A population PKPD model for neutropenia during Hyper-CVAD chemotherapy in non-Hodgkin lymphoma

Semi-mechanistic PKPD models [1] have been previously used to describe the time-course of granulopoiesis and resulting neutropenia from cytotoxic cancer chemotherapy. The B cycle of Hyper-CVAD comprises of intravenously administered high-dose methotrexate (MTX) followed by short sequential infusions of cytarabine for treatment of aggressive non-Hodgkin lymphoma (NHL) for up to four cycles [2]. Neutropenia is the most common toxicity associated with Hyper-CVAD, with the depth and length of neutropenic nadir determining dose intensity and timing of subsequent cycles. The PKPD relationship of the neutrophil time-course and Hyper-CVAD remains to be characterised.

A MTX population PK model was developed (using non-linear mixed effects modelling) from retrospectively collected observations of 108 adults at a tertiary referral metropolitan hospital receiving Hyper-CVAD chemotherapy for NHL during 2002 to 2012. A population PKPD model was built from the collected neutrophil observations by adapting a literature model for myelosuppression [1] based on the MTX population PK model and fixed cytarabine population PK values [3].

The final MTX PK model was a two-compartmental model incorporating renal function and body size as covariates influencing clearance and volume of distribution of the central compartment respectively. The PKPD model captured the neutropenic nadir and associated rebound back to baseline neutrophil counts through 5 compartments in the bone marrow. Preliminary results suggest that linear rather than Emax or sigmoid Emax models best described drug effects for MTX and cytarabine.

A population MTX PK model was successfully combined with a literature myelosuppression model to describe the neutrophil time course during Hyper-CVAD chemotherapy. Further work is required to characterise the variability in the PD between subjects and Hyper-CVAD cycles.

[1] Quartino AL, Friberg LE, Karlsson MO. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs. 2012;30:833-45.
[2] Kantargian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD), a dose-intensive regimen in adult acute lymphocytic leukemia. Cancer. 2004;101:2788-801.
[3 ]Krogh-Madsen M, Bender B, Jensen MK, et al. Population pharmacokinetics of cytarabine, etoposide and daunarubicin in the treatment of acute myeloid leukemia. Cancer Chemother Pharmacol. 2012; 69:1155-63.