A mechanism‐based pharmacokinetic‐enzyme model for cyclophosphamide autoinduction in breast cancer patients

Hassan, Moustapha; Svensson, U; Ljungman, Per; Björkstrand, B.; Olsson, Hanna; Bielenstein, Margareta; Abdel‐Rehim, Mohamed; Nilsson, Christína; Johansson, M; Karlsson, Mats O.

doi:10.1046/j.1365-2125.1999.00090.x

Cited by 61 publications

(55 citation statements)

References 39 publications

(75 reference statements)

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“…It is known that the disposition of highdose CY by the CYP450 enzymes is a saturable process 50 while on the other hand, CY also shows autoinduction. 21,24,25,49 Hence, the increase in AUC and decrease in Cl of CY that we observed on day 4 in some of our patients in this study could be due to nonpredictable variations in the balance between enzyme saturation and autoinduction.…”

Section: Discussionmentioning

confidence: 85%

“…21,24,25,49 Several studies have shown detectable autoinduction of CY within 24 h after the initiation of CY infusion resulting in shorter CY T1/2, increased Cl/F and decreased AUC. 21,24,25,49 The AUC of CY was increased and Cl decreased (Figure 3) after the fourth dose in as many as half of the patients included in this study. Phenytoin was used to prevent BU-induced seizures, and hence residual effects of phenytoin upon drug metabolism and transport would be present for day 1 but not for day 4.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, CY is known to exhibit autoinduction of its metabolism in patients receiving repeated administra-tion of CY for various disease conditions. 24,25 In the context of conditioning for HSCT using chemotherapy alone, CY treatment is almost always preceded by BU, which has been shown to influence the PK of CY as well as aggravate the toxic effects including SOS, hemorrhagic cystitis and permanent alopecia. 26 --28 It is possible that wide inter-individual variation (IIV) in the PK of CY might be responsible for individual differences in toxicities or treatment outcome.…”

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confidence: 99%

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Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian

Desire

Panetta

et al. 2012

Bone Marrow Transplant

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CY in combination with BU is a widely used conditioning regimen for haematopoietic SCT (HSCT). The aim of this study was to evaluate the pharmacokinetics (PK) of CY and its major metabolite 4-hydroxyCY (HCY) in patients with thalassemia undergoing HSCT. A total of 55 patients received BU (16 mg/kg) followed by CY (160 --200 mg/kg) both over 4 days before HSCT. A population PK model was developed to describe the disposition of CY and HCY and the inter-individual (IIV) and inter-occasion variability (IOV). The model was also used to determine the effects covariates including: demographics, Lucarelli classification and polymorphisms in enzymes involved in the metabolism or biotransformation of CY had on CY and HCY disposition. Overall, 17 --114% IIV and 12 --103% IOV in CY and HCY PK parameters were observed. Body weight and age were the main covariates, which explained the largest portion of the IIV. In addition, CYP2C9*2 explained a significant portion of the IIV in the clearance (Po0.002) and thus the area under the concentration curve (Po0.05) of CY. This covariate model may be used to design and plan targeted dose therapy in this group of pediatric patients, if clinical outcome association with CY PK are proved and target range established.Bone Marrow Transplantation (2012) 47, 1178 --1185; doi:10.1038/bmt.2011.254; published online 9 January 2012Keywords: CY; pharmacokinetics; thalassemia, HSCT INTRODUCTION CY in combination with BU has been a commonly used conditioning regimen in HSCT for malignant and non-malignant diseases. 1 --3 Even though advances in transplantation practices including reducing the intensity of the conditioning regimen have improved the outcome of HSCT in recent years, 4,5 doselimiting toxicities such as sinusoidal obstruction syndrome (SOS) and hemorrhagic cystitis 6,7 remain as the major problems associated with BU-CY-based myeloablative-conditioning regimen. We and others have previously shown that BU pharmacokinetics (PK) influences toxicity and outcome associated with HSCT in patients with thalassemia major treated with BU/CY conditioning. 8 --10 The PK and pharmacodynamics of CY in pediatric patients receiving myeloablative doses of CY are limited and to the best of our knowledge, there is no report on CY PK in pediatric patients undergoing HSCT with myeloablative BU/CY-conditioning regimen. A recent study on the PK of CY and its metabolites in pediatric patients receiving high-dose myeloablative therapy 11 showed very little inter-patient variation in CY elimination, which is largely accounted for by body surface area, suggesting that high-dose chemotherapy resulted in minimal differences in CY PK as compared with more conventional dosage regimens. A population PK model was developed for the first time in children with neuroblastoma, 12 which showed substantial inter-patient variability in the PK of CY and its metabolites. Neither of these two studies described any pharmacodynamics associations. Several studies in adult patients have shown association between the incidence of SO...

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Balasubramanian

Desire

Panetta

et al. 2012

Bone Marrow Transplant

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“…4,9,20 Part of the variation was considered to be caused by regulatory phenomena at the transcriptional or translational level. 5,21,22 Subsequently, genetic polymorphism of this enzyme was discovered 23,24 and this contributes to the variation. An amino-acid substitution, Gln 172 His, caused by the G516T (CYP2B6*6) SNP was described to enhance 7-ethoxycoumarin O-deethylase activity.…”

Section: Introductionmentioning

confidence: 99%

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

et al. 2003

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The role of polymorphic CYP2B6 in cyclophosphamide (CPA) bioactivation was investigated in human liver microsomes. A total of 67 human liver specimens were first genotyped with respect to the CYP2B6*5 and CYP2B6*6 variant alleles. CYP2B6 apoprotein levels in 55 liver microsomal preparations were assessed by immunoblotting. 4-Hydroxy-CPA and hydroxy-bupropion were quantified by using HPLC and LC-MS, respectively. 7-Ethoxy-4-trifluoromethyl coumarin O-deethylase activity was measured fluorometrically. The frequencies of CYP2B6*5 and CYP2B6*6 mutant alleles were 9.0 and 16.4%, respectively. CYP2B6 protein expression was detected in 80% of the samples, with a large variation (0.003-2.234, arbitrary units). There was a high correlation between CYP2B6 apoprotein content and CPA 4-hydroxylation (n ¼ 55, r ¼ 0.81, Po0.0001). When based on the CYP2B6 apoprotein levels, the *6 carriers had significantly higher CPA 4-hydroxylation (Po0.05). CPA 4-hydroxylation also correlated significantly with other CYP2B6-specific reactions (n ¼ 20, Po0.0001). V max and K m for CPA 4-hydroxylation in recombinant CYP2B6 enzyme were 338 nmol/min/nmol enzyme and 1.4 mM, respectively. CYP2B6 showed much higher in vitro intrinsic clearance than previously observed in recombinant CYP2C19 and CYP2C9 variants in yeast expression system. Our results demonstrate that the polymorphic CYP2B6 is a major enzyme in the bioactivation of CPA. Moreover, we identified a strong impact of CYP2B6*6 on CPA 4-hydroxylation.

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“…[21][22][23] Through this course, CYP2C9, CYP2B6, and CYP3A4 are induced in human hepatocytes; this mechanism is called autoinduction. 24,25 Autoinduction results in the increased clearance of the drug during treatment with an increased formation of 4-HC, phosphoramide mustard, and 2-dechloroethylcyclophosphamide. 22,23,[26][27][28][29][30] In general, autoinduction is detectable within 24 h of administration.…”

Section: Centration; Conditioning Regimen; Drug Interactionmentioning

confidence: 99%

Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation

Nagamura

Takahashi

Takeuchi

et al. 2003

Bone Marrow Transplant

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Summary:We retrospectively analyzed the factors that affect serum cyclosporine (CsA) concentrations up to day 14 after allogeneic hematopoietic stem cell transplantation (HSCT). In all, 103 transplant recipients who received MTX and CsA for acute GVHD prophylaxis were analyzed. No significant relationships between serum CsA concentrations and gender, age, serum creatinine levels, AST/ALT levels, or antibiotic/fluconazole administration were found by comparing median CsA concentrations or by using longitudinal or regression multivariate analyses. However, the mean of the median serum CsA concentration in patients (n ¼ 54) receiving the regimen containing cyclophosphamide (CY) (149.7 ng/ml; 95% confidence interval (CI): 132.1-167.4) was significantly (Po0.0001) lower than that in patients (n ¼ 49) receiving the non-CY regimen (217.3 ng/ml; 95% CI: 198.9-235.6). Longitudinal analysis and regression multivariate analysis showed that only administration of CY had a significant effect on the serum CsA concentration. Our results suggest that administration of CY during conditioning can reduce the effects on serum CsA concentrations during the 2 weeks following HSCT. The mechanism of this effect is not clear, but it may be due to the autoinduction of CY.

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A mechanism‐based pharmacokinetic‐enzyme model for cyclophosphamide autoinduction in breast cancer patients

Cited by 61 publications

References 39 publications

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Population pharmacokinetics of cyclophosphamide in patients with thalassemia major undergoing HSCT

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation

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