V. M. M. Herben

Clinical pharmacokinetics of topotecan

SummaryTopotecan (Hycamtin®), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase I in vitro and has demonstrated encouraging antitumour activity in a wide variety of tumours, including ovarian cancer and small cell lung cancer. Now approved in the US, topotecan has completed single-agent phase I testing; phase II/III trials are ongoing.Under physiological conditions the lactone moiety of topotecan undergoes a rapid and reversible pH-dependent conversion to a carboxylated open-ring form, which lacks topoisomerase I inhibiting activity. At equilibrium at pH 7.4 the open-ring form predominates. Topotecan is stable in infusion fluids in the presence of tartaric acid (pH < 4.0), but is unstable in plasma, requiring immediate deproteinisation with cold methanol after blood sampling and storage of the extract at −30°C to preserve the lactone form.Topotecan has been administered in phase I trials in several infusion schedules ranging from 30 minutes to 21 days. The plasma decay of topotecan concentrations usually fits a 2-compartment model. Rapid hydrolysis of topotecan lactone results in plasma carboxylate levels exceeding lactone levels as early as 45 minutes after the start of a 30-minute infusion. The peak plasma concentrations and the area under the plasma concentration-versus-time curves (AUC) show linear relationship with increasing dosages. No evidence of drug accumulation is seen with daily 30-minute infusions for 5 consecutive days.Topotecan lactone is widely distributed into the peripheral space, with a mean volume of distribution (Vd) at steady-state of 75 L/m2. The mean total body clearance of the lactone form is 30 L/h/m2, with a mean elimination half-life (t½β) of 3 hours; renal clearance accounts for approximately 40% of the administered dose with a large interindividual variability.The oral bioavailability of topotecan is approximately 35%. The low bioavailability may be caused by hydrolysis of topotecan lactone in the gut, yielding substantial amounts of the open-ring form, which is poorly absorbed.Renal dysfunction may decrease topotecan plasma clearance. Creatinine clearance is significantly, but poorly, correlated with topotecan clearance. Hepatic impairment does not influence topotecan disposition.Indices of systemic exposure (steady-state concentrations and AUC) are correlated with the extent of myelotoxicity. Sigmoidal functions adequately describe the relationships between systemic exposure and the percentage decrease in neutrophils.

Oral topotecan : bioavailability and effect of food co-administration

SummaryThe aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m–2 day–1 of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m–2 day–1) or i.v. (1.5 mg m–3 day). They crossed over to receive the alternate regimen on day 2. On days 3–5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93 ± 0.23 (90% confidence interval (CI) 0.83–1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6 ± 4.4 ng ml–1) or without food (9.2 ± 4.1 ng ml–1) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8–6.1) compared to fasted conditions (2.0 h, range 1.1–8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42 ± 13% (90% CI 37– 47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9 ± 1.0 h) than after i.v. administration (2.7 ± 0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption.

Phase I and Pharmacokinetic Study of Irinotecan Administered as a Low-Dose, Continuous Intravenous Infusion Over 14 Days in Patients With Malignant Solid Tumors

PURPOSE To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m(2)/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m(2)/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m(2)/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% +/- 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION The recommended dosage is 10 mg/m(2)/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.

Phase I and Pharmacologic Study of the Combination of Paclitaxel, Cisplatin, and Topotecan Administered Intravenously Every 21 Days as First-Line Therapy in Patients With Advanced Ovarian Cancer

PURPOSE To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Phase I and pharmacological study of sequential intravenous topotecan and oral etoposide.

We performed a phase I and pharmacological study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytotoxic regimen of the novel topoisomerase I inhibitor topotecan in combination with the topoisomerase II inhibitor etoposide, and to investigate the clinical pharmacology of both compounds. Patients with advanced solid tumours were treated at 4-week intervals, receiving topotecan intravenously over 30 min on days 1-5 followed by etoposide given orally twice daily on days 6-12. Topotecan-etoposide dose levels were escalated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m-2 day-1)/(mg bid). After encountering DLT, additional patients were treated at 3-week intervals with the topotecan dose decreased by one level to 1.0 mg m-2 and etoposide administration prolonged from 7 to 10 days to allow further dose intensification. Of 30 patients entered, 29 were assessable for toxicity in the first course and 24 for response. The DLT was neutropenia. At doses of topotecan-etoposide 1.25/40 (mg m-2)/(mg bid) two out of six patients developed neutropenia grade IV that lasted more than 7 days. Reduction of the treatment interval to 3 weeks and prolonging etoposide dosing to 10 days did not permit further dose intensification, as a time delay to retreatment owing to unrecovered bone marrow rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h. Total body clearance was 13.8 +/- 2.7 l h-1 m-2 with a steady-state volume of distribution of 36.7 +/- 6.2 l m-2. N-desmethyltopotecan, a metabolite of topotecan, was detectable in plasma and urine. Mean maximal concentrations ranged from 0.23 to 0.53 nmol l-1, and were reached at 3.4 +/- 1.0 h after infusion. Maximal etoposide plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57 micromol l-1 were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20 and 40 mg respectively. The topotecan area under the plasma concentration vs time curve (AUC) correlated with the percentage decrease in white blood cells (WBC) (r2 = 0.70) and absolute neutrophil count (ANC) (r2 = 0.65). A partial response was observed in a patient with metastatic ovarian carcinoma. A total of 64% of the patients had stable disease for at least 4 months. The recommended dose for use in phase II clinical trials is topotecan 1.0 mg m-2 on days 1-5 and etoposide 40 mg bid on days 6-12 every 4 weeks.

Isolation and structural confirmation of N-desmethyl topotecan, a metabolite of topotecan

Abstract A sensitive high-performance liquid chromatography (HPLC) method for the determination of topotecan and total levels of topotecan (lactone plus its ring-opened hydroxycarboxylate form) was developed by the authors and used in several pharmacokinetics studies. During the analysis of plasma and urine samples collected in those studies, an additional peak eluting just after topotecan was observed. Approximately 100 ng of this potential metabolite was isolated from human urine using a solid-phase extraction procedure and purification by HPLC. Analysis of the isolated material by HPLC showed it to be approximately 95% pure. Mass spectrometry data along with the HPLC retention data and fluorescence data (in comparison with synthetic reference standard) are consistent with the metabolite’s being N-desmethyl topotecan. The maximal concentrations of metabolite deteced in human plasma and urine were relatively low. When topotecan was given as a 30-min infusion at 1.0 mg/m2 daily for 5 days every 3 weeks, the maximal plasma metabolite concentration (lactone plus the ring-opened hydroxycarboxylate form) was about 0.7% (n=4) of the maximal total topotecan concentration. The average amount of metabolite excreted in urine during the treatment was 1–4% (n=20) of the delivered dose.

Clinical pharmacokinetics of camptothecin topoisomerase I inhibitors.

In this review the clinical pharmacokinetics of camptothecin topoisomerase I inhibitors, an important new class of anticancer drugs, is discussed. Two prototypes, topotecan and irinotecan, are currently marketed in many European countries and the USA for the treatment of patients with ovarian and colorectal cancer, respectively. Other camptothecin derivatives, including lurtotecan, 9‐aminocamptothecin (9‐AC) and 9‐nitrocamptothecin (9‐NC), are at different stages of clinical development. The common property of camptothecin analogues is their action against DNA topoisomerase I, but beyond this similarity the compounds differ widely in terms of antitumour efficacy, pharmacology, pharmacokinetics and metabolism. We review chemistry, mechanism of action, stability and bioanalysis of the camptothecins. Dosage and administration, status of clinical application, pharmacokinetics, pharmacodynamics and drug interactions are discussed.

Sensitive Determination of the Carboxylate and Lactone Forms of the Novel Antitumor Drug Irinotecan and Its Active Metabolite in Plasma by HPLC

Abstract A sensitive high-performance liquid chromatographic (HPLC) method has been developed and validated for the determination of the lactone and carboxylate forms of the novel antitumor drug irinotecan (CPT-11) and its active metabolite SN-38 in plasma. The instability of the compounds required immediate bed-side protein precipitation of plasma samples with an ice-cold mixture of methanol and acetonitrile. These methanolic extracts could be stored at −70°C for at least 3 months without degradation of the analytes. Separation of the lactone and carboxylate forms of CPT-11 and SN-38 was achieved on a C18 reversed phase column with a mobile phase composed of a mixture of 0.1 M ammonium acetate, triethylamine, and acetonitrile (800:1:156, w/v/w) and 5 mM tetra-butyl ammonium phosphate. Detection was performed fluorimetrically. Within-run and between-run precision was always less than 11% in the concentration ranges of interest (1.0–100 ng/mL and 0.5–25 ng/mL, for CPT-11 and SN-38, respectively). The metho...

Phase I and Pharmacokinetic Study of a Daily Times 5 Short Intravenous Infusion Schedule of 9-Aminocamptothecin in a Colloidal Dispersion Formulation in Patients With Advanced Solid Tumors

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks. PATIENTS AND METHODS Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m(2)/d. The MTD was assessed on the first cycle and was defined as the dose at which > or = two of three patients or > or = two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography. RESULTS Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m(2)/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m(2)/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal E(max) models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1. 1 mg/m(2)/d.

High-performance liquid chromatographic analysis of the investigational anticancer drug 9-aminocamptothecin, as the lactone form and as the total of the lactone and the hydroxycarboxylate forms, in micro-volumes of human plasma

A high performance liquid chromatographic (HPLC) assay is described for the determination of the investigational anticancer drug 9 aminocamptothecin (9-AC) as the lactone form (9AC(lac)) and as the total of the lactone and hydroxycarboxylate forms (9AC-(tot)), in micro volumes of plasma. The analytical methodology reported here involves a protein precipitation step with cold methanol (-30 degrees C) as sample pretreatment procedure. The methanolic extract is used for the determination of 9AC-(tot). The intact (active) lactone form of 9-AC is separated from the hydroxycarboxylate form in the methanolic plasma extract by solid phase extraction within 48 h after sampling and deproteination. After evaporation to dryness (nitrogen, 40 degrees C) the extract can be stored at -70 degrees C for at least 3 weeks. The drug is analysed by reversed-phase liquid chromatography on a Zorbax SB RP-18 column, using methanol-water eluent (pH 2.2) and fluorescence detection. The presented assay is linear over a concentration range 0.2-100 ng.ml-1 with a detection limit and a limit of quantitation of 0.05 and 0.2 ng.ml-1, respectively, for both 9-AC(tot) and 9-AC(lac) using a 100 ml plasma sample. The proposed method has been implemented in a phase I clinical trial for pharmacokinetic evaluation of this potential new drug.