The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

Abstract

Cyclophosphamide is an alkylating agent used in the treatment of solid and haematological malignancies and as an immunosuppressive agent. As a prodrug, it is dependent on bioactivation to the active phosphoramide mustard metabolite to elicit its therapeutic effect. This focused review will highlight the evidence for the role of germline pharmacogenetic variation in both plasma pharmacokinetics and clinical outcomes. There is a substantial indication from 13 pharmacokinetic and 17 therapeutic outcome studies, in contexts as diverse as haematological malignancy, breast cancer, systemic lupus erythematosus and myeloablation, that pharmacogenetic variation in both CYP2C19 and CYP2B6 influence the bioactivation of cyclophosphamide. An additional role for pharmacogenetic variation in ALDH1A1 has also been reported. Future studies should comprehensively assess these 3 pharmacogenes and undertake appropriate statistical analysis of gene–gene interactions to confirm these findings and may allow personalised treatment regimens.

Phenotyping Study of Cyclophosphamide 4-Hydroxylation in Malay Cancer Patients

“…Determination of the type of drug metabolism rate can be seen phenotypically based on the bioactivity ratio value, 11 but no literature has published for the classification of the three types of CP 4-hydroxylation rate (PM, EM, and UM) with the limiting value of the bioactivity ratio. Previously it has been agreed in some literature that CYP2B6 wild type is categorized as extensive metabolizer (EM) type.…”

“…From several studies, CYP2B6 *6 allele variant carrier had greater 4-hydroxylation activity than noncarriers. 11 , 20–22 However, in a study on Japanese patients, correlation between the CP 4-hydroxylation rate with CYP2B6 *6 and *9 alleles was not found. 6 Differences between study results might be due to several factors including ethnicity, number of subjects, CP dose, or co-medication.…”

“… 9 , 10 CYP2B6 is highly induced and can be auto-induced by CP within 24 h after continuous infusion or after repeated administration for several days. 11 Increased CP activation will increase the 4-OHCP levels and CP clearance. 12 The pharmacogenetics of CYP2B6 is very complex because SNPs encoding common proteins can exist in various haplotype combinations.…”

“…The CP metabolism is a manifestation of genetic expression (DME genetic polymorphism factor) combined with the environment factors (diet, lifestyle, co-medication, comorbidity, age, sex, pollutants, etc) so that phenotypes are not always correlated according to the genotype. 7 , 11 However, some researchers still consider genetic factors to play a relatively large role in influencing the metabolic phenotype compared to other factors. The genotype is a detailed gene structure in an individual whereas phenotype is more commonly measured using drugs as a marker of a particular DME and measuring the ratio of metabolite levels to their parent drug.…”

Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy

“…To the best of our knowledge, the effects of patient factors, such as sex, BSA, and biochemistry covariates, on VCR CL in elderly patients have not yet been clarified. Recently, it has been reported that gene polymorphisms of drug-metabolizing enzymes or transporters affect the pharmacokinetics of these cytotoxic anticancer drugs 23,[27][28][29][30] . Thus, various factors have a potential impact on the pharmacokinetic exposure of elderly patients receiving CHOP therapy.…”