Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients
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 pharma...
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| Format: | Article |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.00406/full |
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| author | Jemal Hussien Ahmed Jemal Hussien Ahmed Eyasu Makonnen Eyasu Makonnen Ronald Kuteesa Bisaso Jackson Kijumba Mukonzo Alan Fotoohi Abraham Aseffa Rawleigh Howe Moustapha Hassan Eleni Aklillu |
| author_facet | Jemal Hussien Ahmed Jemal Hussien Ahmed Eyasu Makonnen Eyasu Makonnen Ronald Kuteesa Bisaso Jackson Kijumba Mukonzo Alan Fotoohi Abraham Aseffa Rawleigh Howe Moustapha Hassan Eleni Aklillu |
| author_sort | Jemal Hussien Ahmed |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T03:26:29Z |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-19T03:26:29Z |
| publishDate | 2020-04-01 |
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| spelling | doaj.art-a8d2f76675124552a809cc60195b81482022-12-21T20:37:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-04-011110.3389/fphar.2020.00406506577Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer PatientsJemal Hussien Ahmed0Jemal Hussien Ahmed1Eyasu Makonnen2Eyasu Makonnen3Ronald Kuteesa Bisaso4Jackson Kijumba Mukonzo5Alan Fotoohi6Abraham Aseffa7Rawleigh Howe8Moustapha Hassan9Eleni Aklillu10Department of Pharmacology and Clinical Pharmacy, Addis Ababa University, Addis Ababa, EthiopiaDivision of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of Pharmacology and Clinical Pharmacy, Addis Ababa University, Addis Ababa, EthiopiaCenter for Innovative Drug Development and Therapeutic Trials, Addis Ababa University, Addis Ababa, EthiopiaDepartment of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, UgandaDepartment of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, UgandaDivision of Clinical Pharmacology, Department of Medicine, Karolinska Institutet, Stockholm, SwedenNon-Communicable Diseases (NCD) Research Directorate, Armauer Hansen Research Institute, Addis Ababa, EthiopiaNon-Communicable Diseases (NCD) Research Directorate, Armauer Hansen Research Institute, Addis Ababa, EthiopiaExperimental Cancer Medicine (ECM), Clinical Research Center (KFC), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, SwedenDivision of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenCyclophosphamide (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.https://www.frontiersin.org/article/10.3389/fphar.2020.00406/fullcyclophosphamidepharmacokineticsCYP3A5CYP2C9body surface areapharmacodynamics |
| spellingShingle | Jemal Hussien Ahmed Jemal Hussien Ahmed Eyasu Makonnen Eyasu Makonnen Ronald Kuteesa Bisaso Jackson Kijumba Mukonzo Alan Fotoohi Abraham Aseffa Rawleigh Howe Moustapha Hassan Eleni Aklillu Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients Frontiers in Pharmacology cyclophosphamide pharmacokinetics CYP3A5 CYP2C9 body surface area pharmacodynamics |
| title | Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients |
| title_full | Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients |
| title_fullStr | Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients |
| title_full_unstemmed | Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients |
| title_short | Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients |
| title_sort | population pharmacokinetic pharmacogenetic and pharmacodynamic analysis of cyclophosphamide in ethiopian breast cancer patients |
| topic | cyclophosphamide pharmacokinetics CYP3A5 CYP2C9 body surface area pharmacodynamics |
| url | https://www.frontiersin.org/article/10.3389/fphar.2020.00406/full |
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