A pharmacokinetic and safety study of a novel polymeric paclitaxel formulation for oral application

Purpose: To investigate the pharmacokinetics, safety, and tolerability of a new oral formulation of paclitaxel containing the polymer polyvinyl acetate phthalate in patients with advanced solid tumors. Patients and methods: A total of six patients received oral paclitaxel as single agent given as a single dose of 100 mg on day 1, oral paclitaxel 100 mg in combination with cyclosporin A (CsA) 10 mg/kg both given as a single dose on day 8, and i.v. paclitaxel (Taxol®) 100 mg as a 3-h infusion on day 15. Results: The AUC (mean ± standard deviation) values of paclitaxel after oral administration without CsA and with CsA were 476 ± 254 and 967 ± 779 ng/ml h, respectively. T _max was 4.0 ± 0.9 h after oral paclitaxel without CsA, and 6.0 ± 3.1 h after oral paclitaxel with CsA. The mean AUC after oral administration as single agent was 13% of the AUC after i.v. administration of paclitaxel, and increased to 26% after co-administration with CsA. No haematological toxicities were observed, and only mild (CTC-grade 1 and 2) non-hematological toxicities occurred after oral intake of paclitaxel with or without CsA. Conclusion: The AUC of the new polymeric paclitaxel formulation increased a factor 2 in combination with CsA, which confirms that CsA co-administration can also improve exposure to paclitaxel after oral administration of a polymeric formulation. Because of the delayed release of paclitaxel from this formulation, we hypothesize that a split-dose regimen of CsA where it is administered before and after paclitaxel administration will further increase the systemic exposure to paclitaxel up to therapeutic levels. The formulation was well tolerated at the dose of 100 mg without induction of severe toxicities.     

Functional studies with a full-length P-glycoprotein cDNA encoded by the Hamster pgp1 gene

We defined the pharmacokinetics of paclitaxel after i. v., i. p., p. o., and s. c. administration of 22.5 mg/kg to CD₂F₁ mice. Additional mice were studied after i. v. bolus dosing at 11.25 mg/kg or 3-h continuous i.v. infusions delivered at 43.24 g kg^–1 min^–1. Plasma was sampled between 5 min and 40 h after dosing. Brains, hearts, lungs, livers, kidneys, skeletal muscles, and, where applicable, testicles were sampled after i.v. dosing at 22.5 mg/kg. Liquid-liquid extraction followed by isocratic high-performance liquid chromatography (HPLC) with UV detection was used to determine paclitaxel concentrations in plasma and tissues. After i.v. administration to male mice, paclitaxel clearance (CL_tb) was 3.25 ml min^–1 kg^–1 and the terminal half-life (t _1/2) was 69 min. After i.v. administration to female mice, paclitaxel CL_tb was 4.54 ml min^–1 kg^–1 and the terminalt1/2 was 43 min. The bioavailability of paclitaxel was 10%, 0, and 0 after i.p., p.o., and s.c. administration, respectively. Paclitaxel bioavailability after i.p. administration was the same when the drug was delivered in a small volume to mimic the delivery method used to evaluate in vivo antitumor efficacy or when it was delivered in a large volume to simulate clinical protocols using i.p. regional therapy. Paclitaxel was not detected in the plasma of mice after i.p. delivery of the drug as a suspension in Klucel: Tween 80. Pharmacokinetic parameters were similar after i.v. delivery of paclitaxel at 22.5 and 11.25 mg/kg; however, the CL_tb calculated in these studies was much lower than that associated with 3-h continuous i.v. infusions. After i.v. administration, paclitaxel was distributed extensively to all tissues but the brain and testicle. These data are useful in interpreting preclinical efficacy studies of paclitaxel and predicting human pharmacokinetics through scaling techniques.This work was supported by contract NO1-CM27711 awarded by the National Cancer Institute, DHHS     

Disposition and metabolism of KW-2149, a novel anticancer agent

KW-2149 is a new derivative of mitomycin C (MMC). The plasma concentrations, distribution, metabolism, and excretion of [³H]-KW-2149 in normal and tumor-bearing mice after i. v. administration of 16.6 mg/kg were investigated. The plasma radioactivity decreased biexponentially after i. v. administration in normal mice. However, the unchanged drug disappeared rapidly, showing a half-life (t _1/2) of 9.7 min, which was shorter than MMC's (18 min). The radioactivity was excreted in mouse urine (33%) and feces (58%) within 144 h. High radioactivity was distributed in the gallbladder, liver, kidney, pancreas, and lung at 1 h after i. v. administration to normal mice. The tumor concentration was lower than the plasma or blood concentration. The lowest radioactivity was observed in the brain. The metabolic rate of KW-2149 was very rapid. The methyl sulfide form (M-16), the symmetrical disulfide dimer (M-18), and the albumin conjugate were detected in plasma, which possessed anticellular activity. The specific anticellular activity of these compounds against uterine carcinoma (HeLa S3) was 1/100, 1, and 1/20 respectively, as compared with that of KW-2149.Abbreviations MMC mitomycin C - LD₁₀ 10% lethal dose - HPLC high-performance liquid chromatography - AUC area under the concentration-time curve - t _1/2 half-life - Vd_ss volume of distribution at steady state - Cl_tot total clearance     

Intraperitoneal administration of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide in the mouse: bioavailability,pharmacokinetics and toxicity after a single dose

Summary The pharmacokinetics, tissue distribution and toxicity of the antitumour agentN-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (AC) were studied after i.p. administration of [³H]-AC (410 mol/kg) to mice. The latter is the optimal single dose for the cure of advanced Lewis lung tumours. AC was rapidly absorbed into the systemic circulation after i.p. administration, with the maximal concentration (C _max) occurring at the first time point (5 min). There was no reduction in bioavailability as compared with previous i.v. studies, but the shape of the plasma concentration-time profile was considerably different, reflecting a 3-fold lowerC _max value (20.9±3.6 mol/l) and a longert _1/2 value (2.7±0.3 h) as compared with that observed after i.v. administration (1.6±0.6 h). Model independent pharmacokinetic parameters after i.p. administration were: clearance (C), 17.5 l h^–1 kg^–1; steady-state volume of distribution (V_ss), 14.1 l/kg; and mean residence time (MRT), 1.46 h. High but variable tissue uptake of AC was observed, with tissue/plasma AUC ratios being 5.7 for heart, 8.4 for brain, 18.9 for kidney and 21.0 for liver but with similar eliminationt _1/2 values ranging from 1.3 to 2.7 h. All radioactivity profiles in plasma and tissues were greater than the respective parent AC profiles and showed prolonged eliminationt _1/2 values ranging from 21 h in liver to 93 h in brain. However, tissue/plasma radioactivity AUC ratios were near unity, ranging from 0.7 to 1.57, with the exception of the gallbladder (15.6), which contained greater amounts of radioactivity. By 48 h, approximately 70% of the total dose had been eliminated, with the faecal to urinary ratio being approximately 2:1. This i.p. dose was well tolerated by mice, with sedation being the only obvious side effect. No major change was observed in blood biochemistry or haematological parameters. Comparisons ofC _max,t _max and AUC values determined for AC in brain after its i.p. and i.v. administration suggest that the reduction in acute toxicity after i.p. administration is not due to reduced exposure of the brain to AC as measured by AUC but may be associated with the lowerC _max value or the slower rate of entry of AC into the brain after i.p. administration.This study was supported by the Cancer Society of New Zealand. The senior author (S.M.H.E.) is the recipient of a Health Research Council of New Zealand Junior Research Award     

Pharmacokinetics and distribution of SN 28049, a novel DNA binding anticancer agent, in mice

Purpose

N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent DNA binding topoisomerase II poison that shows excellent antitumour activity in a colon-38 murine tumour model in comparison to standard topoisomerase II poisons. We report here the preclinical pharmacokinetics of SN 28049.

Methods

C57 Bl/6 mice (n = 3 per time point) were treated with a single i.v., i.p. or p.o. administration (8.9 mg/kg). Plasma and tissue samples were analysed using a validated LC/MS method utilizing a homologue as an internal standard.

Results

The assay range was 0.062–2.5 μM with a quantitation limit of 0.062 μM and a detection limit of 0.025 μM. Acceptable intra- and inter-assay accuracy (95–105%) and precision (<6.5% RSD) were achieved. Following i.v. administration, SN 28049 demonstrated 2-compartment model kinetics with a volume of distribution of 42.3 ± 4.1 l/kg, a plasma clearance of 12.1 ± 0.5 l/h per kg and distribution and elimination half-lives of 0.15 ± 0.02 and 2.8 ± 0.2 h (mean ± SE), respectively. For all administration routes, SN 28049 concentrations in normal tissues (brain, heart, liver, lung, and kidney) were 12- to 120-fold higher than those in plasma, but half-lives and mean residence times were similar. The i.p. and p.o. bioavailabilities were 83.1 ± 1.5 and 54.5 ± 1.1%, respectively. In the tumour tissue, elimination half-life (9.1 ± 0.7 h) and the mean residence time (18.2 ± 0.7 h) were significantly (P < 0.001) longer than those of plasma and normal tissues. The tumour area under the concentration–time curve (AUC) (1,316 ± 66 μM h) was also 693-fold greater than the plasma AUC, and considerably higher (~5-fold) than any other tissue examined, indicating selective uptake and retention of SN 28049 in the tumour.

Conclusion

We conclude that SN 28049’s high tumour exposure and long tumour retention time is likely to contribute to its high antitumour activity in vivo.     

Pharmacokinetics and tumor uptake of a derivatized form of paclitaxel associated to a cholesterol-rich nanoemulsion (LDE) in patients with gynecologic cancers

Objective: A cholesterol-rich nanoemulsion termed LDE concentrates in cancer tissues after injection into the bloodstream. The association of a derivatized paclitaxel to LDE showed lower toxicity and increased antitumoral activity as tested in a B16 melanoma murine model. Here, the pharmacokinetics of LDE–paclitaxel oleate and the ability of LDE to concentrate the drug in the tumor were investigated in patients with gynecologic cancers. Methods: Either LDE–paclitaxel oleate doubly labeled with [¹⁴C]-cholesteryl oleate and [³H]-paclitaxel oleate or [³H]-paclitaxel-cremophor was intravenously injected into eight patients. Blood samples were collected over 24 h to determine the plasma decay curves. Fractional clearance rate (FCR) and pharmacokinetic parameters were calculated by compartmental analysis. Also, specimens of tumors and the corresponding normal tissues were excised during the surgery for radioactivity measurement. Results: The LDE and paclitaxel oleate FCR were similar (0.092 ± 0.039 and 0.069 ± 0.027 h⁻¹, respectively, n = 5, P = 0.390). FCR of paclitaxel oleate associated to LDE was smaller than that of paclitaxel-cremophor (0.231 ± 0.128 h⁻¹, P = 0.028). Paclitaxel oleate T _1/2 and AUC were greater than those of paclitaxel-cremophor (T _1/2 = 14.51 ± 3.23 and 6.62 ± 2.05 h and AUC = 2.49 ± 0.35 and 1.26 ± 0.40, respectively, P = 0.009, P = 0.004). The amount of paclitaxel and LDE-radioactive labels in the tumor was 3.5 times greater than in the normal tissues. Conclusion: Paclitaxel oleate associated to LDE is stable in the bloodstream and has greater plasma half-life and AUC than those for paclitaxel-cremophor. LDE concentrates 3.5 times more paclitaxel in malignant tissues than in normal tissues. Therefore, association to LDE is an interesting strategy for using paclitaxel to treat gynecologic cancers.     

Pharmacokinetics and tumor concentration of intraarterial and intravenous cisplatin in patients with head and neck squamous cancer

Summary Tumor-tissue platinum levels and major pharmacokinetic parameters were determined in 11 patients with head and neck squamous cancer (HNSC) who were given cisplatin (50 mg/m² daily x 2 days) and 5-fluorouracil (5-FU; 1000 mg/m², continuous infusion x 5 days) either i.a. or i.v. The plasma peak platinum concentrations (c _max) and the areas under the curve for total platinum concentration versus time (AUC) during i.a. infusions were lower than the i.v.c _max (mean, 1.92±0.28 and 4.08±2.80 mg/l, for i.a. and i.v. infusions, respectively) and AUC values (mean, 22.55±4.96 and 40.66±10.71 mg h^–1 l^–1 for i.a. and i.v. treatment, respectively), suggesting a first-passage extraction of the drug by the tumor mass during i.a. infusion. However, no statistically significant difference was found in platinum tumor concentrations after i.a. administration versus i.v. infusion. The lack of a difference in tumor platinum concentrations between the i.a. and the i.v. administration routes might be explained either by a relatively high blood supply to the tumor area, enabling efflux of the surplus free platinum from the tissue, or by the delay between drug infusion and biopsy. After three cycles of i.a. treatment good tumor remission was obtained with minimal local toxicity. Larger clinical studies testing the advantages of the i.a. administration route over i.v. infusion appear to be necessary.Abbreviations HNSC head and neck squamous cancer - AUC area under the total platinum concentration versus time curve - OS overall survival - 5-FU 5-fluorouracil - DFS disease-free survival - CR complete response - PR partial response - SD stable disease - PRO progression This study was supported by grants from the AIRC (Italian Association for Cancer Research) and by grant from the Regione Veneto. One of the Authors (P.A.) is the recipient of an MPI 40% grant     

Diffusion of Oral and Intravenous 400 mg Once-Daily Moxifloxacin into Lung Tissue at Pharmacokinetic Steady-State

Abstract

The degree of penetration of an antibiotic into the infection site is an important factor for its therapeutic efficacy, particularly in respiratory tract infections. In the present study, we examined the lung tissue diffusion of moxifloxacin at a dose of 400 mg administered intravenously or orally once-daily, and the results were correlated to microbiological data to estimate the clinical efficacy of moxifloxacin in lower community-acquired respiratory infections. This was a prospective, randomized, parallel-group trial, open-label, single-center study. Patients undergoing lung surgery for bronchial cancer which necessitates the removal of an anatomical piece of lung tissue were randomized into twelve treatment groups, dependent upon the time of surgery and the moxifloxacin formulation, i.v. or oral, administered. During surgery, one blood sample was taken at the time of tissue collection to determine moxifloxacin plasma concentration. At the same time, tissue samples were taken by pulmonary exeresis. A validated new high performance liquid chromatography assay was used to determine moxifloxacin concentrations in plasma and lung tissue. A total of 49 patients (25 for i.v. administration, 24 for oral administration, 44 men and 5 women, mean age, 61 years, mean body weight, 72 kg, mean creatinine clearance was 84 ml/min/1.73 m²) were enrolled. The mean ± SD steady-state moxifloxacin ratios between lung and plasma concentrations were respectively: 3.53 ± 1.89 and 4.36 ± 1.48 for i.v. and oral administration.

The mean steadystate moxifloxacin maximal lung concentrations (Cmax) were respectively 12.37 μg/g and 16.21 μg/g for i.v. and oral administration. Moxifloxacin both intravenously and orally exhibits high penetration in lung tissue, with tissue concentrations far above the MIC_90s for most of the susceptible pathogens commonly involved, thus underlining its suitability for the treatment of community-acquired, lower respiratory tract infections.     

Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors

Purpose: Evaluation of inter- and intrapatient variability of topotecan oral bioavailability and disposition was performed in children with malignant solid tumors. Patients and methods: Topotecan i.v. formulation was given orally on schedules of daily for 21 consecutive days (d × 21) or daily for 5 days per week for 3 weeks [(d × 5)3], in both cases repeated every 28 days. Topotecan doses of 0.8 and 1.1 mg/m² per day were evaluated on both schedules. Serial plasma samples were obtained after oral and i.v. administration of topotecan at the beginning and end of the first course of therapy. Topotecan lactone and total concentrations were measured by a high-performance liquid chromatography (HPLC) assay, and a one-or two-compartment model was fit to the plasma concentration-time data after oral or i.v. administration, respectively. Topotecan oral bioavailability (F) was calculated as the ratio of the AUC determined after oral treatment (AUC_po) divided by the AUC calculated after i.v. administration. Results: Pharmacokinetics studies were performed on 15 and 11 patients receiving 0.8 and 1.1 mg/m² per day, respectively. After oral administration the topotecan lactone AUC_po and F determined for 0.8 and 1.1 mg/m² per day were 13.6 ± 5.8 and 25.1 ± 12.9 ng ml⁻¹ h and 0.34 ± 0.14 and 0.34 ± 0.16, respectively. The within-patient variance for AUC_po and F was much smaller than the between-patient variance. The ratio of topotecan lactone to total concentration was consistently higher after oral as compared with i.v. administration. Conclusions: Large interpatient variability was noted in topotecan pharmacokinetics, whereas intrapatient variability was relatively small. Further studies of oral topotecan are warranted to evaluate the tolerance of shorter courses and to define further the interpatient variability. Received: 14 August 1998 / Accepted: 9 November 1998     

Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors

Purpose Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors.Experimental design Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m² i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml×min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml×min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed.Results The administered regimen of paclitaxel (225 mg/m² i.v. over 3 h) and carboplatin (AUC 6 mg/ml×min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m² i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease.Conclusions The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.     

Optimal doses of paclitaxel and carboplatin combination chemotherapy for ovarian cancer: a phase I modified continual reassessment method study

Background. A multicenter, phase I study of combination therapy with paclitaxel and carboplatin for epithelial ovarian cancer was conducted to determine the safety and recommended dosages for Japanese women. Methods. Paclitaxel was administered intravenously over a 3-h period, followed by carboplatin administered intravenously over a 1.5-h period. A modified continual reassessment method (mCRM) was used in two treatment arms to establish the maximum tolerated dose (MTD) and recommended doses of the combination. In group A, the dose of paclitaxel (175 mg/m²) was constant and the dose of carboplatin was increased from 4 to 7 in terms of the target area under the plasma concentration-versus-time curve (AUC). In group B, the dose of carboplatin was constant (AUC 6) and paclitaxel was administered at two dose levels (160 and 175 mg/m²). In both groups, the carboplatin dose was limited to a maximum of 800 mg/body for each administration. Results. Because the calculated probability of toxicity was greatest at a dose of paclitaxel 175 mg/m² and carboplatin AUC 7, this dose was designated the MTD in group A. Based on this result, treatment in group B was initiated at doses of paclitaxel of 160 mg/m² and carboplatin AUC 6. While the dose of paclitaxel was escalated to 175 mg/m², the safety of the combination was confirmed. The most frequent adverse effect was neutropenia, which resolved promptly with the appropriate use of granulocyte-colony stimulating factor (G-CSF). No other severe hematologic or nonhematologic toxicities were observed. Conclusions. Our study demonstrated that the recommended dose for this combination regimen should be paclitaxel 175 mg/m² plus carboplatin AUC 6 (maximum dose, 800 mg/body). Received: March 5, 2001 / Accepted: September 6, 2001     

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 limited sampling strategy for estimation of the cladribine plasma area under the concentration versus time curve after intermittent i.v. infusion,s.c. injection,and oral administration

 Cladribine is a newly developed antimetabolite with promising activity in lymphoproliferative disorders. Recent pharmacokinetics investigations have suggested that there is a relationship between its plasma area under the concentration versus time curve (AUC) and the degree of neutropenia posttreatment as well as the therapeutic outcome in hairy-cell leukemia. To enable a simple estimation of the plasma AUC, a limited sampling strategy was developed. Stepwise linear regression was used to determine which were the most important data points for estimation of the plasma AUC after 2-h i.v. infusion, s.c. injection (5 mg/m²), and oral administration (10 mg/m²) in 27 patients. The most important data points after i.v. infusion in 12 patients were 1, 4, and 24 h, in order of importance. The AUC could be estimated as 2.9081×C _1h ⁺5.1851×C _4h ⁺20.3265×C _24h .The accuracy and precision (mean value±SD for the determined/estimated AUC was 0.99±0.053) of the model could not be increased by the addition of more data points. A somewhat lower accuracy and precision (0.96± 0.089) was seen with the 2-, 4-, and 24-h data points. These were used to test the regression technique prospectively for the estimation of the AUC after i.v. administration in another set of 10 patients. The accuracy and precision of the estimation of the AUC was similar in this group (1.01±0.109). In all, 11 patients were treated orally (10 mg/m²) and 10 patients were treated by s.c. injection (5 mg/m²). The most important data points for estimation of the AUC were 2.5, 24, and 0.5 h after oral administration (AUC=0.8630×C _0.5 h+ 4.2337×C _2.5h ⁺45.4364×C _24h ) and 9, 1, and 16 h after s.c. injection (AUC=1.8821×C _1h +16.4256×C _9h ⁺ 25.4518×C _16h ). The accuracy and precision were 1.01±0.064 after oral dosing and 0.99±0.11 after s.c. injection. The derived mathematical models are reliable for estimation of the plasma AUC of cladribine after 2-h i.v. infusion, oral administration, and s.c. injection. Received: 8 October 1995/Accepted: 1 March 1996     

Safety and efficacy of sequential chemotherapy with carboplatin plus gemcitabine followed by weekly paclitaxel in advanced non-small cell lung cancer

Background

Improving survival in non-small cell lung cancer (NSCLC) will require new strategies or new drugs. Sequential administration of conventional non-cross-resistant cytotoxic drugs offers an opportunity to increase drug diversity while maintaining dose intensity. This Phase II trial was designed to assess the efficacy and feasibility of such a regimen in advanced NSCLC.

Methods

Patients with NSCLC stage IIIB or IV received as first-line treatment four cycles of carboplatin (AUC 5) (day 1) plus gemcitabine 1000 mg/m² (days 1 and 8) every 3 weeks. Thereafter, treatment continued with 12 weekly cycles of paclitaxel 80 mg/m².

Results

In total, 46 patients were included. Median age was 59.6 years (range 41.3–74.3 years) and 93.5 % (n = 43) had Eastern Cooperative Oncology Group performance score of 0 or 1. All but 6 had stage IV disease, and 13 (28.3 %) had squamous cell carcinomas. Thirty-six (78 %) patients completed 4 cycles of carboplatin–gemcitabine and 35 patients received at least 1 cycle of paclitaxel, of whom 16 (46 % of total) patients completed 12 cycles of paclitaxel. The overall objective response rate was 49 %. Sixteen (37 %) patients had a response to carboplatin–gemcitabine, increasing to 21 (49 %) patients after administration of paclitaxel. Of the 13 assessable patients who showed a partial response (PR) on carboplatin–gemcitabine, 12 (92 %) patients showed also a PR on paclitaxel. Of 19 assessable patients with stable disease (SD) on carboplatin–gemcitabine, 4 (21 %) had a PR and 13 (68 %) SD on paclitaxel. Toxicity was moderate: 24 % stopped because of toxicity.

Conclusion

Sequential chemotherapy with carboplatin–gemcitabine and weekly paclitaxel is active and feasible in advanced NSCLC patients.     

Inhibition of paclitaxel elimination in the isolated perfused rat liver by Cremophor EL

Purpose: Cremophor can alter the pharmacokinetics of cytotoxic drugs, including doxorubicin and etoposide. In view of its presence in the formulation of paclitaxel, the aim of this study was to investigate the influence of Cremophor on the hepatobiliary elimination of paclitaxel. Methods: In a recirculating isolated perfused rat-liver system the elimination of 1.7 mg paclitaxel given as a bolus into the perfusate reservoir was monitored in perfusate and bile in controls and after the administration of either 80 or 800 μl Cremophor. The higher dose of Cremophor yields clinically relevant perfusate concentrations. Paclitaxel was measured in perfusate, bile, and liver tissue by high-performance liquid chromatography. Results: Cremophor caused a dose-dependent inhibition of the elimination of paclitaxel, with a statistically significant mean value ± SD, n = 3; (P < 0.05 versus controls Bonferroni t-test) 9-fold increase in AUC (2227±106 versus 245 ± 40 g ml⁻¹min), 9-fold decrease in total clearance (0.8±0.1 versus 7.0±1.1 ml/min), and 5-fold increase in elimination half-life (92±14 versus 18±4 min) being observed after a dose of 800 μl Cremophor. With the addition of Cremophor the amount of paclitaxel remaining after 3 h increased in perfusate from none to 20, increased in liver tissue from 4 to 18, and remained constant in bile at 11–13%. In the control group, 86 of the paclitaxel dose was recovered in bile as five putative metabolites, which were measured in paclitaxel equivalents, with the major metabolite. M3 co-eluting with 3′-p-hydroxypaclitaxel. This decreased to 45 of the dose on the addition of Cremophor, and the ratio of M3 to paclitaxel in bile decreased. Conclusions: Cremophor inhibits the hepatic elimination of paclitaxel in the isolated perfused rat liver, primarily by preventing the drug from reaching sites of metabolism and excretion. The presence of Cremophor in the paclitaxel formulation may therefore contribute to the nonlinear pharmacokinetics and pharmacodynamics of paclitaxel. Received: 24 February 1998 / Accepted: 22 June 1998     

Drug distribution and pharmacokinetic/pharmacodynamic relationship of paclitaxel and gemcitabine in patients with non-small-cell lung cancer

Background:Gemcitabine and paclitaxel are two of the mostactive agents in non-small-cell lung cancer (NSCLC), and pharmacologicinvestigation of the combination regimens including these drugs mayoffer a valuable opportunity in treatment optimization. The presentstudy investigates the pharmacokinetics and pharmacodynamics ofpaclitaxel and gemcitabine in chemotherapy-naive patients with advancedNSCLC within a phase I study. Patients and methods:Patients were given i.v. paclitaxel 100 mg/m² byone-hour infusion followed by gemcitabine 1500, 1750 and 2000mg/m² by 30-min administration. Plasma levels of paclitaxel,gemcitabine and its metabolite 2,2-difluorodeoxyuridine(dFdU) were determined by high-performance liquid chromatography (HPLC).Concentration-time curves were modeled by compartmental andnon-compartmental methods and pharmacokinetic/pharmacodynamic (PK/PD)relationships were fitted according to a sigmoid maximum effect(E_max) model. Results:Paclitaxelpharmacokinetics did not change as a result of dosage escalation ofgemcitabine from 1500 to 2000 mg/m². A nonproportionalincrease in gemcitabine peak plasma levels (C_max, from 18.56± 4.94 to 40.85 ± 14.85 µg/ml) and area under theplasma concentration-time curve (AUC, from 9.99 ± 2.75 to 25.01± 9.87 h·µg/ml) at 1500 and 2000mg/m², respectively, was observed, suggesting the occurrenceof saturation kinetics at higher doses. A significant relationshipbetween neutropenia and time of paclitaxel plasma levels 0.05µmol/l was observed, with a predicted time of 10.4 h to decreasecell count by 50%. A correlation was also observed betweenpercentage reduction of platelet count and gemcitabine C_max,with a predicted effective concentration to induce a 50% decreaseof 14.3 µg/ml. Conclusion:This study demonstratesthe lack of interaction between drugs, the nonproportionalpharmacokinetics of gemcitabine at higher doses and the E_maxrelationship of paclitaxel and gemcitabine with neutrophil and plateletcounts, respectively. In addition, gemcitabine 1500 mg/m² isthe recommended dosage in combination with paclitaxel 100mg/m² for future phase II studies, due to its predictablekinetic behaviour and less severe thrombocytopenia than expected.     

A randomized study of epirubicin at four different dose levels in advanced breast cancer. Feasibility of myelotoxicity prediction through single blood-sample measurement

Summary Detailed pharmacokinetic analysis and subsequent evaluation of myelotoxicity were performed in 55 patients who had been randomized to 4 different doses of epirubicin (40, 60, 90 or 135 mg/m² given i.v. every 3 weeks). A significantly positive correlation was demonstrated between the AUC and the myelotoxicity of epirubicin. A similar correlation was observed when the metabolite epirubicinol was also considered. The decrease in leucocyte count as expressed by the logarithmic ratio between nadir WBC and initial WBC was linearly correlated with the AUC of either epirubicin alone (r=–0.55,P<0.001) or epirubicin and epirubicinol together (r=–0.63,P<0.001). As a relationship between the concentration of epirubicin in a single plasma sample taken at 6 h following i.v. administration and the AUC of the drug has been established, a log-linear relationship between the expected decrease in leucocytes and the concentration at 6 h after administration could be calculated. The proposed model is expressed as the equation: log WBC_nadir=log WBC_initial–0.0073×c ₆ (ng/ml) –0.14.This work was supported by the Lundbeck Foundation, the Michaelsen Foundation and Farmitalia Carlo Erba Ltd.     

Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients

Summary In an effort to improve the treatment of metastatic malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rIL-2) in a phase I–II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the pharmacokinetics of DTIC and its major metabolite, 5-aminoimidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m², 24-h i.v. infusion) was given on day 1 and rIL-2 (2–4 million Cetus units/m², 30-min i.v. injection), on days 15–19 and 22–26 of each course of therapy. The second DTIC dose was given on day 29, i.e., 3 days after the last rIL-2 administration. DTIC and AIC were assayed by reversed-phase HPLC. DTIC plasma levels showed a significant decrease after rIL-2 administration as compared with DTIC values obtained in the same patients before rIL-2 administration. DTIC area under the curve (AUC) values obtained after rIL-2 were lower than those obtained on day 1 before rIL-2 administration (P=0.02). After rIL-2, the total body clearance (Cl_T) was increased (P=0.04), as was the volume of distribution at steady state (V_ss;P=0.02). The decrease in AUC after rIL-2 administration became more pronounced as the rIL-2 dose was increased (P=0.03). No significant difference was detected in the elimination phase of DTIC when halflives obtained before and after rIL-2 administration were compared; the mean half-lives were 0.7 and 2.8 h for the - and -phases, respectively. The model-independent mean residence time was 3.4 h. The plasma AUC for the metabolite AIC did not charge after rIL-2 administration. AIC biphasic plasma elimination was also similar after rIL-2 administration, with - and -half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC did not differ after rIL-2 administration; the overall DTIC excretion was 39% of the dose over 48 h, and AIC urinary excretion was 25% of the DTIC dose. The observed decrease in the DTIC plasma AUC after rIL-2 administration appears to be due to an increase in the volume of distribution, since other factors such as half-lives, urinary excretion, and metabolism were not significantly altered. The clinical consequences of the rIL-2-DTIC interaction remain difficult to assess based on presently available data, but this drug interaction should be taken into consideration in the development of future chemo-immunotherapy regimens that include high-dose rIL-2.This study was supported by a contract from Cetus Corporation (Emeryville, California) and by Wayne State University Ben Kasle Trust Fund for Cancer Research     

Pharmacokinetics of temozolomide in association with fotemustine in malignant melanoma and malignant glioma patients: comparison of oral, intravenous, and hepatic intra-arterial administration

Purpose: Depletion of the DNA repair enzyme O⁶-alkylguanine-DNA alkyltransferase (AT) has been shown to increase tumor sensitivity to chloroethylnitrosoureas. Temozolomide (TMZ), an analogue of dacarbazine, can deplete AT, suggesting that it may be used to sensitize tumors to chloroethylnitrosoureas. However, the influence of nitrosoureas on the pharmacokinetics of TMZ is unknown, and a pilot study was performed to assess the pharmacokinetics of TMZ given via, various routes to 29 patients (27 malignant melanomas, 2 gliomas) with or without sequential administration of i.v. fotemustine. Methods: On day 1, TMZ was given intravenously (i.v.), orally (p.o.), or by intrahepatic arterial infusion (h.i.a.) at four ascending dose levels (150 to 350 mg/m² per day). On day 2 the same dose of TMZ was given by the same route (or by another route in six patients for determination of its bioavailability), followed 4 h later by fotemustine infusion at 100 mg/m². Plasma and urinary levels of TMZ were determined on days 1 and 2 by high-performance liquid chromatography after solid-phase extraction. Results: The pharmacokinetics of i.v. TMZ appeared linear, with the area under the curve (AUC) increasing in proportion to the dose expressed in milligrams per square meter (r = 0.86 and 0.91 for days 1 and 2, respectively). The clearance after i.v. administration was 220 ± 48 and 241 ± 39 ml/min on days 1 and 2, respectively. The apparent clearance after p.o. and h.i.a. administration was 290 ± 86 and 344 ± 77 ml/min, respectively. The volume of distribution of TMZ after i.v., p.o., and h.i.a. administration was 0.4, 0.6, and 0.6 l/kg on day 1 and 0.5, 0.5, and 0.6 l/kg on day 2, respectively. The absolute bioavailability of TMZ was 0.96 ± 0.1, regardless of the sequence of the i.v.-p.o. or p.o.-i.v. administration, confirming that TMZ is not subject to a marked first-pass effect. A comparison of TMZ pharmacokinetics after i.v. and h.i.a. treatment at the same infusion rate revealed little evidence of hepatic extraction of TMZ. However, the systemic exposure to TMZ (AUC) appeared to decrease at a lower infusion rate. TMZ excreted unchanged in the urine accounted for 5.9 ± 3.4% of the dose, with low within-patient and high interpatient variability. TMZ crosses the blood-brain barrier and the concentration detected in CSF amounted to 9%, 28%, and 29% of the corresponding plasma levels (three patients). The equilibrium between plasma and ascitic fluid was reached after 2 h (assessed in one patient). Conclusion: The sequential administration of fotemustine at 4 h after TMZ treatment had no clinically relevant influence on the pharmacokinetics of TMZ. The potential clinical effect of TMZ given by h.i.a. or by locoregional administration has yet to be established, as has the impact of the infusion duration on patients' tolerance and response rate. Received: 9 March 1998 / Accepted: 2 June 1998     

Preclinical pharmacology of the novel antitumor agent adaphostin, a tyrphostin analog that inhibits bcr/abl

Purpose: To define several pharmacological properties for the potential anticancer agent, adaphostin, in order to determine whether the compound is appropriate for clinical evaluation as an anticancer agent. Methods: The analytical procedure involved high-performance liquid chromatography and utilized an analytical J’Sphere ODS H-80 column. Results: The stability of adaphostin at two different concentrations was determined at temperatures of 37°C, 4°C, and -80°C, in the plasma of mice, rats, dogs, and humans. The compound was most stable at the lower temperatures. At all temperatures, adaphostin was generally most stable in human plasma and least stable in dog plasma. Adaphostin bound strongly (>93%) to proteins in plasma from all four species. Following intravenous (i.v.) administration to mice (50 mg/kg; 150 mg/m²), plasma concentrations declined rapidly from 50 μM at 2 min to 1 μM at 2 h. Elimination was triexponential, with t _1/2 values of 1.1, 9.1, and 41.2 min. The Cl_tb was 0.411 L/(min·m²), the V _dss was 24.6 L/m², and the AUC was 927 μM·min. In a comparison of vehicles for intraperitoneal (i.p.) dosing, PEG 300 allowed the highest plasma concentrations of adaphostin. Bioavailability following an i.p. dose was greater than that following a subcutaneous dose, or that for a dose administered by oral gavage. For rats dosed i.v. with adaphostin (50 mg/kg; 300 mg/m²), plasma concentrations also decreased triexponentially, with t _1/2 values of 1.8, 10.6, and 136 min. Other pharmacokinetic values were Cl_tb = 0.466 L/(min·m²), AUC = 1,161 μM·min, and V _dss=8.0 L/m². Analysis of samples collected from two dogs dosed i.v. with adaphostin (7.5 mg/kg; 150 mg/m²) showed that plasma concentrations decreased in a biphasic manner, with individual values for t _1/2α of 6.0 and 9.8 min for the distribution phase and t _1/2β of 40.6 and 66.2 min for the elimination phase. Other pharmacokinetic values were Cl_tb = 0.565 and 0.852 L/(min·m²), AUC = 673 and 446 μM min, and V _dss = 29.6 and 56.8 L/m². Conclusions: The stability of adaphostin in plasma varies with species. In mice and dogs dosed with adaphostin, plasma concentrations of the compound decreased rapidly. The clearance of adaphostin from plasma, on an m² basis, was equivalent for mice and rats but more rapid in dogs. These results are relevant for assessing the pharmacologic and toxicologic profiles and the antitumor activity of adaphostin in humans.