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     

Clinical and pharmacokinetic study evaluating the effect of food on the disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in patients with solid tumors

Background: 9-Nitrocamptothecin (9NC) is an orally administered camptothecin analogue that has completed phase III trials for pancreatic cancer. In biological matrices, camptothecin analogues exist in equilibrium between the active-lactone (LAC) and inactive-hydroxy acid (HA) forms. 9NC has been administered on an empty stomach; however, it is unclear if food alters the absorption and disposition of 9NC and its 9-aminocamptothecin (9AC) active-metabolite. Thus, we evaluated the disposition of 9NC and 9AC after administration of 9NC under fasting conditions and after a standard meal. Methods: Patients were randomized to receive 9NC as a single oral dose at 1.5 mg/m² with 8 ounces (oz) of an acidic beverage under fasting conditions, or after a meal consisting of two eggs, 8 oz of orange juice, buttered toast, 8 oz of milk, and 4 oz of hash brown potatoes. Following a 72 h washout period, 9NC was administered with the alternative condition (i.e., with food or fasting). 9NC was then continued for 5 days of every week. Serial blood samples were obtained prior to and from 0.25 to 24 h after administration of 9NC. The total (sum of LAC + HA) of 9NC and 9AC were measured by an LC-MS/MS assay. Area under the plasma concentration versus time curve (AUC) for 9NC and 9AC total were calculated. After the pharmacokinetic section of the study, patients received 9NC 1.5 mg/m² orally under fasting conditions daily for 5 days per week for 8 weeks. Results: Sixteen patients with median (range) age 62 (47–83) years, diagnoses of colorectal (six patients), lung (two patients), and other (eight patients) malignancies, received 83 [median (range) 4 (2–9)] weeks of therapy. Patients with toxicities greater than grade 2: were diarrhea (1), nausea (2), vomiting (2), fatigue (2), anemia (3), neutropenia (3), and febrile neutropenia (2). Three patients (lung, unknown primary, and colon) had stable disease for eight weeks. The mean±SD of 9NC AUC_food and 9NC AUC_fast (n=9) were 330±182 and 558±379 ng/ml·h, respectively (P<0.05). The mean±SD of 9AC AUC_food and 9AC AUC_fast (n=9) were 244±60 and 256±101 ng/ml·h, respectively (P>0.05). The mean ± SD ratio of 9NC AUC_food to AUC_fasting in individual patients (n=9) was 0.67±0.22. The mean ± SD ratio of 9AC AUC_food to AUC_fasting in individual patients (n=9) was 1.14±0.61. Conclusions: Co-administration of 9NC with food reduces the oral absorption of 9NC; however, there was no difference in the exposure of 9AC. The is high interpatient variability in the effect of food on the absorption of 9NC and the interpatient variability in the effect of food on the disposition of 9AC is even greater when compared to 9NC. Supported, in part, by grant NCI 2P30 CA47904, grant NIH / NCRR / GCRC /#5M01 RR00056, and a grant from Supergen Inc., Dublin, California     

Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093)

Objective Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated.Patients and methods A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated.Results The apparent relative oral bioavailability of docetaxel was 26±8%. Orally administered docetaxel combined with oral OC144-093 resulted in a C_max of 415±255 ng ml^–1, an AUC_0– of 844±753 ng h ml^–1 and k_el of 0.810±0.296 h^–1. These values differed significantly from those following i.v. administration of docetaxel, with a C_max of 2124±1054 ng ml^–1, an AUC_0– of 2571±1598 ng h ml^–1 and a k_el of 1.318±0.785 h^–1 (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21.Conclusion The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.     

Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors.

PURPOSE: 9-Nitrocamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m(2)/day x 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration. EXPERIMENTAL DESIGN: On schedule A, 9NC was administered orally daily x 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily x 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography. RESULTS: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m(2)/day, respectively, each providing the same dose intensity (i.e., 24 mg/m(2)/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of approximately 4 to 1. CONCLUSIONS: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m(2) basis does not reduce pharmacokinetic variability.     

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     

Oral uracil and Ftorafur plus leucovorin: pharmacokinetics and toxicity in patients with metastatic cancer

Purpose: To assess the pharmacokinetics of Ftorafur (tegafur, FT), 5-fluorouracil (5-FU), and uracil in 31 cancer patients who were enrolled in phase I studies of oral uracil and FT (UFT). The correlation between pharmacokinetic parameters and toxic effects of UFT was evaluated. Methods: Uracil and FT were orally administered in a 4:1 molar ratio at FT doses of 200–400 mg/m² per day. Patients also received leucovorin at 150 mg/day. Daily doses were divided into three doses and administered at 8-h intervals for 28 consecutive days. Plasma FT concentrations were measured by high-performance liquid chromatography, and plasma 5-FU and uracil concentrations were determined using gas chromatography-mass spectrometry. National Institutes of Health Common Toxicity Criteria were used for assessment of toxicity. Results: The concentrations of FT, 5-FU, and uracil showed wide interpatient variations. Maximum plasma concentrations (Cp_max) of all three compounds were achieved in 0.3 to 4.0 h. At the various study doses, the terminal half-life (t_1/2β) of FT ranged from 3.9 to 5.9 h, the area under the concentration-versus-time curve (AUC_0–6h) ranged from 16,220 to 52,446 (ng/ml)h, the total clearance (Cl_T) ranged from 100 to 175 ml/min, and the steady-state volume of distribution (Vd_ss) ranged from 18.3 to 28.7 l. The 5-FU generated from FT had an apparent distribution half-life (t_1/2α) and an apparent elimination half-life (t_1/2β) of 0.3–1.3 h and 4.9–7.0 h, respectively. The AUC_0–6h of 5-FU ranged from 120 to 325 (ng/ml)h. Uracil had a t_1/2α of 0.2–0.5 h and the level quickly returned to the endogenous level. The AUC_0–6h for uracil ranged from 605 to 3764 (ng/ml)h, the Cl_T ranged from 3225 to 7748 ml/min, and the Vd_ss ranged from 341 to 1354 l. The Cp_max and AUC_0–6h of both FT and uracil were significantly correlated with FT doses (P-values of 0.0244 and 0.0112) and with uracil doses (P-values of 0.0346 and 0.0083), respectively. In addition to interpatient variations, intrapatient variations were also observed in six patients who had pharmacology studies done on days 1 and 26 ± 2 at the same study dose. We found that the repeated treatment with UFT caused cumulative increases in the values of Cp_max, C_trough, and AUC_0–6h of FT and 5-FU. The major toxic effects observed were diarrhea and nausea and vomiting. The occurrence of these toxic effects correlated significantly with the Cp_max and AUC_0–6h of 5-FU. Conclusions: The pharmacology studies showed that FT and uracil were readily absorbed orally and that FT was rapidly converted to 5-FU. The preliminary findings suggest that determination of plasma levels of 5-FU after oral administration of UFT may help predict subsequent toxic effects. Received: 2 September 1999 / Accepted: 14 April 2000     

Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure

 Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m² per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC_closed) was 8.74 (range 2.3–16.3)  μM min per day, and the mean AUC of the ring-opened form (AUC_open) was 11.5 (range 3.2–46.0)  μM min per day (interpatient variability 34–61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC_closed and that of 12.6%, for the AUC_open. There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small. Received: 15 June 1995/Accepted: 19 October 1995     

The effect of cimetidine on cyclophosphamide metabolism in rabbits

Summary Six female rabbits were given 20 mg/kg cyclophosphamide (containing 100 Ci [³H-chloroethyl]-cyclophosphamide) alone or 1 h following 100 mg/kg cimetidine. Serial plasma and urine specimens were collected and levels of cyclophosphamide and its metabolites (4-hydroxycyclophosphamide, 4-ketocyclophosphamide, phosphoramide mustard, and carboxyphosphamide) were measured. 4-Ketocyclophosphamide was the major metabolite present in rabbit plasma and urine, with lesser amounts of 4-hydroxycyclophosphamide, carboxyphosphamide, and phosphoramide mustard also being identified. Cimetidine pretreatment resulted in prolongation of cyclophosphamide's half-life from 24.3±7.3 to 33.5±9.5 min (mean ± SD;P=0.036) but did not significantly alter the AUC_{0–8 h} for the latter drug. Cimetidine pretreatment resulted in a significantly greater AUC_{0–8 h} for 4-hydroxycyclophosphamide (189.4±77 vs 364.6±126.7 mol min/l^–1;P=0.016) as compared with control values. A higher AUC_{0–8 h} value for phosphoramide mustard (53.7±69.2 vs 95.7±34.7 mol min/l^–1) was also observed after cimetidine dosing but the difference was not significant (P=0.21). Kinetics of 4-ketocyclophosphamide and carboxyphosphamide were not significantly affected by cimetidine treatment. Cimetidine was added to hepatic microsomes isolated from phenobarbital-treated rabbits; it did not inhibit cyclophosphamide's metabolism in vitro, suggesting that its in vivo effect may be mediated through mechanisms other than cytochrome P-450 inhibition. Cimetidine pretreatment increases exposure to cyclophosphamide and its major activated metabolite, 4-hydroxycyclophosphamide. Potentiation rather than inhibition of cyclophosphamide's pharmacodynamic effect is to be predicted when cimetidine is given concomitantly with the former. Alterations in hepatic blood flow or mechanisms other than microsomal inhibition by cimetidine may explain this potentiation.Supported in part by the Department of Veteran Affairs and grant CA-49186 from the National Institutes of Health (NIH)Department of Clinical Pharmacology, Sun Yat-sen University of Medical Sciences, Guangzhou, People's Republic of China     

Pharmacokinetics of Anandron in patients with advanced carcinoma of the prostate

Summary The pharmacokinetics of total radioactivity and unchanged drug were studied in patients receiving Anandron (Nilutamide, RU 23908) after a single dose of [¹⁴C] Anandron and after q12 h dosings of unlabelled drug for 2–7 weeks. The results indicate that the radioactivity in plasma consists of unchanged drug and metabolites. The plasma decay of Anandron after the absorption phase was biexponential in all patients, with the terminal phase half-life ranging from 23.3–87.2 h. The plasma decay of total radioactivity after the absorption phase was biexponential in 3/12 and monoexponential in 9/12 patients. The calculated terminal phase half-lives for total radioactivity after [¹⁴C] Anandron were 34.5–137.3 h. The AUC_0– of the unchanged drug in plasma represented 23%–38% of the AUC_0– of total radioactivity. Urinary radioactivity consisted primarily of metabolites, the majority of which were chloroform-nonextractable. Urinary excretion of radioactivity at 120 h ranged from 49%–78% of the administered dose; the unchanged Anandron (at 72 h) was 0.6%–1.3% of the dose. In three patients studied, the fecal excretion of Anandron was 1.4%–7.0%. Steady-state plasma levels (4.4–8.5 g/ml) were attained within approximately 2 weeks from the initiation of twice daily dosing of Anandron. When the plasma pharmacokinetics of radioactivity and unchanged drug after the first single dose were compared with that during steady state, AUC_{0–12 h} of unchanged Anandron during steady state was significantly higher than the AUC_0– after the first single dose, suggesting that the plasma clearance of Anandron is lowered upon chronic administration of the drug, assuming that the bioavailability is constant.     

Bioavailability and pharmacokinetics of the investigational anticancer agent XK469 (NSC 698215) in rats following oral and intravenous administration

Purpose To determine the oral bioavailability of R-XK469, a water-soluble investigational anticancer agent undergoing phase I clinical trials as an intravenous product.Methods R-XK469 was administered to two groups of catheterized Sprague-Dawley rats via the oral and IV routes at a dose of 10 mg/kg and blood samples were collected at predetermined times. XK469 in plasma samples was quantified using a HPLC method. The pharmacokinetic parameters were computed using WinNonlin 4.0.1 software.Results The pharmacokinetic parameters of XK469 following oral and IV administrations, respectively, were (mean±SD): C_max 138±64 and 404±355 g/ml; AUC_0– 2381±773 and 2854±1924 g h/ml; and elimination half-life (T_1/2) 12.9±5.8 and 13.5±7.8 h T_max was 2.92±1.92 h following oral dosing. Oral R-XK469 was 83% bioavailable.Conclusion Together with the antitumor efficacy of oral XK469 shown in preclinical models and its schedule dependency, these results indicate the promise of developing an oral dosage form of R-XK469 for clinical development.     

Pharmacokinetics of acridine-4-carboxamide in the rat,with extrapolation to humans

Summary The pharmacokinetics ofN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) were investigated in rats after i. v. administration of 18, 55 and 81 mol/kg [³H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (±SD) model-independent pharmacokinetic parameters were; clearance (Cl), 5.3±1.1 1 h^–1 kg^–1; steady-state volume of distribution (Vss), 7.8±3.0 l/kg; mean residence time (MRT), 1.5±0.4 h; and terminal elimination half-life (t _1/2Z), 2.1±0.7 h (n=10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1–8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05–0.10; 95% confidence limits) 1 h^–1 kg^–1 and a V_ss value of 0.63 (range, 0.2–1.1) l/kg for total drug concentrations in humans.     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993     

Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec,STI571) in healthy subjects

Objective This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure.Methods The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15. Rifampicin treatment (600 mg once daily) for CYP4503A induction was initiated on study day 8 and maintained until day 18. Imatinib pharmacokinetics were determined up to 96 h after dosing on day 1 (no induction) and on days 15–18 (during concomitant rifampicin). Plasma concentrations of imatinib and its main metabolite CGP74588 were determined using a LC/MS/MS method. The ratio of 6-hydroxycortisol to cortisol excreted in the urine was measured to monitor the induction of CYP3A.Results During concomitant rifampicin administration, the mean imatinib C_max, AUC_0–24 and AUC_0– decreased by 54% (90% CI: 48–60%), 68% (64–70%) and 74% (71–76%), respectively. The increase in clearance (Cl/f) was 385% (348–426%) during rifampicin treatment. The mean C_max and AUC_0–24 of the metabolite CGP74588 increased by 88.6% (68.3%–111.4%) and 23.9% (13.5%–35.2%) after rifampicin pretreatment. However, the AUC_0– decreased by 11.7% (3.3–19.4%). All subjects demonstrated a marked induction of hepatic microsomal CYP3A analyzed by the excretion ratio of 6-hydroxycortisol to cortisol from a mean baseline concentration of 5.6 U to 50.5 U.Conclusion Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.This work was submitted as an abstract to the 44th Annual Meeting of The American Society of Hematology (ASH), Philadelphia, USA. Abstract published in Blood, vol 100, no. 11, abstract no. 4364, November 2002.A.E.B., B.P., M.H., A.K.-B. and R.C. are employees of Novartis U.K. and M.S. received grant support from Novartis Pharma AG for the conduct of the study.     

Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities

This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m² per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m²). A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by highperformance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUC_FUrd) and for FdUrd (AUC_FdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUC_FUrd values (mean±SEM, 2.9±0.7 g ml^–1 h) and high AUC_FdUrd values (14.1±2.7 g ml^–1 h), respectively, whereas courses with myelosuppression (WHO grades 2–4) showed inverse profiles with high AUC_FUrd values (16.3±2.3 g ml^–1 h) and low AUC_FdUrd values (3.1±1.0 g ml^–1 h), respectively. A statistically significant difference in AUC_FdUrd values was also observed between cycles with and those without mucositis (P=0.0027), with AUC_FdUrd values being 22.6±5.6 and 7.8±1.9 g ml^–1 h, respectively. Whereas hematotoxicity could be correlated with both AUC_FUrd and AUC_FdUrd values, mucositis was associated with high AUC_FdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P=0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.     

Surfactants influence the distribution of taxanes in peritoneal dissemination tumor-bearing rats

The effects of surfactants on the disposition kinetics of docetaxel and paclitaxel were examined in tumor-bearing rats. Taxol and Taxotere were administered intraperitoneally to AH130 tumor-bearing rats. Plasma and ascitic AUCs (AUC_p,0–24 h and AUC_a,0–24 h) of paclitaxel were ∼2- and 6-fold larger than those of docetaxel, respectively. The AUC_{a,0–24 h,ascite}/AUC_p,0–24 h ratio of paclitaxel was ∼3-fold larger than that of docetaxel. The first-order peritoneal cavity–systemic circulation absorption rate constant of paclitaxel was 1/8 that of docetaxel. Docetaxel concentrations in free and solid tumors in the peritoneal cavity were higher than those of paclitaxel. The in vitro uptake of paclitaxel by AH130 cells was inhibited by Cremophor EL and Polysorbate-80. Docetaxel uptake was only slightly affected by these surfactants. These results indicated that Taxol scarcely released paclitaxel, while Taxotere easily released docetaxel, enabling its distribution to tumors disseminated in the peritoneal cavity.     

Bioavailability and pharmacokinetics of the cardioprotecting flavonoid 7-monohydroxyethylrutoside in mice

Purpose The pharmacokinetics and bioavailability of monoHER, a promising protector against doxorubicin-induced cardiotoxicity, were determined after different routes of administration.Methods Mice were treated with 500 mg.kg^–1 monoHER intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.) or with 1000 mg.kg^–1 orally. Heart tissue and plasma were collected 24 h after administration. In addition liver and kidney tissues were collected after s.c. administration. The levels of monoHER were measured by HPLC with electrochemical detection.Results After i.v. administration the AUC_{0–120 min} values of monoHER in plasma and heart tissue were 20.5±5.3 mol.min.ml^–1 and 4.9±1.3 mol.min.g^–1 wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 M monoHER was maintained from 5 to 15 min after administration. The AUC_{0–120 min} values of monoHER were 6.1±1.1 mol.min.ml^–1 and 1.6±0.4 mol.min.g^–1 wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 M) between 10 and 20 min after administration. The AUC_{0–120 min} values of monoHER in plasma, heart, liver and kidney tissues were 8.0±0.6 mol.min.ml^–1, 2.0±0.1, 22.4±2.0 and 20.5±5.7 mol.min.g^–1, respectively. The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively. After oral administration, monoHER could not be detected in plasma, indicating that monoHER had a very poor oral bioavailability.Conclusions MonoHER was amply taken up by the drug elimination organs liver and kidney and less by the target organ heart. Under cardioprotective conditions (500 mg/kg, i.p.), the C_max was 131 M and the AUC was 6.3 M.min. These values will be considered endpoints for the clinical phase I study of monoHER.     

Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates

Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m²) or 0.5 mg/kg (10 mg/m²), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m²) or 11.6 mg/kg (225 mg/m²), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN-38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 l/kg per h, a volume of distribution at steady state (Vd_ss) of 1.6 ± 0.7 l/kg and a half-life (t_1/2) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUC^CSF: AUC^P) was only 3.5 ± 2.1%. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vd_ss was 7.1 ± 1.3 l/kg, and the t_1/2 was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 ± 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6% of the total SN-38 in plasma. The AUC^CSF: AUC^P ratio for irinotecan lactone was 14 ± 3%. SN-38 lactone and carboxylate could not be measured (<1.0 nM ) in CSF. The AUC^CSF: AUC^P ratio for SN-38 lactone was estimated to be ≤ 8%. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUC^CSF: AUC^P ratio of 32%. Received: 15 July 1997 / Accepted: 8 October 1997     

Pharmacokinetics and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide after i.v. administration in the mouse

Summary The pharmacokinetics, tissue distribution and toxicity of the antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide(AC) were studied after i.v. administration to mice. Over the dose range of 9–121 mol/kg (3–40 mg/kg), AC displayed linear kinetics with the following model-independent parameters: clearance (C), 21.0±1.9 l h^–1 kg^–1; steady-state volume of distribution (V_ss), 11.8±1.4 l/kg; and mean residence time (MRT), 0.56±0.02 h. The plasma concentration-time profiles for AC fitted a two-compartment model with the following parameters:C _c, 19.4±2.3 l h^–1 kg^–1; V_c, 7.08±1.06 l/kg;t _1/2 13.1±3.5 min; andt _1/2Z, 1.60±0.65 h. AC displayed moderately high binding in healthy mouse plasma, giving a free fraction of 15.9%–25.3% over the drug concentration range of 1–561 M. After the i.v. administration of 30 mol/kg [³H]-AC, high radioactivity concentrations were observed in all tissues (especially the brain and kidney), showing a hight _1/2c value (37–59 h). At 2 min (first blood collection), the AC concentration as measured by high-performance liquid chromatography (HPLC) comprised 61% of the plasma radioactivity concentration (expressed as AC equivalents/l). By 48 h, 73% of the dose had been eliminated, with 26% and 47% of the delivered drug being excreted by the urinary and faecal routes, respectively; <1% of the total dose was excreted as unchanged AC in the urine. At least five distinct radiochemical peaks were distinguishable by HPLC analysis of plasma extracts, with some similar peaks appearing in urine. The 121-mol/kg dose was well tolerated by mice, with sedation being the only obvious side effect and no significant alterations in blood biochemistry or haematological parameters being recorded. After receiving a dose of 152 mol/kg, all mice experienced clonic seizures for 2 min (with one death occuring) followed by a period of sedation that lasted for up to 2h. No leucopenia occurred, but some mild anaemia was noted. There was no significant change in blood biochemistry. A further 20% increase in the i.v. dose (to 182 mol/kg) resulted in mortality, with death occurring within 2 min of AC administration.Supported by the Auckland Medical Research Foundation and the Cancer Society of New Zealand     

Pharmacokinetics of cisplatin given at a daily low dose as a radiosensitiser

Summary A total of 25 patients with inoperable cervical cancer were treated by daily radiotherapy (2 Gy); sensitisation was obtained by administration of 5 mg cisplatin 30 min before each irradiation session. The total cumulative dose of cisplatin varied between 50 and 150 mg. A complete kinetic profile (0–24 h) of platinum (Pt) was established after the first dose and at the end of treatment for 22 patients. Pt was quantified by atomic absorption spectrophotometry using Zeeman-effect background correction for trace analysis. The total Pt AUC_{0–24 h} increased from 1.53±0.77 to 7±3.55 g·h·ml^–1 between the start and the end of treatment (P<0.001). Ultrafilterable Pt (Pt UF) rose from 0.079±0.038 to 0.138±0.095 g·h·ml^–1 (P<0.01). Elimination half-lives were unchanged for total Pt but rose for Pt UF; these kinetic modifications in Pt UF did not correlate with any significant change in individual serum creatinine levels. No clear correlation was found between the cumulative cisplatin dose and tumor levels measured in 13 patients, and the tumor cisplatin dose did not correlate with response to treatment. Patients with hematological toxicity were characterised by an increase in their residual Pt UF level during treatment. Overall, our findings strengthen the notion of Pt UF kinetic variability during repeated treatment.     

Steady-state plasma concentrations and effects of taxol for a 250 mg/m2 dose in combination with granulocyte-colony stimulating factor in patients with ovarian cancer

Taxol, a natural product initially isolated from the stem bark of the western yewTaxus brevifolia, is undergoing phase II and III evaluation due to its reported activity against a variety of tumors. Previous studies have described correlations between plasma concentrations and toxicity when taxol is given (a) at lower doses, (b) for shorter infusion times, and (c) without granulocyte-colonystimulating factor. Because the 24-h infusion schedule is most commonly used in current clinical trials, we attempted to correlate steady-state plasma concentrations of taxol achieved with a 24-h continuous i.v. infusion with toxicities and responses. Plasma samples from 48 refractory ovarian cancer patients were obtained 1–2 h prior to the end of the first taxol infusion. Taxol concentrations were measured by high-performance liquid chromatography (HPLC). Interpatient variation of taxol plasma concentrations was small (mean±SD, 0.85±0.21 M. Total taxol body clearance was 256±72 ml min^–1m^–2 (mean±SD). Taxol plasma protein binding was 88.4%±1.3% (mean±SD,n=9). Grade 3–4 hematologic toxicity, mainly leukopenia, occurred in 92% of the patients. The leukopenia was transient and did not warrant a reduction in the dose of taxol. Grade 3–4 nonhematologic toxicity occurred in 8% of the patients. No severe hypersensitivity reaction or grade 3–4 neurotoxicity was observed. Correlations of plasma concentrations and toxicities were not feasible due to the high frequency of hematologic effects and the low frequency of nonhematologic toxicity. The low degree of interpatient variation in plasma concentrations hindered the development of correlations with response.