Cytotoxic drug treatment

Mechanism of action and pharmacokinetics

Cyclophosphamide is an oxazaphosphorine that contributes alkyl groups to DNA, forming covalent linkages. It depletes T and B cells and suppresses antibody production. It is metabolized to 4-hydroxycyclophosphamide and its tautomer aldophosphamide by liver cytochrome P450 enzyme. In target cells, aldophosphamide is converted to the alkylating phosphoramide mustard and acrolein. Tautomers are detoxified to inactive carboxycyclophosphamide. According to the level of detoxification, individuals experience different drug efficacy and toxicity.

Drugs that induce hepatic microsomal enzymes (barbiturates, alcohol, phenytoin, and rifampicin) increase cyclophosphamide’s efficacy and toxicity; conversely, inhibitors of hepatic microsomal enzymes (antimalarials, allopurinol, and tricyclic antidepressants) decrease its efficacy and toxicity.

The protocols for CYC administration are presented in Table 64.2 . Oral and intravenous administration of cyclophosphamide (IV-CYC) result in similar plasma concentrations. Its half-life in serum is 6 hours. Metabolites are excreted by the kidneys therefore dosage should be adjusted to creatinine clearance.

Use in renal disease

In proliferative (class III or IV) lupus nephritis (LN), induction therapy with pulse IV-CYC is effective in delaying renal scarring, preserving renal function and reducing risk for end-stage renal disease (ESRD). Combination of pulse IV-CYC with monthly pulses of IV methylprednisolone (IV-MP) improves renal outcomes without increasing toxicity. In patients with compromised eGFR, IV-CYC and mycophenolate mofetil had similar efficacy in the short-term. In European patients, induction therapy with low-dose IV-CYC (6 fortnightly pulses 500 mg each in combination with 3 daily doses IV-MP 750 mg) followed by maintenance therapy with azathioprine had comparable efficacy and less toxicity than 8 pulses of IV-CYC also followed by maintenance therapy with azathioprine. At 10 years follow-up, rates of death, sustained doubling of serum creatinine and ESRD did not differ between the two regimens. Low-dose IV-CYC was also comparable in safety to oral mycophenolate mofetil in less severe cases of LN, as evidenced by relative risks for major infection, diarrhea, alopecia, and ovarian failure. In Asian-Indians and North Americans, low-dose IV-CYC had similar short-term results in complete response rate when compared to mycophenolate mofetil, suggesting that the low-dose regimen could be an alternative option as an induction therapy for both Caucasians and non-Caucasians with moderately severe LN.

In membranous (class V) LN , induction therapy with IV-CYC every alternate month (0.5–1 g/m2) for 11 months combined with alternate day oral prednisone appears to be as effective as cyclosporine A in inducing remission of nephrotic syndrome and is associated with significantly lower relapse rates. No difference in response rates were observed between low-dose IV-CYC and oral mycophenolate mofetil.

Use in extra-renal disease

Cyclophosphamide administered as monthly pulses IV-CYC in combination with IV-MP pulses followed by oral glucocorticoids is effective in the management of severe or refractory extra-renal lupus manifestations, such as severe thrombocytopenia (platelets <20,000/mm3), autoimmune hemolytic anemia, neurologic disease, acute pneumonitis, alveolar hemorrhage, abdominal vasculitis, and extensive skin disease. There is no published data to support the use of low-dose regimen in treating the aforementioned conditions.

Adverse effects

Common adverse effects are nausea, vomiting, hair thinning, and reversible alopecia. Serious but less frequent adverse effects are bone marrow, gonadal and bladder toxicity, and malignancy. Mucosal ulceration, skin pigmentation, liver, lung, and cardiac toxicity have also been reported. Cyclophosphamide is teratogenic and is generally contraindicated in pregnancy.

Myelotoxicity is dose- and age- dependent. Severe thrombocytopenia is rare. With IV administration, nadir of lymphocytes occurs on days 7–10, and that of granulocytes on days 10–14. Recovery from granulocytopenia occurs after 21–28 days. An increased risk of infection, including bacterial and opportunistic infections (pneumocystitis jiroveci, fungal infections, and nocardia) and reactivation of latent herpes zoster, mycobacterium tuberculosis, and human papilloma virus, have been reported. Risk of infection is increased with concomitant use of high-doses of glucocorticoids (especially more than 0.5 mg/kg/day) and/or when leukocytes fall below 3000/mm3.

Sustained amenorrhea rates were 0% in patients <25 years who received short course of IV-CYC (≤7 pulses), 12% in those aged 26–30 years, and 25% in those >30 years. Longer treatment course (≥15 pulses) induced sustained amenorrhea in 17% of patients aged <25 years, 43% of those aged 26–30 years, and 100% of those older than 30 years. In males, gonadal toxicity may develop with as little as 7g cumulative cyclophosphamide dose. Conversely, the low-dose IV-CYC regimen is associated with minimal impact on ovarian reserve.

Bladder toxicity is time-dependent and includes sterile hemorrhagic cystitis, presenting with microscopic or gross hematuria and voiding symptoms. Bladder carcinoma can occur and risk is life-long. Risk factors are cumulative dose of cyclophosphamide above 100 g and smoking. After excluding renal causes, patients with hematuria should be evaluated with cystoscopy.

Patients exposed to cyclophosphamide have increased risk of hematologic malignancies (including myelodysplastic syndrome, acute leukemia and non-Hodgkin’s lymphoma), mainly if treated more than 2-3 years or with cumulative doses above 100 g.

Mechanism of action and pharmacokinetics

Azathioprine is transformed into 6-mercaptopurine by glutathione. 6-mercaptopurine is subsequently converted to thioinosinic acid and 6-thioguanine that are integrated into DNA and RNA, thus impairing their synthesis. Consequently, azathioprine inhibits the proliferation of lymphocytes. Thioinosinic acid and 6-thioguanine are degraded by xanthine oxidase or S-methyltrasnferase into 6-thiouric acid, which is excreted by the kidneys. Therefore, azathioprine dosage is adjusted to creatinine clearance. Co-administration with allopurinol increases the risk of toxicity and should be avoided. Azathioprine has been associated with resistance to warfarin. Dosage and monitoring are presented on Table 64.3 .

Use in renal disease

The European League Against Rheumatism (EULAR) recommends the use of azathioprine as induction therapy only in mild proliferative LN (i.e. with sub-nephrotic proteinuria and normal renal function) when other agents such as cyclophosphamide or mycophenolate cannot be used. Azathioprine is recommended for maintenance therapy in proliferative LN. In addition, it can be used as steroid-sparring agent in nonproliferative forms of LN (class V, class I-II LN) with persistent proteinuria >1 g/day despite optimal renin-angiotensin-aldosterone axis blockade.

Use in extra-renal disease

Azathioprine can be administered in moderately severe lupus manifestations, such as thrombocytopenia (platelets 20–50 × 103/mm3), serositis, neurological disease, usually in combination with moderate to high doses of glucocorticoids.