Therapeutic Drug Monitoring of Antineoplastic Drugs

Methotrexate is a competitive inhibitor of dihydrofolate reductase, a key enzyme for biosynthesis of nucleic acid. The cytotoxic activity of this drug was discovered in 1955. The use of leucovorin to rescue normal host cells has permitted the higher doses of methotrexate therapy in clinical practice. Methotrexate is used in the treatment of acute lymphoblastic leukemia (ALL), osteogenic sarcoma, brain tumors, and carcinomas of the lung. Most of the toxicities of this drug are related to serum concentrations and pharmacokinetic parameters. Methotrexate is also approved for the treatment of refractory rheumatoid arthritis. Usually, low doses of methotrexate are used for treating rheumatoid arthritis (5-25 mg once weekly). One study found that splitting a weekly dose of 25-35 mg of methotrexate into spilt doses separated by 8 h improved the bioavailability of the drug (156). Although toxicity from low-dose treatment is rare, toxic manifestation with low-dose methotrexate has been reported. Izzedine et al. commented that permanent discontinuation of methotrexate therapy in 1 of 10 patients occurs because of toxicity. Moreover, nephrotoxicity, which is common with high doses of methotrexate, may also occur with low doses of therapy in patients receiving methotrexate (157). A frequent adverse reaction seen is myelosuppression, which manifests as leucopenia and thrombocytopenia. Therapeutic drug monitoring is strongly recommended during high-dose treatment of methotrexate.

Table 11

Therapeutic Drug Monitoring of Antiretroviral

Table 11

Therapeutic Drug Monitoring of Antiretroviral

Drug

Specimen Requirement

Therapeutic Rangeh Trough (ng/mL)

Cost"

Amprenavir

Serum

150-400

Atazanavir

Serum

100

Indinavir

Serum

80-120

$$$$

Lopinavir

Serum

700

Nelfinavir

Serum

700-1000

$$$$

Saquinavir

Serum

100-250

$$$$

Nevirapine

Serum

150-400

$$$$

Efavirenz

Serum

100

a$$$$; >$150. The costs are based on published charge for these tests according to the 2006 catalog price of Mayo Medical Laboratories, Rochester, MN, which offers therapeutic drug monitoring of these antiretroviral drugs.

b Therapeutic ranges are courtesy of Jennifer King, Pharm.D., assistant professor at the division of Clinical Pharmacology, University of Alabama at Birmingham. Reference ranges are recommended ranges only and may vary between institutions. The Department of Laboratory Medicine of Children's Hospital National Medical Center, Washington, DC, performs monitoring of antiretroviral drugs. Jewish Medical Center at Denver also offers therapeutic drug monitoring of antiretroviral drugs. This service may be available in other medical centers and reference laboratories in the USA, which the author may not be aware of.

a$$$$; >$150. The costs are based on published charge for these tests according to the 2006 catalog price of Mayo Medical Laboratories, Rochester, MN, which offers therapeutic drug monitoring of these antiretroviral drugs.

b Therapeutic ranges are courtesy of Jennifer King, Pharm.D., assistant professor at the division of Clinical Pharmacology, University of Alabama at Birmingham. Reference ranges are recommended ranges only and may vary between institutions. The Department of Laboratory Medicine of Children's Hospital National Medical Center, Washington, DC, performs monitoring of antiretroviral drugs. Jewish Medical Center at Denver also offers therapeutic drug monitoring of antiretroviral drugs. This service may be available in other medical centers and reference laboratories in the USA, which the author may not be aware of.

The elimination half-life of methotrexate is 7-11 h, and on administration, less than 10% is oxidized to 7-hydroxymethotrexate irrespective of the route of administration. The protein-binding ranges vary from 30-70%, and albumin is the major binding protein in the serum (158). Peak serum concentration of methotrexate correlates with the outcome in the treatment of osteosarcoma. Modification of the dosage to achieve a peak serum concentration between 700 and 1000 ^mol/L has been recommended (159). Omeprazole may delay elimination of methotrexate, and therefore, when prescribing methotrexate to a patient, an alternative to omeprazole should be used (160). One case study reported that amoxicillin decreased the renal clearance of methotrexate probably by competition at common tubular secretion system and by secondary methotrexate-induced renal impairment (161).

The platinum derivative cisplatin is used in the treatment of testicular cancer. In most studies determining pharmacokinetic parameters of cisplatin, free fractions were measured in plasma or tumor. There is a high variability between individual patients, and the therapeutic window is narrow. Dosage is often based on body surface area. Recently, Salas et al. (162) described therapeutic drug monitoring of cisplatin using total platinum measurement in plasma. Gietema et al. (163) reported that platinum was detectable in plasma in patients 20 years after being cured from metastatic testicular cancer following cisplatin therapy. Impaired bioavailability of phenytoin in a 24-year-old woman treated with cisplatin, vinblastine, and bleomycin has been reported. Data revealed mean phenytoin absorption of 32% (normal greater than 80%) establishing malabsorption of phenytoin because of cancer chemotherapy (164). Since the 1960s, 5-fluorouracil has been used either alone or as part of a combination therapy with other drugs to treat various solid tumors and is also a standard therapy for colorectal cancer. Pharmacoki-

netic studies showed that clinical response as well as toxicity of 5-fluorouracil are related to AUC. Individual dosage adjustments based on pharmacokinetic monitoring lead to higher response rate of this drug as well as survival rates associated with tolerability. A limited sampling strategy using just two plasma concentrations can be used to predict AUC of 5-fluorouracil (165). Pharmacokinetic monitoring of other anticancer drugs, such as doxorubicin, etoposide, mitoxantrone, mensa and dimensa, taxol, aminoglutethimide, tamoxifen and acrolein, and cyclophosphamide, may also be beneficial (166).

There is a narrow therapeutic window between suboptimal therapy and toxicity in the treatment with antineoplastic drugs. Genetic polymorphism in phase I and phase II enzymes is present in the population and may explain in part the variations in the pharmacokinetic parameters of a particular drug between individual patients. The potential for applying pharmacogenetic screening before cancer chemotherapy may have applications with several cytochrome P450 enzymes, in particular with CYP2B6 (cyclophosphamide treatment), CYP2C8 (paclitaxel therapy), and CYP3A5 (167).

8. conclusions

There are many effective drugs in the clinical practice today, which are also highly toxic because of a narrow therapeutic window. Successful therapy with such drugs require individualization of dosages based on serum drug concentrations, and therapeutic monitoring of such drugs are routinely offered in most hospital-based clinical laboratories. Moreover, reference laboratories, as well as academic-based hospital laboratories, usually offer a wider menu of drugs that can be monitored compared with community hospital-based laboratories. Therapeutic drug monitoring is also useful to identify non-compliant patients. Moreover, therapeutic drug monitoring is cost effective in health care (168). However, despite cost effectiveness and demonstrated clinical utility, therapeutic drug-monitoring service is underutilized in patient care. A recent report by Raebel et al. based on 17,748 ambulatory patients at 10 health maintenance organizations indicated that 50 percent or more patients receiving digoxin, theophylline, procainamide, quinidine, or primidone were not monitored and 25-50% of patients receiving divalproex, carbamazepine, phenobarbital, phenytoin, or tacrolimus were not monitored. The authors concluded that a substantial proportion of ambulatory patients receiving drugs with narrow therapeutic ranges did not have serum drug concentrations monitored during 1 year of use (169). Therefore, more patient education is needed to utilize therapeutic drug monitoring in patient management for maximum therapeutic benefit of a drug with a narrow therapeutic window.

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