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© 2002 American Society for Clinical Oncology Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918ByFrom the Department of Medical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital; Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and GlaxoSmithKline, Research Triangle Park, NC. Address reprint requests to J.H.M. Schellens, MD, PhD, Department of Medical Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands; email: jhm{at}nki.nl
PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate–binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(-/-) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m2 oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m2 intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 ± 9.6 µg·h/L without GF120918 to 78.7 ± 20.6 µg·h/L when GF120918 was coadministered (P = .008). The mean maximum plasma concentration of total topotecan increased from 4.1 ± 1.5 µg/L without GF120918 to 11.5 ± 2.4 µg/L with GF120918 (P = .008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P = .008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.
TOPOTECAN IS A semisynthetic water-soluble analog of the alkaloid camptothecin and inhibits topoisomerase I, an essential enzyme involved in DNA replication.1,2 Topotecan has demonstrated antitumor activity in several tumor types, including ovarian cancer3 and small-cell lung cancer.4 The unique mechanism of action and lack of cross-resistance with other antitumor agents may provide therapeutic advantage in first- and second-line treatment and in combination therapy.5-7 Clinical studies indicate enhanced antineoplastic activity of topotecan when administered daily for prolonged periods of time.8-11 Because the oral route of administration may provide a more convenient way of achieving prolonged exposure, an oral capsule formulation was developed. Previous studies reported 30% to 44% bioavailability of the intravenous formulation of topotecan administered orally.12-14 In a phase I study, the maximum-tolerated oral dose for topotecan was 2.3 mg/m2 for the daily-times-five dosing schedule.15 Toxicity of the oral regimen is comparable with the intravenous schedule.15 Oral administration of topotecan, however, was accompanied by a substantially increased interpatient variability in systemic exposure.12,14 There is no mechanistic explanation for the low bioavailability of orally administered topotecan. The drug is soluble and chemically stable under physiologic conditions, and there is no significant first-pass metabolism.16 In humans, the urinary recovery of intravenous topotecan is approximately 40%, and this concerns mainly the carboxylate form. Thus, 60% of topotecan undergoes elimination through other routes. These may include biliary secretion and hepatic metabolism.16 Recently, we isolated and quantified an N-desmethyl metabolite of topotecan in plasma, urine, and feces.17,18 In addition, another study demonstrated also O-glucuronidation as being a metabolic pathway for topotecan and N-desmethyl topotecan.19 The breast cancer resistance protein (BRCP) was first described by Doyle et al20 in human MCF-7/Adr VP multidrug-resistant breast cancer cell lines and acts as an adenosine triphosphate–dependent xenobiotic transporter. This protein is also expressed in ovarian cancer cell lines (IGROV-1) that were made resistant to topotecan (T8), and results in a major increase of the efflux rate of topotecan and related topoisomerase I inhibitory drugs.21 BCRP is highly expressed in the small intestine and was also found in the bile ducts of the liver and in the colon, placenta, veins, and capillaries.22 GF120918 is a new potent inhibitor of P-glycoprotein (P-gp),23 and in clinical studies, this agent has been well tolerated in doses of 1,000 mg bid over 5 consecutive days in combination with doxorubicin and as a single dose of 1,000 mg with paclitaxel.24,25 Recently, this compound has been demonstrated to be an efficient inhibitor of BCRP, in both human and murine systems.26,27 A recent study has shown that GF120918 is a potent reversal agent of BCRP-mediated resistance to camptothecins, with almost complete reversal noted at 100 nmol/L.28 Preclinical studies performed in our institute in groups of mdr1a/1b(-/-) P-gp knockout mice and wild-type mice, which were treated with oral topotecan in combination with one single oral dose of GF120918, have shown that the systemic exposure of oral topotecan increased almost seven-fold and almost 10-fold, respectively.29 Administration of intravenous topotecan in combination with oral GF120918 resulted in a decreased plasma clearance and hepatobiliary excretion of topotecan and increased reuptake by the small intestine.29 These results suggest that GF120918 may also be an effective inhibitor of BCRP. We know that the affinity of topotecan for P-gp is low,30 so the affinity of topotecan for this putative drug transporter (BCRP) is the most plausible explanation for the limited absorption of orally administered topotecan when given alone. On the basis of these laboratory results, we hypothesized that the systemic exposure in humans after oral administration of topotecan will increase and the interpatient variation may decrease by oral GF120918 coadministration. However, we have to realize that we cannot generalize the results of the preclinical studies to humans. Therefore, we have investigated this in a proof-of-concept study in patients with solid tumors. In addition, we have determined the effect of GF120918 on the systemic clearance of topotecan.
Eligibility Criteria Patients with histologic proof of cancer for whom no standard therapy of proven benefit existed were eligible for this study. Prior treatment with topotecan or a camptothecin analog was not allowed. Previous radiotherapy or chemotherapy were allowed but treatment had to be stopped at least 4 weeks before study entry and any resulting toxicities had to be resolved. Patients had to have acceptable bone marrow (WBC count > 3.0 x 109/L and platelets > 100 x 109/L), liver (serum bilirubin  25 µmol/L; liver enzymes AST, ALT, and alkaline phosphatase two times upper limits of normal unless explained by liver metastases, then five times upper limits of normal was accepted; serum albumin > 25 g/L), and kidney (serum creatinine 160 µmol/L or clearance  50 mL/min) functions. All patients had to have a World Health Organization (WHO) performance status 2. Patients were excluded if they suffered from uncontrolled infectious disease, neurologic disease, bowel obstruction, or motility disorders with the potential to influence the absorption of drugs. Patients with symptomatic brain metastases were not eligible. Further exclusion criteria were concomitant use of known multidrug-resistant converting drugs, H2-receptor antagonists, or proton pump inhibitors. The trial was approved by the ethics committee of the institute, and all patients gave written informed consent.
Treatment Plan and Study Design In the second cohort (cohort B), eight other patients received intravenous topotecan at two occasions, which were randomized. They received on day 1 or day 8 a single dose of 1.0 mg/m2 intravenous topotecan with a single oral dose of 1,000 mg GF120918, and on day 1 or day 8 a single dose of 1.0 mg/m2 intravenous topotecan without GF120918. All patients in cohorts A and B continued on day 15 with intravenous topotecan 1.5 mg/m2 daily for 5 days every 3 weeks (5-day course). Dose reduction by 0.25 mg/m2/d was mandated for patients who experienced grade 4 neutropenia, neutropenic fever, grade 4 thrombocytopenia, or grade 3 or 4 nonhematologic toxicity excluding untreated grade 3 nausea, grade 3 or 4 vomiting, and alopecia. Treatment cycles were to be repeated every 21 days, provided that the patients had recovered from any drug-related toxicity associated with the previous course. Patients continued to be treated until disease progression was observed or unacceptable toxicity occurred.
Drug Administration For the oral intake of topotecan, the intravenous formulation was used. The formulation was drunk by the patient after dilution with 100 mL of tap water. This is the same procedure as has been applied in a previous study in which the oral bioavailability of topotecan was determined in patients.14 All the patients had to be fasted from 24:00 hours overnight and a standard breakfast consisting of two slices of white bread with ham and cheese and a cup of tea was consumed 30 minutes before start of the course. GF120918 (GlaxoSmithKline, Research Triangle Park, NC) was ingested as 100-mg tablets 60 minutes before oral intake or intravenous administration of topotecan. Oral granisetron 1 mg was administered to all patients 30 minutes before every course to prevent nausea and vomiting.
Toxicity and Response Evaluation
Plasma Pharmacokinetics
Statistical Analysis
Patient Characteristics Sixteen patients (seven males and nine females) with solid tumors (one patient with a hematologic malignancy) were entered onto this pharmacologic study. As listed in Table 1, the median age of the patients was 53 years (range, 35 to 65 years) and the median WHO performance status was 1 (range, 0 to 2). All patients received prior chemotherapy, and the most frequent tumor types were ovary (n = 4), lung (n = 3), and gastrointestinal (n = 4).
Toxicity The combination of topotecan and oral GF120918 was well tolerated in all patients. No significant side effects were seen after the first 14 days of treatment with topotecan in combination with GF120918. Toxicities clearly associated with GF120918 administration were not observed. Most frequently reported toxicities in these patients were hematologic, as is common for the daily-times-five schedule of topotecan. Neutropenia grade 3 and 4 was recorded in nine patients (56.3%). Anemia grade 3 was reported in three patients (12.5%) and thrombocytopenia grade 3 and 4 in five patients (31.3%). Nonhematologic toxicities consisted mainly of mild nausea and vomiting, fatigue, and alopecia. These toxicities developed during the period of standard treatment with daily-times-five intravenous topotecan.
Response
Pharmacokinetics
As listed in Table 4, for cohort A the AUC and Cmax of the metabolite N-desmethyl topotecan, for both total and lactone form, increased significantly when GF120918 was coadministered with oral topotecan. The excretion of total topotecan in the urine as a percentage of the administered dose in cohort A was 14.9% ± 3.7% without and 35.1% ± 12.8% with GF120918. The excretion in the urine of N-desmethyl topotecan as a percentage of the administered topotecan dose was not significantly different at the two occasions and was low (less than 5%). The topotecan lactone/total AUC ratio was 26.8% ± 8.0% without GF120918 and 29.4% ± 8.0% with GF120918 in cohort A (not significant). There was also no statistically significant difference in the topotecan pharmacokinetic values between the patients who started with oral topotecan with GF120918 on day 1 versus those who started with this combination on day 8. For cohort B (Table 3), the mean AUC of total topotecan was 82.2 ± 32.5 µg·h/L without GF120918 and increased significantly to 96.3 ± 31.6 µg·h/L with GF120918 (P = .02). Consequently, the systemic clearance of total topotecan decreased on average 10% from 24.8 ± 8.0 L/h to 22.3 ± 5.8 L/h (P = .02). In contrast, the AUC of topotecan lactone did not increase significantly (21.8 ± 3.1 µg·h/L without GF120918 and 24.1 ± 7.2 µg·h/L with GF120918) (P = .84). Also, no statistically significant effect was found on t1/2 and Cmax of total topotecan and topotecan lactone. The Cmax of total topotecan was 26.6 ± 6.2 µg/L without GF120918 and 24.2 ± 3.0 µg/L with GF120918 (P = .15). No significant effect was seen on AUC and Cmax of N-desmethyl topotecan (total and lactone form) at the two occasions. As mentioned above, the apparent bioavailability of oral topotecan increased to 97.1% when GF120918 was coadministered, but when we accounted for the reduced effect of GF120918 on systemic clearance, we also calculated the bioavailability of oral topotecan in the presence of GF120918. This was defined as the ratio of the mean AUC of topotecan with GF120918 after oral and after intravenous administration and was 81.7%. The excretion of total topotecan in the urine as a percentage of the total administered dose in cohort B was 30.1% ± 22.4% without and 38.8% ± 22.9% with GF120918 (not significant). The excretion in the urine of N-desmethyl topotecan was low at both occasions (less than 2%). The topotecan lactone/total AUC ratio was 29.2% ± 8.4% without GF120918 and 27.5% ± 3.9% with GF120918 in cohort B (not significant). Also, in this cohort randomization had no influence on pharmacokinetic values. No important conclusions could be drawn from the results of the fecal excretion. The excretion of topotecan and N-desmethyl topotecan in all fecal samples in both cohorts and at both occasions (with and without GF120918) was too low for quantification. The pharmacokinetic values of GF120918 are listed in Table 5. The mean Cmax levels were 157 ± 93 ng/mL in cohort A and 242 ± 122 ng/mL in cohort B, and these concentrations were reached between 3.6 and 4.6 hours, respectively. The AUC of total topotecan in cohort A was not significantly correlated with the AUC of GF120918 (R2 = .164, P = .32).
Our results reveal that coadministration of oral GF120918 in combination with topotecan results in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% to 97.1%. Preclinical studies have shown that the adenosine triphosphate–binding cassette transporter BCRP mediates apically directed transport of its drug substrates and is important in preventing intestinal reuptake and hepatobiliary excretion of transported drugs. BCRP is present in the small intestine and colon.21,22 Our studies in mdr1a/1b/(-/-) P-gp knockout mice and wild-type mice have also shown that inhibiting BCRP by GF120918 resulted in a significant increase in the oral bioavailability of topotecan.29 We know from the literature that GF120918 is an inhibitor of P-gp and of BCRP.28,29 Although topotecan is also a substrate for P-gp, the affinity for this transporter is low,30 and therefore, it is most likely that the increase in oral bioavailability in our study is mediated by inhibition of intestinal BCRP. The plasma concentration-time curves of a patient in cohort A show that the most plausible explanation for the difference between the two curves is enhanced absorption of topotecan caused by coadministration of GF120918. As a consequence, the peak plasma concentration and AUC of total topotecan were increased. The elimination phase in the two curves is comparable, and no significantly different values in the t1/2 were found (Table 2). Topotecan is to a large extent excreted through the kidneys. In this study, the percentage of urinary excretion of the total dose of topotecan was 14.9% ± 3.7% after oral administration and 30.1% ± 22.4% after intravenous administration. This is in agreement with previously published data.16 Coadministration of GF120918 resulted in an increased systemic exposure of orally administered topotecan. As expected, this resulted in a significantly higher percentage of urinary excretion of topotecan after oral administration (35.1% ± 12.8%). Significant absorption enhancement by temporary inhibition of drug transport mechanisms, as shown in this study, has also been achieved in mice and patients for the taxanes paclitaxel and docetaxel. These drugs have low oral bioavailability, at least partly because of their high affinity for the drug efflux pump P-gp, which is highly expressed in the gastrointestinal tract.36 In combination with a single dose of 15 mg/kg of the effective P-gp inhibitor cyclosporine, the oral bioavailability of paclitaxel and docetaxel increased significantly.37-39 As previously reported, the interpatient variability in the AUC of oral topotecan is moderate (26% to 41%).12,14 Several phase I studies revealed that the AUC is correlated with myelosuppression, which is the dose-limiting toxicity of intravenous topotecan.40,41 In this study, the interpatient variability in the bioavailability and in the AUC of topotecan in a small cohort of eight patients were 17% and 30%, respectively. Upon coadministration of GF120918, the variability was 11% and 26%, respectively, indicating that an increased bioavailability and AUC resulted in a slight decrease of the interpatient variations, and this might be of clinical benefit. However, this needs to be validated in clinical studies with larger patient cohorts. The results of the patients treated with intravenous topotecan with or without GF120918 (cohort B) show that GF120918 had a small but significant effect of approximately 10% on AUC and systemic clearance of total topotecan, but no effect on t1/2 and Cmax of total topotecan. There was also no significant effect on the pharmacokinetic parameters of topotecan lactone. When we accounted for the reduced effect of GF120918 on systemic clearance of topotecan, the bioavailability of oral topotecan increased to 81.7%. Although the effect on systemic clearance was statistically significant, we have to interpret these results with caution because this significant effect, in a population cohort of eight patients, was small. Therefore, we calculated an apparent oral bioavailability of 97.1%. The apparent oral bioavailability was calculated with an AUC value obtained after intravenous administration of topotecan estimated from one time point.33 The accuracy of this model is remarkably good. Only large deviations from the planned sampling time (more than 7.5 minutes) affect the precision of the prediction.33 In the current study, maximal deviations from the planned sampling time were only 4 minutes, and almost all samples were taken within a time window of 1 minute of the planned sampling time. Jonker et al29 have also shown a significant increase on AUC and a decreased plasma clearance in mdr1a/1b(-/-) knockout and wild-type mice when topotecan was given intravenously in combination with oral GF120918. This effect was more pronounced in mice than in humans. Possibly, the activity of BCRP in the kidneys is lower in humans than in mice, and therefore, temporary inhibition of this protein has less influence on the systemic clearance of topotecan in humans. Another explanation is that the plasma concentrations of unbound GF120918 that were reached in the kidneys of humans were lower than those reached in mice, but in studies of mice, we did not determine the plasma concentrations of GF120918. A previous pharmacologic study has demonstrated substantial interpatient variability in the plasma levels of GF120918 because the absorption is food-dependent.42 Apparently, this is not a major obstacle for inhibition of intestinal BCRP. The local concentration of GF120918 in the intestinal lumen is probably high enough because we demonstrated in cohort A increased bioavailability of oral topotecan. The effect of GF120918 on hepatobiliary excretion and possibly renal excretion might also affect the systemic exposure and plasma clearance of topotecan. Therefore, the increase in systemic exposure of oral topotecan might be a result of multiple mechanisms caused by GF120918, including enhanced absorption and decreased clearance. Oral administration of drugs is highly preferred for its convenience, for potential use on an outpatient basis, and for development of chronic treatment schedules. However, the therapeutic use of orally administered drugs is frequently limited by the poor and highly variable bioavailability. On the basis of the results of this study, oral administration of BCRP substrates (eg, topotecan) may be more effective when combined with an inhibitor of BCRP. Also, we have to realize that concomitant drugs that are also substrates for the same transporters can also lead to enhanced bioavailability and probably result in unanticipated toxicity. Unfortunately, studies with daily or twice-daily schedules of oral topotecan were hampered by dose-limiting diarrhea.11,43 Conversely, diarrhea has never been reported as a major side effect with intravenously administered topotecan. The exact underlying mechanism of the diarrhea is unknown. Possibly, the cause of diarrhea with chronic oral administration is a local effect of topotecan on the intestinal mucosa. The combination of topotecan with GF120918 may result in an increased intestinal absorption of topotecan, and presumably this will affect the toxicity profile of chronic oral schedules. Diarrhea may thereby become less frequently observed and less severe, but this needs clinical validation. In future studies, we will determine the minimal dose of GF120918 resulting in maximal increase in oral bioavailability of topotecan. The combination will also be used in studies with chronic schedules to assess the maximum-tolerated dose and the toxicity profile. Our proof-of-principle study may have important clinical implications for the oral application of topotecan and other topoisomerase I inhibitors and drugs with low oral bioavailability because of affinity for BCRP. In conclusion, coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the apparent bioavailability of oral topotecan.
We thank Harm van Tinteren for statistical assistance and Sindy Jansen for performing the bioanalytical assays.
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ABSTRACT
INTRODUCTION
