Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry

Dobbs, N; Twelves, Chris; Gillies, H.; James, Christopher; Harper, P.; Rubens, R. D.

doi:10.1007/bf00685796

Cited by 96 publications

(41 citation statements)

References 16 publications

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“…Both dose and weight influenced V1 when included as single covariates but combining these factors offered no significant advantage. In contrast to the results of Amantea et al (1997) in a larger group of 43 patients who received pegylatedliposomal doxorubicin, body surface area was not found to influence the clearance of PK1, nor was clearance reduced in female patients, as previously shown by Dobbs et al (1995) with standard doxorubicin. However, a larger number of subjects would be required to investigate these influences properly.…”

Section: Discussioncontrasting

confidence: 86%

“…The elimination half-life of 85 h identified in this analysis was longer than the typical values of 20Ð50 h reported in many studies with doxorubicin (Bronchud et al, 1990;Piscitelli et al, 1993;Dobbs et al, 1995;Jaquet et al, 1996). It is possible that these differences are influenced by sampling strategy.…”

Section: Discussioncontrasting

confidence: 40%

“…Although a biexponential model appeared to describe the data well overall, there was an underestimation of peak concentrations in some patients at low doses which may suggest a model misspecification problem or a formulation effect. Previous studies have identified triexponential elimination after the administration of doxorubicin (Bronchud et al, 1990;Piscitelli et al, 1993;Dobbs et al, 1995;Jaquet et al, 1996). However, when data from two patients who received the highest dose, and had the highest number of concentration measurements, were analysed individually it was not possible to characterize the parameters of a triexponential model.…”

Section: Discussionmentioning

confidence: 97%

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Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours

et al. 1999

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Doxorubicin pharmacokinetics were determined in 33 patients with solid tumours who received intravenous doses of 20–320 mg m −2 HPMA copolymer bound doxorubicin (PK1) in a phase I study. Since assay constraints limited the data at lower doses, conventional analysis was not feasible and a ‘population approach’ was used. Bound concentrations were best described by a biexponential model and further analyses revealed a small influence of dose or weight on V1 but no identifiable effects of age, body surface area, renal or hepatic function. The final model was: clearance (Q) 0.194 l h −1 ; central compartment volume (V1) 4.48 × (1+0.00074 × dose (mg)) l; peripheral compartment volume (V2) 7.94 l; intercompartmental clearance 0.685 l h −1 . Distribution and elimination half-lives had median estimates of 2.7 h and 49 h respectively. Free doxorubicin was present at most sampling times with concentrations around 1000 times lower than bound doxorubicin values. Data were best described using a biexponential model and the following parameters were estimated: apparent clearance 180 l h −1 ; apparent V1 (l) 1450 × (1+0.0013 × dose (mg)), apparent V2 (l) 21 300 × (1–0.0013 × dose (mg)) × (1+2.95 × height (m)) and apparent Q 6950 l h −1 . Distribution and elimination half-lives were 0.13 h and 85 h respectively. © 1999 Cancer Research Campaign

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Section: Discussioncontrasting

confidence: 86%

Section: Discussioncontrasting

confidence: 40%

Section: Discussionmentioning

confidence: 97%

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Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours

et al. 1999

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“…Interestingly, the AUC for fluorouracil appears higher in females, 24 and doxorubicin, which is a key component of chemotherapy for HL, ES and OS, has demonstrated significant gender-and body compositionrelated differences in pharmacokinetic profile. [30][31][32][33][34] Our studies add to these findings by suggesting that almost all of the survival gap in AYAs may be linked to relative underdosing of males based on current dosing algorithms.…”

Section: Discussionmentioning

confidence: 56%

Gender‐specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood

Khamly

Thursfield

Fay

et al. 2009

Intl Journal of Cancer

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Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender‐related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms. © 2009 UICC

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“…Milano et al (18) reported that the capacity to clear 5-FU is lower in women than in men. Dobbs et al (19) demonstrated that, among patients with normal liver function, men exhibit a higher rate of doxorubicin clearance compared to women. Higher response to chemotherapy in females observed in this study may partly be due to the higher blood concentrations of chemotherapeutic agents.…”

Section: Univariate Analysis Multivariate Analysis ------------------mentioning

confidence: 99%

Early response to neoadjuvant chemotherapy in advanced esophageal cancer evaluated by computed tomography predicts the utility of a second cycle of chemotherapy

Motoori

Yano

Yasuda

et al. 2013

Molecular and Clinical Oncology

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Abstract. Multi-course neoadjuvant chemotherapy (NACT) followed by surgery is a promising treatment for advanced esophageal cancer. However, non-responders may continue to receive ineffective treatment, since there are no definitive criteria for early discontinuation of NACT. In this study, we analyzed 103 advanced esophageal cancer patients treated with 2 cycles of NACT followed by surgery. Patients with >20% decrease in the size of the primary tumor as evaluated by computed tomography (CT) following the first cycle of chemotherapy, were defined as early responders and the remainder as early non-responders. Clinicopathological factors and prognosis were compared between the 2 groups. The reduction rate of the second cycle and progression-free survival (PFS) of early non-responders were significantly worse than those of early responders (p=0.0001 and 0.0375, respectively). In addition, pathological T stage, pathological assessment of tumor regression and number of metastatic lymph nodes were significantly unfavorable in early non-responders (p=0.023, 0.007 and 0.0041, respectively). Among the clinical factors that were available prior to administration of the second cycle, clinical T3 stage and early non-responder status were the only independent unfavorable factors (p=0.028 and 0.0062, respectively). Patients with both unfavorable factors had a significantly poorer PFS compared to the remaining patients and a PFS similar to those who had both factors but received only 1 cycle of NACT. In conclusion, the reduction rate of the primary tumor as evaluated by CT following the first cycle of NACT, may aid physicians in determining whether to administer a second cycle. In early non-responders bearing T3 tumors, NACT should be discontinued after the first cycle.

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Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry

Cited by 96 publications

References 16 publications

Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours

Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours

Gender‐specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood

Early response to neoadjuvant chemotherapy in advanced esophageal cancer evaluated by computed tomography predicts the utility of a second cycle of chemotherapy

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