Dosing


Chemotherapy dose adaptations


Dosing of chemotherapy drugs is complicated owing to their extreme toxic nature and variable pharmacokinetic and pharmacodynamic characteristics. Also, data on dose modifications in specific patient groups are often sparse


Sabine Kaestner PhD MRPharmS Plymouth Primary Care Trust, Plymouth, UK


In the treatment of cancer it is almost impossible to achieve tumour remission without adverse effects, some of which may be very serious and life-threatening. However in those cancers where there is the potential for a curative effect, for example some malignant lymphomas and breast cancers, toxic effects that would be considered unacceptable in the treatment of non-malignant disease can be clinically justified. In other cancers, or in the adjuvant and palliative settings, benefits need to be carefully weighed up against risks.


The dosing of traditional


chemotherapy drugs is complicated by therapeutic indices which are generally lower than for any other drugs in use, and also by large intra- and inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). Dose individualisation based on body surface area (BSA) has been practised for many years based on studies which indicated that ‘effective’ and maximum tolerated doses were similar for animals and humans when normalised to BSA.1,2 Current research indicates that BSA- based doses fail to reduce the variability in PK and PD for the majority of drugs in adults, and it is widely known that the BSA method fails to account for several factors known to be relevant for drug disposition.3


These include, for example,


hepatic and renal function, body composition, nutritional status, specific enzyme expression/activity, drug


duration, the use of different drug formulations (for example, liposomal formulations of doxorubicin) or analogue drugs (for example, cisplatin versus carboplatin), and the use of supportive care (for example, mesna with cyclophosphamide). For example, the common three-week cycle length was mainly based on the time an average patient needs to recover from the myelosuppressive effect from the previous course of chemotherapy to be able to manage the next course.


Dose modifications according to organ impairment Renal and hepatic dysfunction Renal and hepatic dysfunction in cancer patients can have multiple causes. Examples that apply to both include metastases, co-administered medication, organ damage caused by drugs and/or


may include cirrhosis in patients who misuse alcohol, or viral hepatitis. However, there are no standardised approaches for defining organ dysfunction in patients with cancer and there is no evidence on whether patients with tumour-related organ dysfunction should be treated differently than those with pre-existing organ dysfunction. In addition, the information on chemotherapy drug PK and PD in patients with hepatic or renal dysfunction is usually limited. Chemotherapy doses are therefore most commonly reduced by fractions, for instance 25% or 50%, based on the degree of organ impairment and extent of hepatic or renal clearance, and as recommended by local guidelines or the drug Summary of Product Characteristics. There is little evidence for individualised dose adjustments,


www.hospitalpharmacyeurope.com


Graham Sewell PhD MRPharmS School of Health Professions, University of Plymouth, Plymouth UK


resistance, drug-binding proteins, gender, age and prior or concomitant medication and disease. However, alternative dosing strategies are generally lacking and approaches to manage chemotherapy toxicity and/or therapeutic effects include alterations of dosage, dosage intervals and/or administration


radiotherapy, or pre-existing intrinsic disease. Electrolyte disorders associated with malignancy or tumour lysis syndrome may also affect the kidneys, while renal hypoperfusion may be caused by dehydration or bleeding, and obstruction to outflow by blood clots, stones or tumour invasion of the kidney, ureters or bladder. Hepatic conditions


“The dosing of traditional chemotherapy drugs is complicated by therapeutic indices which are generally lower than for any other drugs in use”


17


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32