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

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

doi:10.3389/fphar.2020.00406

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

Front Pharmacol. 2020 Apr 23:11:406. doi: 10.3389/fphar.2020.00406. eCollection 2020.

Authors

Jemal Hussien Ahmed^{1

2}, Eyasu Makonnen^{1

3}, Ronald Kuteesa Bisaso⁴, Jackson Kijumba Mukonzo⁴, Alan Fotoohi⁵, Abraham Aseffa⁶, Rawleigh Howe⁶, Moustapha Hassan⁷, Eleni Aklillu²

Affiliations

¹ Department of Pharmacology and Clinical Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia.
² Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
³ Center for Innovative Drug Development and Therapeutic Trials, Addis Ababa University, Addis Ababa, Ethiopia.
⁴ Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda.
⁵ Division of Clinical Pharmacology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶ Non-Communicable Diseases (NCD) Research Directorate, Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
⁷ Experimental Cancer Medicine (ECM), Clinical Research Center (KFC), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

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 (V_D) 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 V_D 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 V_D. The mean V_D (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.

Keywords: CYP2C9; CYP3A5; body surface area; breast cancer; cyclophosphamide; pharmacodynamics; pharmacokinetics.