|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology
Boosting Bioavailability of Topotecan: What Do We Gain?Fox Chase Cancer Center, Philadelphia, PA THERE IS MUCH to be said for the oral administration of chemotherapy. Provided efficacy is at least equivalent and toxicity no worse, patients prefer the ease of oral dosing to the discomfort and inconveniences of intravenous chemotherapy.1 For multiple consecutive days of dosing such as the daily-times-five schedule commonly used for topotecan, the inconvenience of intravenous administration is magnified. And for agents that produce optimal antitumor effects on more prolonged or continuous schedules, the oral route is even more desirable, averting the cost of invasive infusion catheters and the accompanying risks of thrombotic and infectious complications. On the other hand, the oral route has some potential disadvantages. To attain therapeutic levels after oral ingestion, a drug must remain stable in the harsh environment of the stomach, be adequately absorbed through a biochemical barrier of efflux pumps and cytochrome P-450 isozymes present in the epithelial lining of the gut, and undergo the first-pass effect that occurs as portal blood carries the agent to the liver for metabolism and biliary excretion. This latter mechanism also involves drug efflux pumps. Ideally, a sufficient fraction of the intact drug or an active metabolite survives these processes to enter the systemic circulation for delivery to the tumor before further metabolism and excretion occur. Bioavailability is the term we use to compare the systemic exposures (area under the plasma concentration-time curve [AUC]) that result after oral administration with the more direct, but less patient-friendly, intravenous administration of a drug. Another potential problem with oral administration of chemotherapy is greater variability in plasma levels and AUCs because of interindividual differences in drug absorption and metabolism. For most drugs, variability in AUC after oral administration is usually no better, and often greater, compared with intravenous infusion. Inasmuch as the therapeutic index for most cytotoxic agents is usually narrow, greater variation in plasma levels could lead to greater risk of both over- and underdosing. This is particularly true for a drug like topotecan, for which there is pharmacodynamic correlation of AUC with toxicity.2 In this issue of the Journal of Clinical Oncology, Kruijtzer et al3 propose a novel approach to increase the bioavailability of topotecan. In experimental work leading up to this clinical trial, the authors convincingly demonstrated that topotecan bioavailability was greatly increased by coadministration of GF120918, an inhibitor of both the P-glycoprotein (P-gp) and breast cancer resistance protein (BRCP) efflux pumps.4 These proteins are members of the adenosine triphosphate–binding cassette family of transmembrane transporters, and both mediate multidrug resistance. Both P-gp and BRCP are concentrated along the apical membrane of intestinal epithelial cells and in cells lining the biliary tree and the renal tubules, where they function to excrete xenobiotics. Because topotecan has much greater affinity for BRCP than P-gp, inhibition of the former protein is likely to be the major mechanism by which GF120918 leads to increased bioavailability of topotecan through greater intestinal absorption and reduced biliary excretion.4 Evidence for the latter mechanism in humans is the finding by Kruijtzer et al3 that GF120918 reduces plasma clearance of total topotecan after intravenous administration. Thus GF120918 increases the apparent bioavailability of oral topotecan by combined effects on intestinal absorption and, to a lesser extent, systemic clearance. Having clearly established that GF120918 increases the bioavailability of oral topotecan, Kruijtzer et al3 propose that this strategy will be advantageous for chronic dosing studies. For several reasons it is unclear why this will be so. The mean bioavailability of topotecan without GF120918 was 40% in the eight patients who formed the oral dosing group in the authors’ current study, a finding consistent with previous studies. Although incomplete, 40% bioavailability alone is not a limitation for oral administration of topotecan or any drug. Of potentially greater importance is the inter- and intrapatient variability of AUC that results from oral administration. For the reasons mentioned above, this could lead to greater under- or overdosing of the drug compared with intravenous administration. However, there was only modest variability of oral topotecan bioavailability both without (17%) and with (11%) GF120918. Clearly, boosting bioavailability with GF120918 did not have a major effect on interpatient variability. A major premise motivating this study is that prolonged exposure to topotecan lactone is required for optimal antitumor activity. Stabilization of topoisomerase I-DNA cleavable complexes by topotecan and other camptothecin analogs, and formation of DNA double-strand breaks—believed to be essential for cytotoxicity caused by these agents—are greatest during the S phase of the cell cycle. In experimental systems, rapid recovery of DNA synthesis results after short-term exposure to topotecan and other camptothecin analogs, whereas cytotoxicity and optimal antitumor activity requires prolonged exposures.5 Thus, if prolonged exposure to a minimum concentration of the drug were required for optimal antitumor activity, daily oral administration would be preferable to continuous intravenous infusion. However, the clinical experience to date has not confirmed greater benefit of longer-term topotecan exposure. Although the authors cite phase I clinical trials demonstrating the feasibility of 10- and 21-day dosing, these studies and several small phase II trials do not indicate superior activity, and none were designed to determine an optimal schedule for topotecan. In fact, assumptions about the importance of prolonged exposure are being reconsidered, judging from recent interest in single-dose weekly schedules of topotecan alone and in combination with other agents.6-9 These intermittent schedules are more conducive to combining topotecan with other agents such as gemcitabine7 and taxanes.9 Regarding these combination studies, Kruijtzer et al3 caution that GF120918 could alter the pharmacokinetics of other P-gp or BRCP substrates administered together with topotecan, thereby potentially increasing toxicity. What can we gain from increasing oral bioavailability of topotecan, and what is the added value of GF120918? Using a second agent to increase systemic exposure to a drug that already has adequate bioavailability with only moderate interpatient variability is not a large step forward, particularly if the pharmacokinetics of additional drugs that the patient is taking may be affected. It is likely that GF120918 will have greater value when administered with orally administered P-gp and BRCP substrates that have much lower and more variable absorption, such as oral paclitaxel.10 In addition, perhaps GF120918 administered with oral or intravenous topotecan might prove advantageous by helping to overcome resistance mediated by BRCP, P-gp, and other drug efflux proteins expressed by tumors that reduce intracellular drug concentrations. REFERENCES
1.
Liu G, Franssen E, Fitch MI, et al: Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15: 110-115, 1997
2.
Gerrits CJH, Schellens JHM, Burris H, et al: A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin). Clin Cancer Res 5: 69-75, 1999
3.
Kruijtzer CMF, Beijnen JH, Rosing H, et al: Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20: 2943-2950, 2002
4.
Jonker JW, Smit JW, Brinkhuis RF, et al: Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst 92: 1651-1656, 2000 5. Gerrits CJ, de Jonge MJ, Schellens JH, et al: Topoisomerase I inhibitors: The relevance of prolonged exposure for present clinical development. Br J Cancer 76: 952-962, 1997[Medline] 6. Homesley HD, Hall DJ, Martin DA, et al: A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol 83: 394-399, 2001[CrossRef][Medline] 7. Sun W, Stevenson JP, Gallagher M, et al: A phase I trial of topotecan and gemcitabine administered weekly for 3 consecutive weeks to patients with advanced tumors. Cancer 92: 414-419, 2001[CrossRef][Medline] 8. Axelrod R, Rose L, Biermann W, et al: Phase I study of topotecan with weekly 5-fluorouracil/leucovorin in patients with advanced malignancies: An update. Proc Am Soc Clin Oncol 20: 82b, 2001 (abstr 2078) 9. Homesley H, Benigno B, Williams J, et al: Weekly topotecan combined with weekly paclitaxel in second- or third-line therapy of epithelial ovarian carcinoma. Proc Am Soc Clin Oncol 20: 191b, 2001 (abstr 2516) 10. Malingre MM, Beijnen JH, Rosing H, et al: Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br J Cancer 84: 42-47, 2001[CrossRef][Medline]
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
