a period of 96 hours. VRL was determined by ion-exchange HPLC in combination with fluorescence detection. Results: The oral bioavailability in wild-type was 16.0±1.4% (mean±SE) and was not significantly higher in mdr1a/1b (−/−) mice (17.9±0.7%). Both after intravenous and oral administration, the AUC was not significantly different between wild-type and mdr1a/1b(−/−) mice. When RTV was co-administered the AUC of intravenous VRL increased significantly by 30% (p = 0.012). Because RTV increased the AUC of oral VRL by 83% the oral bioavailability was increased to 22.5±2.3% (p = 0.016). The fecal recovery of unchanged VRL was about 34 and 6% of the dose in wild-type and mdr1a/1b(−/−) mice, respectively, and was not altered by RTV. Conclusion: This study shows that P-gp has little effect on the disposition and oral bioavailability of VRL. A substantial fraction of an oral dose of VRL is absorbed from the gut of wild-type mice. Consequently, first-pass metabolism is the most important factor for explaining the modest oral bioavailability, but the results with RTV suggest that cyp3a plays only a modest role in metabolic breakdown in mice. Apparently, other routes of metabolic elimination are more important. These results suggest that also in patients the oral bioavailability may not gain substantially from the co-administration of a potent P-gp and/or Cyp3a inhibitor.     

Phase I clinical and pharmacology study of 502U83 given as a 24-h continuous intravenous infusion

Summary 502U83 is an arylmethylaminopropanediol that displays significant antitumor activity in a number of murine and human tumor-model systems. In the present phase I study, a 24-h continuous intravenous infusion of this agent was given every 28 days to patients with advanced or refractory solid tumors. In all, 46 patients received a total of 96 cycles of 502U83 at doses ranging from 25 to 8,000 mg/m². No significant hematologic, gastrointestinal, or neurologic toxicity was observed. At doses of 2,000 mg/m² and higher, prolongation of the corrected QT interval on ECG was evident in most patients but was completely reversible, was not associated with arrhythmias, and was not dose-limiting. Dose-limiting pulmonary toxicity characterized by acute onset of dyspnea, severe hypoxemia, interstitial pulmonary edema, and death occurred in three patients treated at the highest dose levels. Plasma concentrations of 502U83 and its metabolites were measured by high-performance liquid chromatography. The 502U83 maximal concentration (C_max) and area under the concentration-time curve (AUC) were proportional to the delivered dose; however, substantial interpatient variability in total body clearance was note at all dose levels. Significant conversion of 502U83 to two glucuronide metabolites was detected. Metabolite concentrations were highest in the three patients who succumbed to pulmonary toxicity, although the precise contribution of these metabolites to the observed toxic effects is unknown. In view of the unfavorable clinical profile of QTc prolongation and pulmonary toxicity produced by 502U83, further clinical development of this agent has been suspended.This work was supported in part by an American Cancer Society Clinical Oncology Career Development Award (to M.J.R.) and by a grant from the Burroughs Wellcome Co.     

A phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients.

PURPOSE: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks. EXPERIMENTAL DESIGN: Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m(2)). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose. RESULTS: Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m(2), but lower doses were well tolerated. No responses were seen, but 28% had stable disease for > or =3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m(2) indicated the following averages: maximum plasma level, 1.6 microM; area under the plasma concentration-time curve, 56 microM.h; terminal half-life, 27 h; urinary recovery, 17% over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at > or =281 mg/m(2)). CONCLUSIONS: Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m(2), which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.     

Phase I study of Datelliptium chloride,hydrochloride given by 24-h continuous intravenous infusion

Summary Datelliptium chloride, hydrochloride (SR 95 156B, NSC 626718X, DHE) was studied in a phase I trial of escalating doses given on a single 24-h continuous intravenous infusion schedule. Doses were escalated from 40 to 500 mg/m² in 19 patients who received a total of 24 courses. Courses were repeated after a minimal interval of 3 weeks. Local venous toxicity occurred at low doses (100 mg/m²) and was circumvented by the use of a central venous access for higher doses. Other clinical adverse events occurred (330 mg/m²), including moderate nausea and vomiting, mild diarrhea, dry mouth, neuropsychiatric manifestations, and fatigue. All of these side effects were reversible and none was dose-limiting. The dose-limiting toxicity was related to hepatic laboratory-test abnormalities in the form of reversible elevations of levels of serum bilirubin and liver enzymes at doses of 330 mg/m². The maximum tolerated dose for this schedule is 500 mg/m². Hematologic toxicity was minimal and non-dose-limiting. Neither drug-related deaths nor objective complete or partial responses were observed. However, a minor response and a long-term disease stabilization were obtained.     

An open study to assess the safety,tolerance and pharmacokinetics of an intravenous infusion of granisetron given at 3 mg over 30 s in patients receiving chemotherapy for malignant disease

Granisetron is a highly potent and selective 5-hydroxytryptamine₃ (5-HT₃) receptor antagonist indicated for the prevention of cytotoxic-induced nausea and vomiting. Clinical trials have demonstrated granisetron to be effective and well tolerated at a standard dose of 40 g/kg or 3 mg given i.v. as a 5-min infusion. In this study, the efficacy and safety of granisetron given as a 30-s infusion was assessed. A total of 21 patients, scheduled to undergo chemotherapy, received a single 3-mg i.v. dose of granisetron over 30 s, completed at 1 h before chemotherapy administration. Patients were allowed two further i.v. doses of granisetron at 3 mg within the 24-h assessment period. Changes from baseline values in vital signs were analysed prior to granisetron administration and at 30 s as well as 1, 10, 15, 30 and 60 min after granisetron administration. Holter ECG recordings were taken for 6 h prior to and 1 h after administration. No significant change was found in vital signs at 30 s or 1 min after granisetron infusion. There was a small but statistically significant fall in diastolic blood pressure as compared with baseline and a non-significant trend in favour of a reduction in heart rate at 10 and 15 min. No ECG abnormality was recorded post-infusion that had not been present pre-infusion. None of these changes was considered to be clinically relevant. The treatment was well tolerated. The most frequenctly reported adverse events were constipation (n=6) and headache (n=5). Maximal plasma levels of granisetron were within the range of 44.57–410 ng/ml except in one patient. The median values recorded for peak concentration (C_max) and area under the curve (AUC) were 195 ng/ml and 71.2 ng h ml^–1, respectively. In conclusion, granisetron at 3 mg was shown to be safe and well tolerated when given as a 30-s i.v. infusion to patients receiving chemotherapy for malignant disease.     

Clinical pharmacokinetics of the irinotecan metabolite 4-piperidinopiperidine and its possible clinical importance

Purpose: To investigate the clinical relevance of 4-piperidinopiperidine (4PP) in the activity of irinotecan (CPT-11), a high-performance liquid chromatography-turboionspray-tandem mass spectrometry assay for plasma 4PP was developed. Methods: Plasma samples were prepared for analysis following C18 solid-phase extraction. Chromatography was performed on a Waters Nova-Pak Phenyl column. Selected reaction monitoring with the mass transitions m/z 169.2 → 84.2 and 139.2 → 98.1 was used for the detection of 4PP and the internal standard (IS), 1-piperidineproprionitrile, respectively. Results: The assay was linear from 14.8 to 591.0 nM with absolute recoveries of 4PP (59.1 nM) and IS (143.7 nM) of 85.7% (n=10) and 86.7% (n=10), respectively. The accuracy and imprecision of the method (total) was ≥96.8% and ≤8.5% over the concentration range studied, respectively. 4PP was detectable in plasma following the administration of 125, 350, 500 mg/m² and 600 mg/m² CPT-11 to patients, with AUC_4PP correlated with the dose (r ²= 0.66). Plasma concentrations of 4PP declined slowly with a long terminal half-life (33.4 ± 17.1 h). Conclusions: Overall, the concentrations of 4PP in plasma were in the sub-micromolar range (<206.9 nM) and substantially lower than those capable of inducing apoptosis of cancer cells. Received: 29 March 1999 / Accepted: 19 July 1999     

The pharmacokinetics of a 1-h paclitaxel infusion

Purpose: To characterize the disposition of paclitaxel (PAC) after a 1-h infusion in humans and define if possible a pharmacodynamic relationship between PAC disposition and the observed toxicity. Patients and methods: PAC pharmacokinetics were studied in 43 courses of therapy in 30 patients (30 first course, 13 PK third course). PAC was administered at 150, 175, 200, 225 and 250 mg/m² by a 1-h infusion to patients with advanced cancer (lung, breast, ovarian, cervix, and head and neck). PAC was quantified by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by noncompartmental and model-dependent methods. Results: Increases in the area under the curve and the peak plasma concentration were not proportional to increases in the dose. However, the deviation from linearity is rather moderate. The dose-limiting toxicity was central neuropathy which was not associated with pharmacokinetic deviations. Owing to the absence of grade 3 or 4 myelotoxicity, no clear correlation between this toxicity and pharmacokinetic parameters could be established. Conclusion: Within the evaluated dose range of the 1-h infusion there was only a moderate nonlinear disposition of PAC in humans and therefore a dose of 225 mg/m² is recommended as safe. The observation of central neuropathy could not be directly related to a pharmacokinetic parameter. The complexity of the formulation which included Cremophor EL and ethanol may offer an explanation for the observed central neurotoxicity. Received: 24 May 1999 / Accepted: 16 December 1999     

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil,and tamoxifen in metastatic breast-cancer patients

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m²) together with different doses of epirubicin (E, 60–100 mg/m²), fixed-dose cyclophosphamide (C, 600 mg/m²), fixed-dose 5-fluorouracil (F, 600 mg/m²), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m². We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.