Pharmacokinetics of cyclophosphamide in Burkitt's lymphoma patients attending Uganda Cancer Institute

Abstract

Cyclophosphamide is one of the most widely used anticancer drugs. It forms part of various combinations used in treating a range of solid and hematologic tumours in both children and adults in Uganda. It is part of the regimen for treating Burkitt’s lymphoma, the most common of all cancers in Ugandan children. The drug has a narrow therapeutic index and large pharmacokinetic variability. A large proportion of administered regimens are associated with toxic outcomes. Treatment outcomes of cyclophosphamide correlate with its pharmacokinetics. Children show a greater variability in cyclophosphamide pharmacokinetics and as such are more prone to unpredictable treatment outcomes. The study investigated pharmacokinetics of the drug in Burkitt’s lymphoma patients; this would help optimise treatment in this group of patients. Methods The study targeted newly diagnosed Burkitt’s lymphoma patients (2-17 years) with normal renal and liver functions. A sparse sampling approach was adopted in which a maximum of 4 blood samples (4 mls per sample) were obtained within a 24 hr period from each patient. Plasma concentration of cyclophosphamide was determined by HPLC and the data analysed using NONMEM (NONMEM, version 7.2) with the First Order Conditional Estimation with Interaction. Results The study enrolled children; Median (Inter Quartile Range) characteristics; Age= 6(5-10) years, Weight=21(16-25) Kg, Body Surface Area= 0.8(0.7-0.96) m2, Serum Creatinine concentration = 30(26-34.7) µM, Alanine Amino Transferase = 15(11-30) U/L. The one compartmental model best fit the data. The estimates, (Mean ± S.D) of Clearence, Volume of distribution and Half Life were 1.12 ± 0.5 Litres/Hour, 18.9 ± 0.645 Litres and 11.69 Hours respectively. Patient weight was the only covariate investigated that significantly affected the pharmacokinetics of the drug. Conclusion Plasma clearence compares to literature reported values however volume of distribution is higher than what is reported; this may be associated with a longer than expected drug exposure.