The effect of dose on the bioavailability of oral etoposide

Summary The bioavailability of orally administered etoposide varies considerably. The effect of dose on bioavailability has not previously been investigated. In this study six patients were each treated with oral etoposide at doses of 200, 400, and 600 mg, and the pharmacokinetics determined. Each patient acted as his own control. The area under the plasma concentration-time curve (AUC) was proportionately greatest at the lowest dose. Doubling the dose from 200 mg to 400 mg increased AUC by only 50%, and a further increase of only 2.2% occurred at a dose of 600 mg. These data show nonlinear bioavailability of etoposide within the range in clinical use and may explain the variable results of reported studies. The data may have important implications for chemotherapy regimens with oral etoposide.     

The effect of food and concurrent chemotherapy on the bioavailability of oral etoposide.

There is no information on the effect of food or concurrent drug administration on the bioavailability of oral etoposide, despite the fact that treatment is frequently administered over several days and most often in combination with other cytotoxic agents. The influence of these factors has been studied in 11 patients, receiving combination cytotoxic therapy for extensive small cell lung carcinoma. Neither food nor concurrent oral or intravenous chemotherapy had a significant effect on the mean plasma concentrations of etoposide, achieved following oral administration. Wide variation in peak plasma concentrations and in area under the concentration time curve (AUC) occurred both between and within patients. It appears unnecessary for patients receiving etoposide (at 100 mg) to fast prior to drug administration. Furthermore, oral etoposide (at 100 mg and at 400 mg) may be given in combination with other cytotoxic agents without compromising its bioavailability.     

Pharmacological attempts to improve the bioavailability of oral etoposide

Etoposide demonstrates incomplete and variable bioavailability after oral dosing, which may be due to its concentration and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concentration-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4±20.3 g ml^–1 h, versus 74.3±25.9 g ml^–1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concentrationt _max from 1.1 to 3.5 h (P<0.01), but again without a significant improvement in drug AUC or bioavailability across the 24-h study period (AUC with etoposide alone 78.3±19.1 g ml^–1 h, versus 88.1±23.6 g ml^–1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay int _max being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stability was markedly improved at pH 3–5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clinical setting.     

The pharmacokinetics of high dose cyclophosphamide and high dose etoposide

We have studied the pharmacokinetics of single agent high dose cyclophosphamide (HDC) (160-240 mg kg-1) given as repeated intravenous (i.v.) infusions to six patients with small cell lung cancer (SCLC), and HDC (180 mg kg-1) combined with etoposide (750-1000 mg m-2) as repeated i.v. infusions to five patients with SCLC and two patients with teratoma. HDC has a similar pharmacokinetic profile to low dose cyclophosphamide, with a half-life of 4.83 +/- 1.3 h. Repeated administration of HDC produced a small but significant shortening of the half life (P = 0.02). The terminal half-life of high dose etoposide was 7.7 +/- 2 h which is similar to our previous results with low dose etoposide (50-300 mg m-2), but the volume of distribution which was 35.5 +/- 11.6 1. was significantly increased (P less than 0.001). Plasma steady state concentrations of 26.2 +/- 11.7 micrograms ml-1 were achieved. The possible mechanism for the alteration of volume of distribution of etoposide will be discussed.     

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.     

The effect of etoposide on human CFU-GM

Etoposide is being used increasingly in the treatment of a variety of malignant conditions and in conjunction with autologous bone marrow transplantation. We have examined the effect of the drug on human CFU-GM as an indication of the response of these bone marrow progenitor cells to measured plasma concentrations. When etoposide is present in the routine assay for 7 days, 50% growth of colony-forming CFU-GM occurs at a concentration of 0.0098 micrograms ml-1. When bovine serum albumin or human serum albumin is present this value is increased to 0.042 and 0.375 micrograms ml-1. Protein binding therefore plays an important part in modifying in vitro response and possibly in vivo response of these progenitor cells to etoposide.     

The bioavailability of oral intermediate-dose methotrexate

Summary The oral bioavailability of methotrexate is variable and may be dose-dependent. The absorption of interval oral methotrexate, which is given between cycles of chemotherapy, is unknown.The bioavailability of oral methotrexate has been studied in eight patients, acting as their own controls, to assess the effect of subdivision of the dose, the formulation, and the timing of the methotrexate within the chemotherapy cycle.The mean bioavailability for all the oral methods of administration was 28.2%±3.7% compared with the same dose given IV. Absorption was uninfluenced by subdivision of the dose, liquid or tablet formulation, or administration on day 1 or day 10 of the chemotherapy cycle.     

The taccalonolides: microtubule stabilizers that circumvent clinically relevant taxane resistance mechanisms

The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature of the taxane family of microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression of P-glycoprotein (Pgp), multidrug resistance protein 7 (MRP7), and the betaIII isotype of tubulin. The ability of four taccalonolides, A, E, B, and N, to circumvent these multidrug resistance mechanisms was studied. Taccalonolides A, E, B, and N were effective in vitro against cell lines that overexpress Pgp and MRP7. In addition, taccalonolides A and E were highly active in vivo against a doxorubicin- and paclitaxel-resistant Pgp-expressing tumor, Mam17/ADR. An isogenic HeLa-derived cell line that expresses the betaIII isotype of tubulin was generated to evaluate the effect of betaIII-tubulin on drug sensitivity. When compared with parental HeLa cells, the betaIII-tubulin-overexpressing cell line was less sensitive to paclitaxel, docetaxel, epothilone B, and vinblastine. In striking contrast, the betaIII-tubulin-overexpressing cell line showed greater sensitivity to all four taccalonolides. These data cumulatively suggest that the taccalonolides have advantages over the taxanes in their ability to circumvent multiple drug resistance mechanisms. The ability of the taccalonolides to overcome clinically relevant mechanisms of drug resistance in vitro and in vivo confirms that the taccalonolides represent a valuable addition to the family of microtubule-stabilizing compounds with clinical potential.     

Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity

We have previously demonstrated that individualized dosing of etoposide (VP16) by 72-hour infusion is feasible and that the extent of leukopenia is a function of plasma concentration, pretreatment WBC (WBCp), albumin (ALB), performance status (PS), and bone marrow function (based on transfusion requirements). In the current study, 45 patients were randomized between a fixed dose of VP16 (125 mg/m2/d) versus individualized dosing to a target WBC nadir (WBCN) of 1,700/microL. The total dose was increased by an average of 22% in the latter patients (459 +/- 130 mg/m2 v 375 mg/m2, P = .002). This was associated with a decrease in both the mean WBCN (1,510 +/- 950 v 2,500 +/- 1,420/microL, P = .013) and in the variability of the WBCN (P = .039). The VP16 clearance (mL/min) was not correlated with body surface area. Partial responses were observed in one patient each with hepatoma and non-Hodgkin's lymphoma. We conclude that pharmacologically based dosing may be a means of increasing dose intensity without increasing the incidence of life-threatening toxicity due to a decrease in variability around a target WBC.     

Toward a clinically relevant cytogenetic classification of acute myelogenous leukemia

Cytogenetic studies with Giemsa banding were performed on the bone marrow cells of 384 patients with acute myelogenous leukemia treated between 1975 and 1983. An abnormal karyotype was detected in 54% of patients, being present in 100% of metaphases (AA) in 31% and only a proportion of cells (AN) in 22%. Specific translocations or other abnormalities were noted in 22% of patients, the most common of which were t(8;21) (q22;q22) in 7%, t(15;17) (q22;q21) and inv (16) (p13q22) in 5.5%, t(9;22) (q34;q11) in 3% and abnormalities of 11q23 in 1.3%. Loss of the Y chromosome was noted in 21 patients, associated with t(8;21) in 11 patients and the sole abnormality in eight patients (45, X, -Y). Most (66%) of the other abnormalities involved addition of chromosome 8 or loss or deletion of 5 or 7 (+8, -5 or -7, 5q- or 7q- group). The remaining patients had miscellaneous abnormalities (MA). A marked assymetry was noted in the distribution of important clinical prognostic variables such as age, sex, history of an antecedent hematologic disorder and presence of Auer rods within the various cytogenetic categories. The specific translocation/abnormalities were more common in younger patients (p less than 0.01). Analysis of response, remission duration and survival demonstrated that inv 16 and t(8;21) were favorable prognostic categories; diploid, t(15;17) and 45,X,-Y had intermediate prognosis, and all other categories were unfavorable prognostic groups. The response rate and survival for diploid patients (NN) was superior to patients with abnormalities. No difference in response rate, CR duration or survival was noted between the AA and AN groups. A prognostic classification according to cytogenetic category based on clinical associations is proposed which will be tested prospectively in subsequent studies.     

A case of recurrent ovarian cancer markedly responding to daily oral administration of low dose etoposide

A 67-year-old woman with recurrent ovarian cancer, who had carcinomatous peritonitis and large abdominal cystic lesions, was treated by daily oral etoposide at a dose of 50 mg/day for 21 consecutive days at 2-week intervals in the outpatient department. After 15 days of administration, the serum level of CA125 decreased from 2,220U/ml to 445U/ml, and that of LDH from 2,725 WU to 906 WU. After the third course of treatment, the abdominal cystic lesions were remarkably reduced, and the performance status improved grade 1 from 3 prior to the administration. No severe side effects except for alopecia and mild myelosuppression were noted during the 3-month treatment.     

Treatment of carcinoma of the breast with high dose oral medroxyprogesterone acetate: Does increased bioavailability improve the therapeutic ratio?

Medroxyprogesterone acetate (MPA) is regarded as a valuable hormonal therapy for metastatic breast cancer. The drug is manufactured by more than one pharmaceutical company, and one particular brand of oral MPA (Provera Tablets, Upjohn) has been reformulated to incorporate micronized particles, providing significantly enhanced bioavailability.The response rate and side-effect data from a pilot study, which used the old formulation Provera Tablets 100 mg at a dosage of 800 mg/day in 28 patients with recurrent breast cancer after treatment with tamoxifen, are compared with those from another study in which 59 similar patients received 800 mg/day of new formulation Provera Tablets 200 mg. Neither of these studies, conducted in the United Kingdom, has previously been published.The response rates were similar in both studies, but there were higher incidences of significant weight gain and increased blood pressure in those patients treated with the new formulation. These side effects have been noticed by other workers employing new formulation MPA at a dosage of 800 mg per day, while it has been reported that reducing the dosage to 400 mg perday is accompanied by a lower incidence of side effects, without affecting the response rate.It is concluded that the increased serum levels of MPA, made possible by the micronized product, do not favourably influence the response of metastatic breast cancer to therapy, but may be associated with a higher incidence of side effects. Reducing the dosage of the new formulation MPA to 400 mg/day may allow a more acceptable side-effect profile, without loss of therapeutic efficacy. Such a dose reduction would make this brand of MPA more cost effective.     

The N-dechloroethylation of ifosfamide: using stereochemistry to obtain an accurate picture of a clinically relevant metabolic pathway

 The cumulative urinary excretions of the enantiomers of ifosfamide [(R)-IFF, (S)-IFF)] and their 2-N-dechloroethylated (2-DCE-IFF) and 3-N-dechloroethylated (3-DCE-IFF) metabolites were determined in 11 adult cancer patients who received a single 3-h infusion of IFF (3 g/m²) with mesna uroprotection. The urine samples were analyzed for the compounds of interest using an enantioselective gas chromatographic- mass spectrometric assay. The results indicated an enantioselective excretion of the parent and N-dechloroethylated metabolites: the urinary recovery of (R)-IFF was significantly greater than that of (S)-IFF (1.73± 0.45 vs 1.43±0.41 mmol, P<0.0001); the excretion of (S)-2-DCE-IFF (0.75±0.53 mmol) was greater than that of (R)-2-DCE-IFF (0.42± 0.22 mmol, P=0.071) while the excretion of (R)-3-DCE-IFF (1.64± 0.76 mmol) was greater than that of (S)-3-DCE-IFF (0.77±0.59 mmol, P=0.012). The study also revealed two distinct metabolic patterns in which the urinary recoveries of (R)-2-DCE-IFF and (R)-3-DCE-IFF were linked as were those of (S)-2-DCE-IFF and (S)-3-DCE-IFF. The results suggest that at least two enzymes are involved in the N-dechloroethylation of IFF. The data also demonstrate the importance of following the metabolic fate of (R)-IFF and (S)-IFF and of determining the relative urinary excretion of all dechloroethylated metabolites. Received: 13 December 1994/Accepted: 14 May 1995     

The effects of food and divided dosing on the bioavailability of oral vinorelbine

 The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m² per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m² per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22±28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (T_max) increased from 1.3±1.6 h in the fasting state to 2.5±1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16±51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized C_max and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity. Received: 4 October 1994/Accepted: 15 December 1995     

Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cis-diamminedichloroplatinum (II) and irradiation

The interaction of cis-diamminedichloroplatinum(II) (c-DDP) and irradiation was investigated in the RIF-1 tumor, skin and duodenum in C3H/Km mice. The c-DDP enhanced the effects of fractionated irradiation in the tumor, as measured by both growth delay and cell survival determined by excision and colony formation in vitro. This enhancement was at least additive and possibly supra-additive. The combined treatment was effective in clinically relevant treatment regimens. The same doses of c-DDP failed to enhance acute radiation skin reactions and caused only a moderate enhancement of the radiation-induced cell killing in duodenal crypt cells. The latter was found when c-DDP was administered immediately before each irradiation dose in a fractionated treatment schedule, but not when it was given in a single larger dose 24 h before the start of fractionated radiotherapy. Comparing the effects on tumor with those on normal tissues, the optimum treatment appeared to be c-DDP given once a week 24 h before daily fractionated irradiation.