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 model for the pharmacokinetics of etoposide given orally

A limited sampling model of etoposide after oral administration to estimate the area under the plasma concentration-time curve from 0 to 24 h (AUC) by determination of the drug plasma levels at only two time points was developed by a multiple regression analysis on a training data set of 15 patients receiving oral doses ranging from 54 to 90 mg/m². The equation describing the model is AUC (g ml^–1 h)=5.183 (g ml^–1 h)+1.193 (h)×C_1h (g/ml)+8.439 (h)×C_4h (g/ml) (R ²=0.93,P=0.0001), whereC _1h andC _4h represent the plasma etoposide concentrations at 1 and 4 h, respectively. The model was validated prospectively on a test data set of 13 patients receiving oral doses ranging from 52 to 87 mg/m² and, additionally, on a data set of 7 patients receiving oral doses ranging between 176 and 200 mg/m², investigated in a previous study. Validation on both test data sets gave a relative mean predictive error of 0.1% and a relative root mean square error of 15.8% and 16.7%, respectively. The present study shows that it is possible to obtain a good estimate of the plasma AUC after oral administration of etoposide using a two-time-point sampling model. The model can be used to monitor the etoposide AUC in patients receiving chronic oral treatment.     

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     

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     

Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors

 Etoposide phosphate, a water soluble prodrug of etoposide, was evaluated at levels potentially useful in transplantation settings in patients with malignancies. For pharmacokinetic studies of etoposide phosphate in this phase I study, 21 patients with solid tumors were treated with etoposide phosphate given as etoposide equivalents of 250, 500, 750, 1000 and 1200 mg/m² infused over 2 h on days 1 and 2, and G-CSF 5 μg/kg per day starting on day 3 until WBC was ≥10 000/μl. Qualitative, quantitative, and pharmacokinetic analysis was performed as reported previously. Rapid conversion of etoposide phosphate into etoposide by dephosphorylation occurred at all dosage levels without indication of saturation of phosphatases. Plasma levels (C_pmax) and area under the curve (AUC) of etoposide phosphate and etoposide demonstrated linear dose effects. For etoposide, plasma disposition demonstrated biphasic clearance, with mean T_1/2α of 2.09±0.61 h, and T_1/2β of 5.83±1.71 h. An AUC as high as 1768.50 μg.h/ml was observed at a dose of 1200 mg/m². The total body clearance (TBC) showed an overall mean of 15.72±4.25 ml/min per m², and mean volume of distribution (V_Dss) of 5.64±1.06 l/m². The mean residual time (MRT) for etoposide was 6.24±1.61 h. In urine, etoposide but not etoposide phosphate, was identified with large quantitative variations (1.83% to 33.45% of injected etoposide equivalents). These results indicate that etoposide phosphate is converted into etoposide with the linear dose-related C_pmax and AUCs necessary for use of this agent at the high dosage levels needed in transplantation protocols. A comparison of pharmacokinetic parameters of high- dose etoposide with the values observed in our study with etoposide phosphate revealed comparable values for the clinically important C_pmax and AUCs, clearance, terminal T_1/2 and MRT. In contrast to the use of etoposide, etoposide phosphate can be delivered in aqueous vehicles and therefore may offer the advantage of ease of administration. Received: 18 July 1995/Accepted: 20 October 1995     

Pharmacokinetics and toxicity of the epipodophyllotoxin derivative etoposide (VP 16-213) in patients with gestational choriocarcinoma and malignant teratoma

Summary Serum levels of etoposide obtained 5 min after administration of 100 mg/m² were between 11 and 30 g/ml. By 24 h after drug administration, serum levels had fallen to between 0.19 and 1.11 g/ml. Interpatient variation of etoposide serum concentrations obtained 5 min after drug administration was low, whereas interpatient variation 24 h later was noticeably higher. A significant correlation was observed (r=-0.698) between the WBC nadir and the mean etoposide serum concentrations, measured 24 h after drug administration, in patients receiving etoposide in combination with cyclophosphamide and actinomycin D. However, a relationship was not observed in those patients receiving etoposide alone.There was no observed difference in the efficacy or toxicity of 500 mg/m² etoposide when the dose was administered either as 100 mg/m² on each of 5 consecutive days or as 250 mg/m² on days 1 and 3. There was no significant difference between AUC values calculated from etoposide concentration versus time profiles in patients receiving the drug on days 1 and 3 and those values obtained with the 5-day schedule.Patients resistant to a conventional dose of etoposide were given a higher dose of 1 g/m²/24 h, but this schedule did not cause an increase in efficacy despite an increase in serum levels of the drug. CSF levels in two of these patients receiving high-dose etoposide were 1.28% and 2.09% of the serum concentrations.     

Phase I and pharmacokinetic study of a water-soluble etoposide prodrug, etoposide phosphate (BMY-40481)

Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and pharmacokinetic study has been performed over the dose range 25–110 mg/m²/day for 5 days (etoposide equivalent doses). The maximum tolerated dose (MTD) was 110 mg/m²/day for 5 days every 3 weeks and the dose-limiting toxicity was neutropenia. Other toxicities were mild, with the exception of 2 patients who displayed significant hypersensitivity reactions. The etoposide phosphate:etoposide area under the plasma concentration versus time curve (AUC) ratio was <1% and the pharmacokinetic parameters for etoposide were within previously reported ranges. Pharmacodynamic analyses demonstrated that etoposide AUC and baseline white blood cell count were significant determinants of leucopenia (model r² = 0.51).     

Clinical and pharmacokinetic study of oral NK611, a new podophyllotoxin derivative

 NK611 is a novel water-soluble podophyllotoxin derivative that has comparable antitumour activity but higher potency and better bioavailability in animals as compared with etoposide. The primary objectives of this study were to determine, after both oral and intravenous administration in the same patient, the bioavailability and the pharmacokinetic profile of NK611. Secondary objectives involved evaluation of the toxicity and the antitumor activity. Patients were randomly assigned to receive oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg/m² on day 1, when pharmacokinetic studies were performed. A daily oral dose of 20 mg/m² was then given from day 4 through day 7 for respective total doses of 85, 90, and 100 mg/m². NK611 and its metabolites were determined in plasma and urine by two different high-performance liquid chromatography (HPLC) methods with UV detection. A total of 21 adult patients entered the study and received the complete first cycle and at least the 1st day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the plasma decay curve of NK611 followed a two-exponential model, and after oral administration it declined monoexponentially in most cases. At all dose levels, bioavailability values were around 100%. At concentrations between 10 and 20 mg/m² after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma clearance, and volume of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to the dose. The urinary excretion of NK611 corresponded to 10–15% of the dose after administration by both routes, whereas that of N-demethyl NK611 and its picroform was highly variable. The features of neutropenia were comparable with those noted for etoposide involving a high degree of interpatient variability and recovery within 1 month after treatment. A daily dose of 20 mg/m² for 5 consecutive days every 4 weeks is the recommended regimen for phase II studies in patients who have never been treated or have undergone previous chemotherapy only once. Received: 26 November 1995: Accepted: 27 March 1996     

Chromosome Aberrations and pharmacokinetics in patients receiving tauromustine as either a single or a repeated dose

Tauromustine (TCNU) is an exploratory drug that has demonstrated activity in various solid tumors. We examined chromosome aberrations and plasma levels of the drug in two groups of patients receiving either a single dose of 130?mg/m² or 40?mg/m² on 3 consecutive days. Peak plasma concentrations (mean ±SD) were obtained at a similar time after both treatments, i.e., at 38±25, 32±24, 28±14, and 40±26 min after administration of 130?mg/m² on day 1 and after that of 40?mg/m² on days 1, 2, and 3, respectively. In addition, the cumulative area under the curve (AUC value) determined after administration of 40?mg/m²×3 was similar to that noted after treatment with a single dose of 130?mg/m², i.e., 180 and 179?μg min ml^-1, respectively. Both treatments induced chromosome aberrations (CAs) in peripheral blood lymphocytes. A dose-dependent increase in the number of CAs was found, with 40?mg/m² producing 5.5% CAs and 130?mg/m² yielding 20.9% CAs at 24?h after treatment. In addition, although the drug concentration declined to a level under the detection limit between the daily treatments, drug-induced chromosome damage was cumulative, with the 90-min values increasing from 4.8% on day 1 to 14.3% CAs on day 3. In individual patients, no correlation was found between CAs and kinetic parameters; however, the total mean CA yield was in agreement with the total drug exposure (CAs, 14.3% and 14.6%, AUC 180±62.8 and 179±115?μg min ml^-1, respectively).     

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.     

Pharmacokinetic Comparison of 120-Hour Infusion Versus Hyperfractionated Oral Administration of Idarubicin

Abstract

The aim of this study was to compare the pharmacokinetics of idarubicin (IDA) and its active metabolite idarubicinol (IDOL) after chronic oral and continuous intravenous (i.v.) IDA administration in order to establish the oral doses needed to reach the i.v. equiactive plasma drug exposure. The pharmacokinetic profile of IDA and IDOL was investigated in 23 patients receiving 12 mg/m² IDA by 120-h i.v. infusion (2.4 mg/m²/day) combined with cyclophosphamide, etoposide and pred-nisone in comparison to 28 patients receiving oral IDA doses ranging from 2 to 10 mg/day for 21 days in a phase I study. We found that IDA AUC_24h/dose/m² was 4.7-fold greater during i.v. than oral administration, whereas IDOL AUC_24h/dose/m² was only about 2-fold higher after i.v. administration. The metabolic ratio between IDOL AUC_24h and IDA AUC_24h in plasma was about 3-fold higher after oral adminis-tration. Based on these results we were able to estimate that equiactive plasma drug exposure was reached with an ～2.5-fold greater oral dose/m² of IDA than the corresponding i.v. dose.     

A phase I clinical and pharmacological study of weekly intravenous infusions of piritrexim (BW301U)

Thirty-eight patients with advanced resistant cancers were enrolled on this study of piritrexim (PTX; BW 301U) administered intravenously weekly for 4 weeks. Of 50 courses of treatment begun, 39 evaluable 4-week courses of the drug were completed by this group of patients. Dosages ranged from 44 to 530 mg/m²/week. One patient at each dosage level received an initial weekly dose of PTX in oral form accompanied by pharmacokinetic blood sampling after the oral dose and also after a subsequent intravenous dose.Toxicities included mild nausea and vomiting, and moderate to severe peripheral vein phlebitis. Anemia and thrombocytopenia were the dominant hematological toxicities. One patient with pulmonary metastases from malignant fibrous histiocytoma experienced a 12-week partial response to PTX treatment at a dosage of 400 mg/m²/week.Pharmacokinetic analysis of plasma for PTX concentrations was accomplished utilizing a competitive protein binding assay. The estimated total body clearance ranged from 136 to 173 ml/min/1.73 m². Mean terminal half-life after intravenous administration was 5.61 ± 2.38 h (S.D.), and after oral administration was 5.72 ± 2.04 h. Mean systemic bioavailability after oral administration was 75 ± 56%.     

Effect of high-dose cyclosporine on etoposide pharmacodynamics in a trial to reverse P-glycoprotein (MDR1 gene) mediated drug resistance

Purpose: The consequences of using cyclosporine (CsA) therapy to modulate P-glycoprotein-mediated multidrug resistance include increased myelosuppression, hyperbilirubinemia, and altered disposition of the cytotoxin. The purpose of this study was to analyze further the relationship between the degree of leukopenia, and etoposide pharmacokinetic factors. Methods: Each patient initially received intravenously-administered etoposide alone (150–200 mg/m²/d × 3). Later it was given in combination with CsA administered at escalating loading doses (range 2–7 mg/kg) as a 2 hour intravenous (IV) infusion followed by a 3 day continuous infusion, at doses ranging from 5 to 21 mg/kg/day. Serial plasma etoposide concentration-time samples were assayed by high-performance liquid chromatography (HPLC). The area under the curve (AUC) of unbound etoposide was calculated from the total plasma etoposide AUC using a previous published equation [22] where % unbound etoposide = (1.4 × total bilirubin) – (6.8 × serum albumin) + 34.4. The percent decrease in white blood cell (WBC) count and the total or unbound etoposide AUC relationship was fitted to a sigmoid Emax model adapted for paired observations, where: In this equation, Z was the variable describing the two treatment groups (0=no CsA and 1=CsA). The fitted parameters were PDRV₅₀, the pharmacodynamic response variable (PDRV) producing 50% of the maximal response; parameter β, which describes the effect of the treatment group on the PDRV₅₀; parameter H (Hill constant), which defines the slope of the response curve and parameter δ, which describes the effect of the treatment group on parameter H. Results: CsA at a median concentration of 1,938 μg/ml resulted in a median increase in the total plasma etoposide AUC by 103% and the calculated unbound plasma etoposide AUC by 104%. This paralleled a 12% greater median percent decrease in WBC count during etoposide + CsA treatment (72% vs. 84%, P=0.03). The percent decrease in WBC count and total or unbound etoposide AUC relationship was fitted to the sigmoid Emax model. The model using the unbound etoposide AUC described the data adequately (r=0.790) and was precise, with a mean absolute error of 6.4% (95% confidence interval: −4.9, 7.8). The fitted parameter-estimates suggested that at equivalent unbound etoposide AUC values above 10 μg × h/ml, the sigmoid Emax model predicted a 5% greater WBC count suppression when CsA was added to the treatment regimen. Conclusion: These findings suggest that a small degree of the enhanced myelosuppression observed with CsA combined with etoposide might be attributable to inhibition of P-glycoprotein in bone marrow precursor cells. However, the majority of the effect observed appears to be due to pharmacokinetic interactions, which result in increases in unbound etoposide. Received: 14 December 1998 / Accepted: 15 September 1999     

Bioavailability of 50- and 75-mg oral etoposide in lung cancer patients

 This study was designed to determine the bioavailability of etoposide capsules administered orally at doses of 50 and 75 mg. Patients with inoperable or relapsed lung cancer, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were eligible. A group of 17 patients were evaluable, all of whom were 75 years old or less, with an ECOG performance status of 0 or 1. The bioavailability of oral etoposide was determined by measuring the area under the etoposide plasma concentration versus time curve (AUC) on days 1, 10 and 21 during a once-daily regimen of oral administration for 21 consecutive days and comparing the value with the AUC achieved following intravenous administration 1 or 2 weeks after the last oral dose. The bioavailability of 50, 75 and 100 mg oral etoposide was determined in six, nine and two patients, respectively. The mean etoposide bioavailabilities (±SD) of the 50-mg and 75-mg doses were 47±11% and 59±18%, respectively, and of the 100-mg dose in two patients were 51% and 33%, respectively. There was no statistically significant difference in bioavailability between the 50-mg and 75-mg doses. The bioavailability of low-dose oral etoposide was the same as that reported in previous higher dose oral etoposide bioavailability studies and that shown on the package insert supplied by the manufacturer. Improved bioavailability of low-dose oral etoposide was therefore not observed in a population of Japanese patients. Received: 12 January 1995/Accepted: 14 May 1995     

Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer

Purpose Etoposide is a widely used cytotoxic drug that is commercially available in both intravenous and oral formulations. High interpatient pharmacokinetic variability has been associated with oral etoposide administration. Various strategies used in the past to reduce such variability have not been successful. Hence, this study was designed to evaluate if pharmacokinetic modulation of oral etoposide with ketoconazole could lead to a favorable alteration of etoposide pharmacokinetics, and to assess the feasibility and safety of this approach. Methods Thirty-two patients were treated with ketoconazole 200 mg daily with an escalating dose of oral etoposide starting at a dose of 50 mg every other day. Pharmacokinetic samples were obtained during the first treatment cycle after the administration of an oral etoposide and ketoconazole dose. Additional baseline pharmacokinetic studies of etoposide alone were performed 4 days prior to the first treatment cycle. Results Dose limiting toxicities were neutropenia and fatigue. Ketoconazole increased the area under the plasma concentration–time curve (AUC) of oral etoposide by a median of 20% (p < 0.005). Ketoconazole did not reduce the interpatient variability in etoposide pharmacokinetics. Pretreatment bilirubin levels correlated with etoposide clearance (Spearman’s r = −0.48, p = 0.008). The maximum tolerated dose was etoposide administered at 50 mg daily and ketoconazole 200 mg qd for 3 of 5 weeks. Conclusions Ketoconazole reduces the apparent clearance of oral etoposide, does not alter its toxicity profile and does not reduce interpatient pharmacokinetic variability. Other methods to reduce the pharmacokinetic variability of oral etoposide are needed.     

Intrahepatic and intravenous administration of adriamycin—A Comparative pharmacokinetic study in patients with malignant liver tumours

The pharmacokinetics of adriamycin in patients with malignant tumours of the liver were studied after peripheral intravenous treatment and after regional administration of the drug either by the arterial route or by the portal vein, with or without hepatic artery ligation. The plasma concentration of adriamycin after intravenous as well as after intrahepatic administration followed a three-compartment open model. The results in the present study confirm previous reports of a large inter-individual variation of the pharmacokinetics of adriamycin. After intravenous administration the individual variations in AUC/mg/m² andC _p,max/mg/m² (dose normalized area under plasma concentration time curve and dose normalized maximum plasma concentration, respectively) were more than 5-fold. The area under the plasma concentration time curve (AUC) was on the average 1.5 times higher after the peripheral intravenous administration than after intrahepatic administration. The reduction of maximum plasma concentration (C _p,max) of adriamycin after intrahepatic administration was even more pronounced than the reduction in AUC (mean valueC _p,max iv/C _p,max ihep=1.7). The plasma concentration of adriamycinol did not exceed 20 ng/ml. The AUC values of adriamycinol were 20% (median value) of the AUC values of adriamycin, indicating the importance of adriamycinol in the adriamycin therapy.     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Plasma and cerebrospinal fluid pharmacokinetics of SU5416 after intravenous administration in nonhuman primates

Purpose: SU5416 is a small, lipophilic synthetic molecule that selectively inhibits the tyrosine kinase activity of the VEGF receptor Flk-1/KDR. The role of this agent in brain tumors is currently being investigated. Pharmacokinetic studies of SU5416 have been performed in humans; however, there have been no studies of its penetration in the cerebrospinal fluid (CSF). We studied the pharmacokinetics of SU5416 in plasma and CSF after intravenous (i.v.) administration using a nonhuman primate model that is highly predictive of the CSF penetration in humans.Experimental design:SU5416 (85 mg/m², about 3.8 mg/kg) was administered i.v. over 20 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion, for determination of SU5416 concentrations. SU5416 was measured in plasma and CSF using high-performance liquid chromatography (HPLC). Concentration-versus-time data were modeled using model-independent and model-dependent methods.Results: Peak plasma concentrations ranged from 6.3 to 14.5 μM and the mean plasma AUC was 620±180 μM min. Disappearance of SU5416 from the plasma was best described by a one-compartment model with a half-life of 39±2.9 min. The volume of distribution was 36±11 l/m² and the clerance was 0.62±0.2 l/min per m². SU4516 was not quantifiable in the CSF.Conclusions: There is minimal penetration of SU5416 into the CSF after i.v. administration. The very low CNS exposure to SU5416 after i.v. dosing suggests that this agent is not optimal for the treatment of leptomeningeal tumors. Published online: 9 October 2003     

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

 Purpose: To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours. Methods: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m²) were administered in combination with etoposide 100 or 120 mg/m², and fixed dose of cisplatin 20 mg/m² and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II–V. Results: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m² dose level (II) was 7.0 ± 3.6 h μmol⁻¹ l⁻¹, for the 175-mg/m² dose level (III) 10.6 ± 2.8 h μmol⁻¹ l⁻¹, for the 200-mg/m² dose level (IV) it was 16.0 ± 5.0 h μmol⁻¹ l⁻¹, and for the 175-mg/m² dose level (V) it was 12.5 ± 6.1 h μmol⁻¹ l⁻¹. The mean peak plasma concentration (C_max) values for dose levels II–V were 1.9 ± 1.1 μmol/l, 3.4 ± 1.2 μmol/l, 4.3 ± 1.0 μmol/l and 3.8 ± 1.2 h μmol/l, respectively. Conclusion: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C_max and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-μmol/l threshold concentration (t > 0.1 μM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded. Received: 29 June 1998 / Accepted: 29 January 1999     

Penetration of etoposide into human malignant brain tumors after intravenous and oral administration

Summary Penetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55–65 mg/m²) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50–150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 g/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44–4.99 g/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7%±0.5%, 3.4%±1.0%, and 7.2% ± 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04–4.80 g/g) was 14.0%±2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.