To understand the therapeutic index of the drug, one needs to know the pharmacokinetics and pharmacodynamics of the drug. Regarding the pharmacokinetics, the volume of distribution(Vd) of the drug is almost equal to the total body water when administered in the IV form. Vd varies with weight as well with age(elderly and pediatric).[15] Vd increases with age and in obese individuals.[2] The half-life of the drug after a single administration is four to seven hours. The total clearance of the drug is 3.6L/h. Usually, fractionation of the drug results in faster rates of elimination.

The most common dose administered is 1.2 gm/m^2/day, given very slowly over 30 minutes for five consecutive days.[2] Complete blood count with differential, renal function, liver function, urine output, and urinalysis are necessary before each dose. Dosing repeats every three weeks or after hematological recovery. Drug levels can be measured in the urine by gas chromatography-mass spectrometry.[21] The therapeutic drug monitoring takes place after assessing the pharmacokinetics of the first course of the drug followed by subsequent alterations in the dose as there is wide variability in the pharmacokinetics of ifosfamide.

Dosing needs to be adjusted in renal impairment as the drug undergoes renal elimination.[22] Dose reduction is to 80% of the dose if creatinine clearance (CrCl) is 46 to 60 mL/minute. However, if CrCl is 31 to 45 mL/minute, administer 75% of the dose and with CrCl under 30 mL/minute, reduce to 70% of the regular dose. There is no requirement for dose adjustment with hepatic impairment, but caution is advisable. The drug requires adjustment according to weight.[23]

The dose also needs to be adjusted according to the toxicity profile. Instances of severe leukopenia or thrombocytopenia require dosage reduction. In case more severe toxicity such as encephalopathy probably requires termination of therapy.

Most of the toxicities of ifosfamide are from its active metabolites. Acrolein plays a significant role in causing major renal and bladder related toxicities. As the kidneys filter these metabolites, they generate reactive oxygen species and nitrogen compounds, which results in damage to the renal as well as urothelial cells. The etiology behind neurotoxicity is similar to that of renal toxicity but is not fully understood. As with other anti-neoplastic drugs, ifosfamide is toxic to the bone marrow. Specific case reports have shown an association between ifosfamide and Fanconi syndrome. It results in cardiac toxicity and can cause pneumonitis. These toxicities include:  

1. Hemorrhagic cystitis

The main adverse effects for years has been hemorrhagic cystitis. The theory behind it was that hepatic metabolism produced a product named acrolein, which was excreted by the kidneys and accumulated in the bladder.[19] Through its apoptotic properties and production of multiple ROS as well as nitric oxide, it results in the release of numerous cytokines that cause ulceration of the bladder epithelium. As a result, it causes hemorrhagic cystitis. Mesna is a drug developed in 1983 to help with this adverse effect of ifosfamide. As described earlier, mesna combines with the urotoxic metabolites at the level of urothelium and results in a non-toxic product for excretion in the urine. It is always important to prevent the development of cystitis rather than treating it. The current treatment options available are continuous bladder irrigation, intravesicular infusion of ammonium potassium sulfate and formalin, and in some instances, cystectomy.[19] Mesna should be administered before, during, and after ifosfamide along with aggressive hydration (at least 2 liters oral of the IV form) per day to prevent urotoxicity.

2. Neurotoxicity

Central nervous system toxicity appears as encephalopathy with varying severity (confusion, hallucinations, drowsiness, coma). It presents in about 30% of the cases.[24] The mechanism is unknown, and the symptoms occur with the administration of high doses of the drug either orally or intravenously but more with oral administration.[24] Usually, the symptoms present within 2 to 96 hours after drug administration and are reversible within 48 to 72 hours following discontinuation of the drug.[15] The mechanism of neurotoxicity is still unknown. Risk factors associated with the development of neurotoxicity include oral administration, previous chemotherapy with cisplatin, impaired renal and hepatic function, low albumin, and brain metastasis. Recent studies showed the utilization of methylene blue for both treatment and prophylaxis of ifosfamide-induced encephalopathy.[25] Methylene blue helps in the reversal of symptoms within 24 hours of its administration. As prophylaxis, the severity of symptoms has reduced when compared to previous cycles and can restore the therapy with ifosfamide. The dosage of methylene blue is 50 mg orally in 5% glucose solution every four hours till recovery.[15] 

3. Hematological toxicity 

Dose-limiting toxicity is myelosuppression. The blood counts reach a nadir in about 8 to 13 days of the treatment cycle. Recovery generally occurs around day 17 of the treatment cycle; this allows starting the next cycle in around three weeks after the first treatment. This effect is dose-related. The incidence of myelosuppression is low when fractionated doses are used rather than higher doses.[26] At a dose of 1.2 gm/m^2/day for five days, the white cell count is below 3 x 109/L, and platelet count below 20000 occurs in 30% of cases.[26]

4. Nephrotoxicity

Most commonly noted in children and is seen when co-administered with cisplatin. It can lead to Fanconi syndrome, in which there is impairment of proximal tubule function resulting in irreversible damage—clinically manifested as metabolic acidosis, polyuria, and renal phosphate wasting. Seen in about 5% of cases.[27] Supplementation with vitamin D and phosphate is essential in the pediatric population affected. Etiology remains unclear.

4. Miscellaneous toxicities: There are reports of arrhythmias, heart failure, and pulmonary toxicity in the form of pneumonitis.[28]

5. Malignancy of ureter and bladder: There have been case reports which demonstrated a case of multifocal urothelial carcinoma in a patient treated with ifosfamide many years ago.[13]            

For chemotherapy drug administration and monitoring, the role of nursing and pharmacy is very crucial. All healthcare providers need to collaborate as an interprofessional team to ensure optimal care and minimal adverse effects with any drug therapy, but even more so with a chemotherapeutic agent like ifosfamide. Nursing is helpful in closely watching the patient during and after drug administration, identifying the adverse reactions, and reporting them immediately. Oncology nurses have specialized training in the administration of chemotherapy. The role of pharmacists is crucial as they help formulate the dosing as well as monitor them for potential toxicity. Both nursing and pharmacists can provide patient counseling about the drug and what to expect following administration and as the cycles progress. For better outcomes, the plan requires detailed discussion among all the members involved in patient care like nurses, pharmacists, physicians as well as family to lower the mortality and morbidity. [Level 5]