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Pharmacokinetics of Irinotecan and Its Metabolites

Austin & Repatriation Medical Centre, Heidelberg, Victoria, Australia

To the Editor:The article by Xie et al¹ in the August 1, 2002, issue of the Journal of Clinical Oncology describes the pharmacokinetics of irinotecan and its metabolites. Their analysis allows us to better comprehend the interindividual clinical pharmacokinetic variability of irinotecan and its metabolites. However, the authors fail to outline the potential importance of the presentation of the initial infusion.

Irinotecan is subject to photodegradation, including the formation of a precipitate.^2,3 Photodegradation occurs under any pH condition, but it is accelerated in neutral and alkaline solutions compared with acidic solutions. At pH 10, photodegradation is very rapid. At pH 3, it is much slower. When irinotecan is prepared using infusion solutions that have a neutral pH, exposure to lighting such as that in a medical facility will result in rapid decomposition.² Raising the pH to more than 6.5 has resulted in 10% loss in as little as 3 hours.^2,3 In isotonic sodium chloride, the rate of decay of irinotecan is similar to that of aqueous solutions with pH greater than 7. The carboxylate form of irinotecan predominates in isotonic sodium chloride when lactonolysis has reached steady state.² This is of clinical importance when irinotecan is prepared in isotonic sodium chloride. This sometimes occurs well in advance of administration. Of equal importance is when the infusion solution has not been protected from light.

In the analysis by Xie et al, the irinotecan infusions were prepared in isotonic sodium chloride. There was no mention of when the infusion solutions were prepared in relation to their administration or whether the infusion solution was protected from light. These factors are important to maintain product quality. This may not influence the final outcome of the analysis. However, it is prudent to ensure the irinotecan infusion is presented in its optimal stable form, that being dextrose 5%, freshly prepared and protected from light.

REFERENCES

1. Xie R, Mathijssen RHJ, Sparreboom A, et al: Clinical pharmacokinetics of irinotecan and its metabolites: A population analysis. J Clin Oncol 20: 3293-3301, 2002[Abstract/Free Full Text]

2. Dodds HM, Craik DJ, Rivory LP: Photodegradation of irinotecan (CPT-11) in aqueous solutions: Identification of fluorescent products and influence of solution composition. J Pharm Sci 86: 1410-1416, 1997[CrossRef][Medline]

3. Trissel LA: Handbook on Injectable Drugs, ed 11 . Bethesda, MD, American Society of Health-Systems Pharmacists, 2001

Response

Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, the Netherlands, Uppsala University, Uppsala, Sweden

In Reply:We thank Dr Siderov for his comments on our article.¹ We share his concern that the topic of photodegradation of anticancer drugs has been seriously underrated in oncology, despite the possible clinical implications. In the case of irinotecan, however, this matter has been studied extensively and the overall clinical impact seems to be very limited.

According to a recent textbook,² aqueous solutions of both 5% dextrose or 0.9% sodium chloride can be used for administration of irinotecan hydrochloride. These mixtures are physically and chemically stable for up to 24 hours at room temperature when exposed to ambient fluorescent light.² When kept refrigerated and protected from light, they remain stable for 48 hours. Nonetheless, refrigeration is not recommended because of occasional visible precipitation.² It is common practice in our hospital to prepare the chemotherapy immediately before (within 1 to 2 hours) the actual drug infusion. In addition, the point raised by Dr Siderov, that a pH value of more than 6.5 results in 10% loss of drug within 3 hours, is only problematic when the irinotecan preparation is directly combined with other drugs, such as methylprednisolone.² Without such combined drug preparation, the pH value remains much lower (since sodium chloride has no buffer capacity), and hence the issue is less relevant. Furthermore, as a result of the low pH value of this solution, the active lactone form of irinotecan predominates instead of the inactive carboxylate form.

Despite these misunderstandings, photodegradation can be a huge problem clinically for a number of structurally related chemotherapy drugs. This is exemplified by the recent observation that photodegradation of lurtotecan leads to formation of a product that is two- to 18-fold more cytotoxic than the parent molecule, topotecan, and the irinotecan metabolite, SN-38.³ In contrast to the photodegradation of lurtotecan, photolysis of irinotecan occurs only at the fragile lactone-ring structure.^4,5 In general, such degradation products are likely of subordinate (clinical) interest, because the reactivity of an intact lactone-ring structure is required for the generation of topoisomerase I–mediated DNA cleavage and antitumor activity of all known camptothecin analogs.⁶

REFERENCES

1. Xie R, Mathijssen RHJ, Sparreboom A, et al: Clinical pharmacokinetics of irinotecan and its metabolites: A population analysis. J Clin Oncol 20: 3293-3301, 2002[Abstract/Free Full Text]

2. Trissel LA: Handbook on Injectable Drugs, ed 11 . Bethesda, MD, American Society of Health-Systems Pharmacists, 2001

3. Loos WJ, Verweij J, Kehrer DFS, et al: Structural identification and biological activity of 7-methyl-10,11-ethylenedioxy-20(S)-camptothecin, a photodegradant of lurtotecan. Clin Cancer Res 8: 856-862, 2002[Abstract/Free Full Text]

4. Dodds HM, Craik DJ, Rivory LP: Photodegradation of irinotecan (CPT-11) in aqueous solutions: Identification of fluorescent products and influence of solution composition. J Pharm Sci 86: 1410-1416, 1997[CrossRef][Medline]

5. Dodds HM, Robert J, Rivory LP: The detection of photodegradation products of irinotecan (CPT-11, Campto, Camptosar), in clinical studies, using high-performance liquid chromatography/atmospheric pressure chemical ionisation/mass spectrometry. J Pharm Biomed Anal 17: 785-792, 1998[CrossRef][Medline]

6. Chourpa I, Riou JF, Millot JM, et al: Modulation in kinetics of lactone ring hydrolysis of camptothecins upon interaction with topoisomerase I cleavage sites on DNA. Biochemistry 37: 7284-7291, 1998[CrossRef][Medline]

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