Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients.

Jemal Hussien Ahmed,Abraham Aseffa,Alan Fotoohi,Eyasu Makonnen,Jackson Kijumba Mukonzo,Ronald Kuteesa Bisaso,Rawleigh Howe,Moustapha Hassan,Eleni Aklillu

doi:10.3389/fphar.2020.00406

Abstract

Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (VD) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average VD compared to patients who received 600 mg/m2. A 0.1 m2 unit increase in body surface area (BSA) was associated with a 5.6% increment in VD. The mean VD (33.5 L) in underweight group (BMI < 18.5 kg/m2) was significantly lower compared to those of overweight (48.1 L) or obese patients (51.9 L) (p < 0.001). AUC of CPA was positively correlated with neutropenic toxicity. In conclusion, we report large between-patient variability in clearance of CPA. CYP3A5 and CYP2C9 genotypes, BSA, BMI, and CPA dosage regimen influence PK of CPA. Plasma CPA exposure positively predicts chemotherapy-associated neutropenic toxicity.

Highlights

Cyclophosphamide (CPA) is a cornerstone of combination chemotherapy for the treatment of breast cancer (Stearns et al, 2004)
CPA concentration was determined from a total of 532 plasma samples obtained from 267 female patients with breast cancer
We developed population pharmacokinetics, pharmacogenetics, and pharmacodynamics (PK-PG-PD) model for CPA in Ethiopian breast cancer patients at conventional CPA regimen

Summary

Introduction

Cyclophosphamide (CPA) is a cornerstone of combination chemotherapy for the treatment of breast cancer (Stearns et al, 2004). Various cytochrome P450 (CYP) enzymes have been implicated to catalyze the 4-hydroxylation of CPA to 4-OH-CPA including CYP2B6 (Xie et al, 2003), CYP2C9, and CYP3A4/5 (Roy et al, 1999), CYP2C19 (Griskevicius et al, 2003; Timm et al, 2005), and CYP2J2 (El-Serafi et al, 2015a) These enzymes are genetically polymorphic and may contribute to interindividual variation in CPA metabolic disposition and clinical response including chemotherapy-induced toxicities (Nakajima et al, 2007; Zanger et al, 2007; Ekhart et al, 2008). A decrease in CPA clearance with increased body weight (Powis et al, 1987), impaired hepatic (de Jonge et al, 2005), or renal function (Haubitz et al, 2002) resulting in an increased systemic drug exposure is reported previously

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