[MOL] Possible Interaction Between Taxanes and Camptothecin Analogues [01106]

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American Society of Clinical Oncology 35th Annual Meeting
Day 2 - May 16, 1999

Possible Metabolic Interaction Between Taxanes and Camptothecin Analogues

William C. Zamboni, PharmD

Taxane (paclitaxel and docetaxel) and camptothecin (topotecan and irinotecan) analogues have a wide range of antitumor activity and are now being used in combination in early Phase I and II cancer trials. However, as a series of reports presented on Sunday suggested, the combination of taxane and camptothecin analogues may result in clinically significant metabolic interactions via metabolism by cytochrome P450 (CYP) isoenzymes.

Shared Metabolic Pathways

Paclitaxel and docetaxel primarily undergo hepatic oxidative metabolism via cytochromes CYP2C8/3A4 and 3A4, respectively. In addition, patients with elevated bilirubin and/or transaminases have reduced paclitaxel and docetaxel clearance and increased toxicity, suggesting that inhibition of hepatic metabolism may lead to increased drug exposure and toxicity.^[1]

Topotecan primarily undergoes renal elimination, but it may undergo clinically significant oxidative metabolism via CYP450. Several studies have reported that topotecan forms an N-desmethyl metabolite, which is consistent with CYP450 metabolism. Phenytoin, a known inducer of CYP450-mediated metabolism, alters the disposition of topotecan and N-desmethyl topotecan.

Irinotecan and its active metabolite, SN-38, are cleared by hepatic metabolism and biliary excretion. Irinotecan is metabolized by carboxylesterase to SN-38. Irinotecan also undergoes hepatic oxidative metabolism via CYP3A4 in the liver to form APC and metabolites. SN-38 undergoes further metabolism via glucuronidation to form the SN-38 glucuronidate. However, it is currently unknown whether SN-38 is metabolized by CYP isoenzymes to additional products.

A Marker of Docetaxel Metabolism

Oguri and colleagues^[2] evaluated induction of CYP3A4 and 2C8 genes in polymorphonuclear leukocytes (PMNs) by docetaxel in previously untreated lung cancer patients. The levels of CYP3A4 and 2C8 genes were measured by RT-PCR. The level of CYP3A4 increased approximately 2-fold (P= .0119) at 6 hours after docetaxel administration; however, there was no change in 2C8 levels. These results suggest that CYP3A4 plays a critical role in docetaxel metabolism and that its expression in PMN may be used as a marker of docetaxel metabolism in clinical studies.

Sequence of Administration Affects Clearance

Zamboni and colleagues^[3] evaluated pharmacokinetic and pharmacodynamic interactions between topotecan and docetaxel when administered in combination as part of a Phase I trial. For cycle 1, docetaxel was administered on day 1 and topotecan was administered on days 1 to 4. For cycle 2, topotecan was administered on days 1 to 4 and docetaxel was administered on day 4.

Pharmacokinetic studies of docetaxel and topotecan were performed on day 1 of cycle 1 and day 4 of cycle 2. Docetaxel clearance was decreased in 7 of 8 patients on cycle 1 compared with cycle 2, with an average decrease in docetaxel clearance of 50%. The average (SD) docetaxel clearance on cycle 1 and cycle 2 were 74.3 (76.3) and 28.7 (16.5) L/h/m², respectively (P < .05). Moreover, there was increased neutropenia on cycle 2 compared with cycle 1. There was no change in topotecan clearance from cycle 1 to cycle 2. To avoid the pharmacokinetic and pharmacodynamic interaction documented by this study, docetaxel should be administered on day 1 and topotecan on days 1 to 4.

Possible Effect of Paclitaxel Vehicle

Yamamoto and colleagues^[4] evaluated the pharmacokinetic interaction between paclitaxel and irinotecan as part of a Phase I trial. Irinotecan was administered as a 1-hour infusion on days 1, 8, and 15, and paclitaxel was administered as a 3-hour infusion on day 1. Paclitaxel was administered 24 hours after irinotecan, and the cycles were repeated every 4 weeks. The maximum tolerated dose was reached at the initial dose level of irinotecan 50 mg/m²/week and paclitaxel at a dose of 135 mg/m². All 3 patients developed grade 4 neutropenia.

In addition, a significant pharmacokinetic interaction was observed, with an increase in irinotecan and SN-38 concentrations after paclitaxel administration in all patients. This drug interaction was evaluated in a rat model in which animals were administered paclitaxel + irinotecan, paclitaxel vehicle + irinotecan, and irinotecan + saline. There was an approximately 2-fold increase in irinotecan and SN-38 drug exposure in the paclitaxel + irinotecan and paclitaxel vehicle + irinotecan groups compared with the irinotecan + saline group. These results suggest that the paclitaxel vehicle may be responsible for this pharmacokinetic interaction.

Nonlinear Pharmacokinetics

Rosen and colleagues^[5] reported no pharmacokinetic interaction between paclitaxel and irinotecan. However, the doses of irinotecan in this study were higher (ie, 225 and 250 mg/m²) than those used in the study by Yamamoto and colleagues.

Moreover, Rosen's study compared the disposition of irinotecan and SN-38 with that observed in a prior study of irinotecan administered alone. This retrospective analysis may be complicated by the nonlinear pharmacokinetics of irinotecan and SN-38, and the high degree of interpatient variability in the disposition of irinotecan and SN-38.

Shepard and colleagues^[6] reported on the metabolism of SN-38 by CYP3A4 to an unidentified metabolite. Thus, metabolism of SN-38 by CYP3A4 may influence efficacy and toxicity. The combination of irinotecan with docetaxel or paclitaxel may also alter the disposition of irinotecan and/or SN-38 via inhibition of CYP3A4.

Future Clinical Trials

Metabolism of paclitaxel, docetaxel, topotecan, irinotecan, and SN-38 via the same CYP metabolic systems provides inherent mechanisms of drug-drug interactions. The interactions between taxane and camptothecin analogues may become even more important when these agents are administered orally in combination in future clinical trials.

In addition, these studies stress the importance of performing well-designed pharmacokinetic studies evaluating the disposition of taxane and camptothecin analogues within the same patients. Such studies allow the patient to act as his or her own control and remove the influence of high interpatient variability in disposition of each agent. In addition, the sequence of administration of each cycle should be randomized to overcome bias based on order of administration.

References

Synold TW, Newman E, Lenz H-J, et al. Prospective evaluation of docetaxel (D) pharmacokinetics and toxicity in patients with tumor related hepatic dysfunction (HD) [Abstract 643]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Oguri T, Isobe T, Fujitaka K, et al. Expression of CYP3A4 Gene in PMN was induced by docetaxel [Abstract 640]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Zamboni WC, Egorin MJ, Van Echo DA, et al. Topotecan (TPT) inhibits docetaxel (DOC) clearance and increases myelosuppression [Abstract 631]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Yamamoto N, Negoro S, Chikazawa H, et al. Pharmacokinetic interaction of the combination of paclitaxel and irinotecan in vivo and clinical study [Abstract 718]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Rosen P, Schaaf LJ, Knuth DW, et al. Phase I and pharmacokinetic trial of CPT-11 and paclitaxel in patients with advanced cancers [Abstract 679]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Shepard DR, Ramirez J, Iyer L, Ratain MJ. Metabolism of SN-38 by CYP3A4 and microsomes from human liver [Abstract 676]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.

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