Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma

Abstract

IntroductionVariation in cyclophosphamide pharmacokinetics and metabolism has been highlighted as a factor that may impact on clinical outcome in various tumour types. The current study in children with B-cell non-Hodgkin's lymphoma (NHL) was designed to corroborate previous findings in a large prospective study incorporating genotype for common polymorphisms known to influence cyclophosphamide pharmacology.MethodsA total of 644 plasma samples collected over a 5 year period, from 49 B-cell NHL patients ≤18 years receiving cyclophosphamide (250 mg/m2), were used to characterise a population pharmacokinetic model. Polymorphisms in genes including CYP2B6 and CYP2C19 were analysed.ResultsA two-compartment model provided the best fit of the population analysis. The mean cyclophosphamide clearance value following dose 1 was significantly lower than following dose 5 (1.83 ± 1.07 versus 3.68 ± 1.43 L/h/m2, respectively; mean ± standard deviation from empirical Bayes estimates; P < 0.001). The presence of at least one CYP2B6*6 variant allele was associated with a lower cyclophosphamide clearance following both dose 1 (1.54 ± 0.11 L/h/m2 versus 2.20 ± 0.31 L/h/m2, P = 0.033) and dose 5 (3.12 ± 0.17 L/h/m2 versus 4.35 ± 0.37 L/h/m2, P = 0.0028), as compared to homozygous wild-type patients. No pharmacokinetic parameters investigated were shown to have a significant influence on progression free survival.ConclusionThe results do not support previous findings of a link between cyclophosphamide pharmacokinetics or metabolism and disease recurrence in childhood B-cell NHL. While CYP2B6 genotype was shown to influence pharmacokinetics, there was no clear impact on clinical outcome.

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

“…Ifosfamide metabolism by CYP2B6.1 is enantioselective, but stereoselectivity with CYP2B6 variants is unknown. Cyclophosphamide hydroxylation by CYP2B6.6 was greater than CYP2B6.1 in vitro , but this was not apparent clinically . The influence of CYP2B6 polymorphisms and stereochemistry on human ifosfamide and cyclosphosphamide metabolism is unknown.…”

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

“…This study did not assess CYP2C19 . In contrast, in children (mean age 11.2 ± 4 years) with non‐Hodgkins lymphoma ( n = 49) an association was observed between the CYP2B6*6 allele and lower clearance of cyclophosphamide both at dose 1 and at dose 5 (after autoinduction) . No association was found in this study with CYP2C19*2 .…”

“…It is clear that the majority of the therapeutic outcome or pharmacokinetic studies have focussed on CYP2B6 and/or CYP2C19 as candidate genes. However, some studies have also reported on selected SNP in other candidate genes such as CYP2C9 , GST or ABCB1 . Whilst not the focus of this review, it is important to note that the role of pharmacogenetics in the risk of excessive toxicity (due to high levels of bioactivation of this cytotoxic drug) have also been assessed.…”

Enantioselectivity in the Metabolism of Cyclophosphamide in Patients With Multiple or Systemic Sclerosis

“…Although the (R)‐(+) and (S)‐(–) enantiomers may differ in their therapeutic responses and toxic effects, the clinical consequences of these differences have not been adequately established. The results of clinical studies investigating enantioselectivity in the kinetic disposition of cyclophosphamide are inconclusive, do not evaluate the individual enantiomers of the active metabolite 4‐hydroxycyclophosphamide, do not evaluate the individual enantiomers of the metabolite carboxyethylphosphoramide mustard, which exposure is related to outcome disease, and involve a small number of patients in different disease states and treated with different combinations of drugs …”

“…The pharmacokinetics of cyclophosphamide and its metabolites, 4‐hydroxycyclophosphamide and carboxyethylphosphoramide mustard, as an enantiomeric mixture is well defined for the cyclophosphamide intravascular administration in high dose (continuous or daily dosing) to patients with cancer . However, there are no data on the enantioselective kinetic disposition and metabolism of cyclophosphamide in patients with chronic inflammatory autoimmune diseases such as multiple sclerosis and systemic sclerosis.…”