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     

Pharmacokinetics of oral O6-benzylguanine and evidence of interaction with oral ketoconazole in the rat

Purpose: O⁶-Benzylguanine (BG) is a modulator of the DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase (AGT). BG is converted in mice, rats and humans to an equally active, yet longer-lived metabolite, O⁶-benzyl-8-oxoguanine (8-oxo-BG) by CYP1A2, CYP3A4 and aldehyde oxidase. Since intravenous BG is expected to enter phase I development with orally administered anticancer agents such as temozolomide, procarbazine or SarCNU, we determined the bioavailability of orally administered BG, as well as the effect of ketoconazole, a potent intestinal and hepatic CYP3A4 inhibitor, on the disposition of BG. Methods: Following intravenous or oral administration of BG in PEG-400/saline (40:60) to Sprague-Dawley rats, the pharmacokinetics of BG and 8-oxo-BG were determined. To determine the effect of CYP3A inhibition on disposition, oral BG was coadministered with ketoconazole. Results: The peak plasma concentration (C_max), time to C_max (t_max), and bioavailability (F) of oral BG were: 2.3 ± 0.9 μg/ml, 2.3 ± 0.6 h, and 65.5% respectively. The AUCs of BG and 8-oxo-BG were 13.1 ± 4.6 μg · h/ml and 1.7 ± 0.4 μg · h/ml after oral administration of BG. Coadministration with ketoconazole resulted in an increase in mean absorption time from 2.0 ± 0.3 h to 6.0 ± 0.9 h, a shift in t_max to 5 ± 3.3 h, a decrease in C_max to 0.96 ± 0.8 μg/ml, and a decrease in AUC_0-inf ratio of 8-oxo-BG:BG from about 0.12 to 0.04 (P < 0.05). The bioavailability of BG was not changed (65.5% vs 56.9%, P=0.78). Conclusions: The oral bioavailability of BG is high, warranting consideration of an oral formulation for clinical development. Coadministration of ketoconazole and BG resulted in delayed oral absorption and inhibition of conversion of BG to 8-oxo-BG in the rat model. Received: 12 July 1999 / Accepted: 11 February 2000     

Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates

Purpose: The antiviral nucleoside analogue ganciclovir is a potent inhibitor of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompromised patients. Ganciclovir is also used in cancer gene therapy studies that utilize the herpes simplex virus thymidine kinase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and children have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir. We studied the pharmacokinetics of ganciclovir in plasma and CSF in a nonhuman primate model that is highly predictive of the CSF penetration of drugs in humans. Methods: Ganciclovir, 10 mg/kg i.v., was administered over 30 min to three animals. Ganciclovir concentrations in plasma and CSF were measured using reverse-phase HPLC. Results: Peak plasma ganciclovir concentrations ranged from 18.3 to 20.0 μg/ml and the mean plasma AUC was 1075 ± 202 μg/ml · min. Disappearance of ganciclovir from the plasma was biexponential with a distribution half-life (t_1/2α) of 18 ± 7 min and an elimination half-life (t_1/2β) of 109 ± 7 min. Total body clearance (Cl_TB) was 9.4 ± 1.6 ml/min/kg. The mean CSF ganciclovir AUC was 168 ± 83 μg/ml · min and the mean peak CSF concentration was 0.7 ± 0.3 μg/ml. The ratio of the AUCs in CSF and plasma was 15.5 ± 7.1%. Conclusions: Ganciclovir penetrates into the CSF following i.v. administration. This finding will be useful in the design of gene therapy trials involving the HSV-TK gene followed by treatment with ganciclovir in CNS or leptomeningeal tumors. Received: 8 May 1998 / Accepted: 25 September 1998     

Clinical pharmacokinetics of intravenous treosulfan in patients with advanced solid tumors

Treosulfan (l-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/m² treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/m² group and 7 were analyzed in the 10-g/m² group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 h. AUC and C_max values were significantly (P < 0.01) higher in the 10-g/m² group (AUC 708 ± 168 versus 977 ± 182 μg ml⁻¹ h, C_max 465 ± 98 versus 597 ± 94 μg/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 h (range 5–49%), and about 20% was excreted during the first 6 h after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/m² treosulfan using a 2-h infusion protocol. Received: 25 August 1997 / Accepted: 15 December 1997     

Pharmacokinetics of 2-chloro-2′-deoxyadenosine administered subcutaneously or by continuous intravenous infusion

Purpose: Cladribine (2-chlorodeoxyadenosine, 2-CDA) is effective in the treatment of various lymphoproliferative disorders. In the standard protocol the compound is administered by continuous intravenous (i.v.) infusion. In order to allow outpatient therapy alternative modes of administration such as subcutaneous (s.c.) injection would be desirable. The aim of the present study was to compare the pharmacokinetics of 2-CDA after i.v. and s.c. administration. Patients and methods: Nine patients received 0.1 mg/kg 2-CDA per 24 h on one occasion by continuous i.v. infusion and on another occasion as a bolus subcutaneously. The concentrations of 2-CDA in the plasma and urine were determined by HPLC. Results: During i.v. infusion the concentration of 2-CDA in the plasma reached a plateau after 4–8 h, whereas with s.c. administration almost ten times higher peak concentrations were reached within 20 to 60 min. A two-compartment model was fitted to the data points whereby the goodness-of-fit statistics showed R ² values of >0.98. The calculated rate of elimination, k_elim, averaged 0.336 h⁻¹ with s.c. and 0.397 h⁻¹ with i.v. administration. The estimated volumes of distribution were 1.67 and 1.58 l/kg. The areas under the concentration time curves (608 ± 65 pmol · h/ml after s.c. administration vs 571 ± 50 pmol · h/ml during i.v. infusion) and the urinary excretion of 2-CDA in 24 h (4.75 ± 0.95 vs 3.55 ± 0.53 μmol/24 h) were similar in both groups, indicating identical bioavailability. Conclusions: Although the pharmacokinetic profile of 2-CDA administered s.c. differs substantially from the profile of a continuous i.v. infusion the areas under the plasma concentration time curves, the urinary excretion of unchanged drug and the estimated pharmacokinetic variables were similar with both modes of administration, indicating that the different time-courses of the plasma concentration did not influence the fraction metabolized or eliminated. Received: 3 November 1999 / Accepted: 3 March 2000     

Pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin

Purpose: Toremifene (Fareston) is an orally administered triphenylethylene derivative with chemosensitizing activity in vitro in estrogen receptor-negative multidrug-resistant human breast cancer cells. The purpose of this study was to evaluate the effects of high-dose toremifene (600 mg/day for 5 days) on the plasma pharmacokinetics of doxorubicin in humans. The 600-mg dose had been previously established as the maximum tolerated dose in a phase I study of 35 patients. Methods: Doxorubicin was administered as an intravenous (i.v.) bolus over 15 min at a dose of 60 mg/m² to 11 patients in the absence of toremifene pretreatment to establish baseline doxorubicin pharmacokinetics. Six of these patients received 600 mg/day toremifene for 5 days 4 weeks later, followed by an i.v. bolus dose of doxorubicin (60 mg/m²) on day 5. During toremifene pretreatment, blood specimens (5 ml) were drawn at 0, 2, 4, and 24 h after dosing to assess peak levels. Following doxorubicin administration in each cycle, blood specimens were collected over a 72-h period for determination of the terminal half-life of elimination. Plasma concentrations of doxorubicin and toremifene were assessed by high-performance liquid chromatography (HPLC). Cumulative linear areas under the time-concentration curve (AUC) for doxorubicin were calculated using a noncompartmental model. Results: Prior to toremifene dosing, baseline doxorubicin pharmacokinetic studies showed an average terminal half-life of elimination of 40.04 ± 7.86 h in 4 patients, and an average AUC of 135 600 ± 67 600 μg/ml · h in 11 patients. In 4 of the patients receiving 600 mg/day toremifene for 5 days, the average terminal half-life of elimination was 38.12 ± 7.81 h, and the average AUC was 141 900 ± 62 900 μg/ml · h in 6 patients, i.e. a slight increase of 4.6%. No statistically significant change in the doxorubicin elimination kinetics with or without toremifene therapy was observed. Conclusions: Toremifene does not appear to interfere with the elimination kinetics of doxorubicin. Received: 1 July 1997 / Accepted: 16 December 1997     

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     

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

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

Preclinical pharmacology and antitumour activity of the novel sequence-selective DNA minor-groove cross-linking agent DSB-120

 We examined the in vitro cytotoxicity, antitumour activity and preclinical pharmacokinetics of the novel sequence-selective, bifunctional alkylating agent DSB-120, a synthetic pyrrolo[1, 4][2, 1-c]benzodiazepine dimer. DSB-120 was shown to be a potent cytotoxic agent in vitro against a panel of human colon carcinomas [50% growth-inhibitory concentration (IC₅₀) 42±7.9 nM, mean±SE, n=7] and two rodent tumours (L1210 and ADJ/PC6). Antitumour activity was assessed in the bifunctional alkylating-agent-sensitive murine plasmacytoma ADJ/PC6 using a variety of administration protocols. The maximal antitumour eff- ects were observed following a single i.v. dose but the therapeutic index was only 2.6. DSB-120 was less effective when given i.p. either singly or by a daily+5 schedule. After a single i.v. dose at the maximum tolerated dose (MTD, 5 mg kg⁻¹) the plasma elimination was biphasic, with a short distribution phase (t _1/2α 4 min) being followed by a longer elimination phase (t _1/3β 38 min). Peak plasma concentrations were 25 μg ml⁻¹, the clearance was 1.3 ml g⁻¹ h⁻¹ and the AUC_0-∞ was 230 μg ml⁻¹ min. Concentrations of DSB-120 in ADJ/PC6 tumours were very low, showing a peak of 0.4 μg g⁻¹at 5 min. The steady-state tumour/plasma ratio was about 5% and the AUC was only 2.5% of that occurring in the plasma. DSB-120 appeared to be unstable in vivo, with only 1% of an administered dose being recovered unchanged in 24-h urine samples. Plasma protein binding was extensive at 96.6%. In conclusion, the poor antitumour activity of DSB-120 may be a consequence of low tumour selectivity and drug uptake as a result of high protein binding and/or extensive drug metabolism in vivo. Received: 5 November 1995/Accepted: 30 January 1996     

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     

Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia

Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubicin registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free daunorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m² IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t_1/2α 4.54 ± 0.87 h; Vd_ss 2.88 ± 0.93 l/m²; Cl 0.47 ± 0.26 l/h/m²) showed that in patients with acute leukemia liposomal-entrapped daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC_0–∞ 456.27 ± 182.64 μg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200- to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 ± 7.13 μg/ml · h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of daunorubicin captation in normal tissues, thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy. Received: 17 March 2000 / Accepted: 25 May 2000     

Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur,in experimental tumor models in rats

 S-1, a new oral antitumor agent, is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is a masked compound of 5-fluorouracil (5-FU) acts as an effector, while both CDHP and Oxo which do not have antitumor activity themselves act as modulators. In this study, the antitumor activity and intestinal toxicity of S-1 were investigated using experimental tumor models in rats, and compared with those of other oral fluoropyrimidines, namely 5-FU, FT, FCD (1 M FT/0.4 M CDHP) and UFT (combination of FT and uracil). In rats bearing subcutaneous Yoshida sarcoma, S-1 inhibited tumor growth at the lowest dose (ED₅₀ value: S-1 5, UFT 22, FT 82, FCD 5, and 5-FU 19 mg/kg per day), and induced the least host body weight suppression, leading to the highest therapeutic index (TI) (S-1 4.5, UFT 1.4, FT 1.8, FCD 2.0, and 5-FU 1.4). S-1 also showed a higher therapeutic effect than UFT against AH-130 and Sato lung carcinoma. After administration of S-1 and UFT at equitoxic doses, S-1 showed a higher and more prolonged concentration of 5-FU than UFT both in plasma (AUC_0-∞: S-1 28 nmol h/ml, UFT 15 nmol⋅h/ml) and in tumor tissue (AUC_0-∞: S-1 95 nmol h/g tissue, UFT 52 nmol h/g tissue), leading to a higher 5-FU level incorporated into the RNA fraction (F-RNA level) in tumor tissue (AUC_0-24: S-1 7.0 nmol h/mg RNA, UFT 4.3 nmol h/mg RNA) and 5–8% higher thymidylate synthase (TS) inhibition in tumor tissue at every time-point through 24 h. Compared with other oral fluoropyrimidines after administration of the maximal tolerable dose (MTD), S-1 caused the lowest rates of intestinal toxicities, such as diarrhea and occult blood in feces. S-1 also showed a higher antitumor effect on Yoshida sarcoma implanted intracolonically than UFT at an equitoxic dose (tumor weight: S-1 64±30 mg, UFT 133±52 mg; P<0.05). These results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, which is an inhibitor of 5-FU phosphorylation, locally protects the gastrointestinal tract from 5-FU-induced toxicity without decreasing the antitumor activity. Received: 13 October 1996/Accepted: 18 May 1996     

Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery

Retinoids have shown promising activity for both cancer chemoprevention and as a treatment for emphysema. However, chronic oral administration of these drugs is limited by systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia, hypercalcemia, and other reactions. In order to improve the pulmonary targeting of this potentially useful therapy, we developed a system for aerosolization of retinoids that substantially increased their local bioavailability. We compared the biodistribution and pharmacokinetics of an inhaled formulation of all-trans-retinoic acid (all-trans-RA), which was packaged in a metered dose inhaler, following both intratracheal (IT) and intravenous (IV) administration in male Sprague-Dawley rats. After drug administration, anesthetized animals were killed at 5 min, and at 1, 2, 4, 6 and 24 h. Plasma and emulsified samples of liver and lung tissues were dissected, extracted, and frozen prior to measurement of all-trans-RA concentration by high-performance liquid chromatography (HPLC). Aerosolization and IT injection of all-trans-RA resulted in a significantly longer pulmonary half-life of the drug (both 5–17 h), lower peak serum concentrations (aerosol 71 ± 31 ng/ml, IT 68 ± 50 ng/ml), and lower liver levels (aerosol 111 ± 28 ng/g, IT 753 ± 350 ng/g) than the same dose administered IV (2 h, 838 ± 56 ng/ml, 4258 ± 1006 ng/g, respectively; P < 0.05 for each comparison). Histologic examination of lungs and trachea showed no focal irritation attributable to the drug after single-dose administration. These results suggest that aerosolization of retinoids may offer a practical alternative to systemic oral administration for chemoprevention trials or treatment of lung diseases. This method may substantially increase the therapeutic index of these compounds by reducing systemic complications associated with long-term dosing. Received: 17 September 1999 / Accepted: 14 April 2000     

Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines

Purpose: We have reported a 6-fold difference in the topotecan (TPT) lactone systemic exposure achieving a complete response in the human neuroblastoma xenografts NB-1691 and NB-1643. However, the relationship between tumor extracellular fluid (ECF) exposure to TPT and the antitumor activity in xenograft and in vitro models has not been established. Methods: TPT was given i.v. to mice bearing NB-1691 and NB-1643 tumors. Prior to dosing, microdialysis probes were placed in tumors of mice bearing NB-1691 and NB-1643 tumors. Plasma and tumor ECF concentrations of TPT lactone were assayed by high performance liquid chromatography. The inhibitory concentration (IC₅₀) was determined for NB-1691 and NB-1643 cell lines in vitro. Results: The TPT AUC_ECF values determined for NB-1691 (n=10) and NB-1643 (n=11) were 7.3 ± 0.84 and 25.6 ± 0.76 ng h ml⁻¹, respectively (P < 0.05). TPT tumor ECF penetration in NB-1691 and NB-1643 was 0.04 ± 0.04 and 0.15 ± 0.11 (P < 0.05), respectively. The IC₅₀ values recorded after 6 h of TPT exposure daily for 5 consecutive days for NB-1691 and NB-1643 were 2.7 ± 1.1  and 0.53 ± 0.19 ng/ml, respectively (P < 0.05). Conclusions: NB-1643 was more sensitive in vitro than NB-1691, and at similar plasma TPT exposures, NB-1643 had a greater degree of TPT tumor ECF exposure and penetration as compared with NB-1691. Potential factors affecting tumor TPT ECF disposition include tumor vascularity, capillary permeability, and interstitial pressure. The clinical importance of this study is underscored by the need to select anticancer agents with a high capacity for tumor penetration and to optimize drug administration to increase tumor penetration. Received: 20 April 1998 / Accepted: 25 August 1998     

Effect of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on plasma concentration of uridine released from 2′,3′,5′-tri-O-acetyluridine, a prodrug of uridine: relevance to uridine rescue in chemotherapy

Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acyclouridine (PSAU) with 2′,3′,5′-tri-O-acetyluridine (TAU) on the levels of plasma uridine in mice. PSAU is a new lipophilic and potent inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral uridine. TAU is a prodrug of uridine and a far superior source of uridine than uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the C_max and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma uridine concentration could be useful in the management of medical disorders that are remedied by administration of uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues. Received: 10 November 1999 / Accepted: 14 March 2000     

Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer

Purpose: d -Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. Methods: A group of 32 patients with refractory solid tumors completed 99 courses of d-limonene 0.5 to 12 g/m² per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of d-limonene at 8 g/m² per day. Intratumoral monoterpene levels were measured in two patients. Results: The MTD was 8 g/m² per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m² per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (C_max) for d-limonene ranged from 10.8 ± 6.7 to 20.5 ± 11.2 μM. Predominant circulating metabolites were perillic acid (C_max 20.7 ± 13.2 to 71 ± 29.3 μM ), dihydroperillic acid (C_max 16.6 ± 7.9 to 28.1 ± 3.1 μM ), limonene-1,2-diol (C_max 10.1 ± 8 to 20.7 ± 8.6 μM ), uroterpenol (C_max 14.3 ± 1.5 to 45.1 ± 1.8 μM ), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of d-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. Conclusions: d-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation. Received: 25 June 1997 / Accepted: 6 November 1997     

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     

Erucylphosphocholine: pharmacokinetics, biodistribution and CNS-accumulation in the rat after intravenous administration

The clinical use of alkylphosphocholines (APC) in cancer patients is restricted because of the high gastrointestinal toxicity and the need for oral administration. Therefore we evaluated the clinical pharmacology of erucylphosphocholine (ErPC), the first derivative of the APC family suitable for intravenous administration with strong antineoplastic activity, in vitro and in vivo in rats. The pharmacokinetic parameters after a single intravenous dose of 40 mg/kg were calculated using a two-compartment model: C_max= 1.6 ± 0.3 μmol/ml, T_1/2α= 0.18 ± 0.09 h, T_1/2β= 3.3 ± 0.88 h, clearance = 9.7 ± 1.2 ml/h, AUC = 2.5 ± 0.3 μmol/ml per h and Vss = 40.4 ± 7.9 ml. Biodistribution studies were performed after repeated ErPC administration at different doses. Intravenous injections of 20 mg/kg given at intervals of 48 h for up to 4 weeks were well tolerated. Neither clinical evaluation nor laboratory parameters (haematology and clinical chemistry) revealed toxic side effects. In contrast, higher doses of ErPC (40 mg/kg per 48 h) led to weight loss. After 2 and 4 weeks of therapy with 20 mg/kg per 48 h a high ErPC accumulation was found in the adrenal glands, small intestine and brain. The brain to serum concentration ratios averaged 2.1 after 2 weeks and 4.5 after 4 weeks. Significant leucocytosis and thrombocytosis were observed after 4 weeks of ErPC treatment. The findings suggest that ErPC is a suitable candidate for clinical trials. In particular, owing to the high accumulation in brain tissue, ErPC is a potential agent for chemotherapy against malignant brain tumours. Received: 4 January 1999 / Accepted: 6 May 1999     

Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas

Background The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin’s lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions. Patients and methods We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n = 7; female, n = 3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m² given intravenously on day 1, and 200 mg/m² orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program. Results Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3 ± 3.7 vs. 12.0 ± 4.2 μg/ml; P = 0.015). The mean bioavailability of oral etoposide was 58 ± 15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m² intravenous and a 200 mg/m² oral dose of etoposide were 74.0 ± 18.3 and 84.9 ± 29.6 μg h/ml (P = 0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4 ± 10.6% after intravenous infusion versus 35.4 ± 9.4% after oral intake (P = 0.422). Renal clearance was also very similar with intravenous and oral route (18.5 ± 7.4 vs. 16.7 ± 6.6 ml/min; P = 0.546). Conclusion The equivalency of AUC after 200 mg/m² of oral and 100 mg/m² of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.     

Effect of filgrastim on the pharmacokinetics of MX2 hydrochloride in patients with advanced malignant disease

Purpose: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. Methods: A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50–80 mg/m² (74–152 mg) with concomitant filgrastim (G-CSF, 5 μg/kg) given daily beginning at 24 h after the dose of MX2. Results: The mean fast distribution half-life (1.5 ± 1.0 min) and the mean plasma clearance (2.18 ± 0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8–107.5 mg) alone (3.3 ± 2.2 min and 2.98 ± 1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8 ± 14.7 and 11.8 ± 5.0 h for M1 and 14.8 ± 4.1 and 12.3 ± 6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2- filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2. Conclusions: This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism. Received: 1 June 1997 / Accepted: 17 September 1997