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

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/m 2 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/m 2. A 0.1 m 2 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/m 2) was significantly lower compared to those of overweight (48.1 L) or

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

“…Our results agree with the findings of this study. BSA, which was an independent variable for predicting the AUC/Ds of DXR and CPA in this study, has been reported to affect pharmacokinetics parameters in other studies [22][23][24] . In addition, in this study, a negative correlation between Alb and AUC/D of DXR was found in elderly patients.…”

“…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.…”

Pharmacogenetics of Breast Cancer Treatments: A Sub-Saharan Africa Perspective

“…In particular, two studies, one on tamoxifen and another on cyclophosphamide among breast cancer patients, have been performed in Ethiopia. 26 , 179 Another study was focused on AIs in South African women with breast cancer. 74 We would like to stress that Ethiopia has a complex admixture component with a dynamic history of several Eurasian ancestries and some Nilotic and Semitic-Cushitic components.…”

“…In Ethiopia, it has been reported that carriers of CYP3A5*3 and CYP3A5*6 had lower cyclophosphamide elimination rate and longer half-life than subjects carrying the wild-type allele. 179 Additionally, increased drug clearance has been reported in carriers of CYP2C9 *2 and CYP2C9 * 3 , 179 similar to the increased activity for other substrates. 180 Allele frequencies for these genes were previously reported in other sections.…”

“…§ When available. a: according to Ahmed et al 179 increased cyclophosphamide clearance was significantly higher in carriers of CYP2C9*2 or *3 alleles who also carry POR*28 allele, therefore an expected fast metabolic phenotype has been measured in association to the two alleles.…”