Pharmacokinetics of Carboplatin in Combination with Low-Dose Cyclophosphamide in Female Dogs with Mammary Carcinoma

This prospective study aimed to evaluate the effect of metronomic cyclophosphamide on carboplatin’s tolerability, efficacy, and pharmacokinetics in dogs with mammary carcinoma. Sixteen female dogs with mammary carcinoma were divided into groups: 300 mg/m2 intravenous (i.v.) carboplatin therapy (G1 = 8) or 300 mg/m2 i.v. carboplatin which was associated with 12.5 mg/m2 oral cyclophosphamide in a metronomic regimen (G2 = 8). The investigated animals underwent a clinical evaluation, a mastectomy, a carboplatin chemotherapy, and serial blood sampling for the pharmacokinetic analysis. The adverse events and survival rates were monitored. A non-compartmental analysis was applied to calculate the pharmacokinetic parameters of carboplatin in the 2nd and 4th chemotherapy cycles. Carboplatin PK showed high interindividual variability with a 10-fold variation in the area under the plasma concentration–time curve (AUC) in G1. The systemic plasma exposure to carboplatin was equivalent in both of the treatments considering the AUC and maximum plasma concentration (Cmax) values. Although the red blood cells (p < 0.0001), platelets (p = 0.0005), total leukocytes (p = 0.0002), and segmented neutrophils (p = 0.0007) were reduced in G2, the survival rate increased (p = 0.0044) when it was compared to G1. In conclusion, adding low daily doses of cyclophosphamide to a carboplatin therapy showed promising outcomes in female dogs with mammary tumors

Pharmacokinetics, metabolism and urinary excretion of doxorubicin in breast cancer patients

O presente estudo visa descrever a farmacocinética, o metabolismo e a excreção renal da doxorrubicina, uma antraciclina utilizada no tratamento do câncer de mama. A doxorrubicina é biotransformada a doxorrubicinol pelas enzimas carbonil redutase 1 e 3 e aldo-ceto redutase. Foram investigadas 12 pacientes portadoras de câncer de mama no primeiro ciclo de tratamento adjuvante ou neoadjuvante com doxorrubicina (60 mg/m2) administrada por infusão intravenosa durante 30 min. As amostras seriadas de sangue foram colhidas até 48 h após o início da infusão e a urina foi coletada em intervalos de 4 h por 48 h. Os métodos de análise da doxorrubicina e doxorrubicinol em urina e em plasma como concentração total e concentração livre foram desenvolvidos empregando LC-MS/MS. Os métodos não apresentaram efeito matriz ou efeito residual e mostraram-se lineares para ambos os analitos nos intervalos de 0,4-200 ng/mL para concentração total em plasma; 0,4-40 ng/mL para concentração livre em plasma e 20-8000 ng/mL de urina. Os parâmetros farmacocinéticos da doxorrubicina foram calculados com base nas curvas de concentração plasmática total versus tempo empregando o programa Phoenix® WinNonlin® por modelo tricompartimental com observação de meias-vidas de distribuição, de eliminação rápida e de eliminação terminal de 0,10; 2,55 e 40,87 h, respectivamente. A fração livre de doxorrubicina foi de 16,05% e de doxorrubicinol de 17,34%. A fração da dose de doxorrubicina recuperada na urina (0-48 h) foi de 2,35% para o fármaco inalterado e de 1,35% para o fármaco metabolizado a doxorrubicinol. Os valores médios de clearances na população do estudo foram de 58,07 L/h para o total, 1,45 L/h para o renal, 56,62 L/h para o hepático e 0,71 L/h para o clearance de formação do metabólito doxorrubicinol. Logo, os dados inferem que a eliminação da doxorrubicina é preponderantemente biliar. Os valores de clearance total não corrigidos em função do peso ou área superficial corpórea mostraram coeficiente de variação de 95,32%, enquanto para valores de clearance total corrigidos em função do peso ou da área superficial corpórea, foram obtidos valores similares, respectivamente, 88,74% e 89,84%. O estudo detalhado da farmacocinética da doxorrubicina e seu metabólito doxorrubicinol permitiu, pela primeira vez, o cálculo da razão de extração hepática (E=0,63) em humanos, classificando a doxorrubicina como um fármaco de extração hepática intermediária.The aim of this study is to describe the pharmacokinetics, metabolism and renal excretion of doxorubicin, an anthracycline used in breast cancer treatment. Doxorubicin is metabolised to doxorrubicinol by carbonyl reductase 1 and 3, and aldo-keto reductase enzymes. Twelve breast cancer patients with indication of adjuvant or neoadjuvant treatment were assessed during the first cycle of doxorubicin administration (60 mg/m2, iv-infusion, 30 min). Serial blood samples were collected up to 48 hours after the start of iv-infusion; urine was collected in 4-hour intervals, during 48 h. Methods for simultaneous quantification of doxorubicin and doxorubicinol in urine, as well as total and unbound fraction in plasma were developed applying LC-MS/MS. Neither matrix effect or carryover effect were observed. The methods were linear for both analytes in the ranges of 0.4-200 ng/mL for total plasma concentration; 0.4-40 ng/mL for unbound fraction concentration in plasma and 20-8000 ng/mL urine. Doxorubicin pharmacokinetic parameters were calculated based on total plasma concentration versus time curves applying Phoenix® WinNonlin® software by tricompartmental model analysis. Distribution, fast elimination and slow elimination half-lives were observed to be 0.10, 2.55 and 40.87 h, respectively. Unbound fractions were 16.05% for doxorubicin and 17.34% for doxorubicinol. The fraction of doxorubicin dose recovered in urine (0-48 h) was 2.35% for the drug excreted unchanged and 1.35% for doxorubicinol. The clearance mean values for the assessed population were 58.07 L/h for total clearance, 1.45 L/h for renal clearance, 56.62 L/h for hepatic clearance and 0.71 L/h for doxorubicinol metabolite formation clearance. Thus, the data suggest that doxorubicin elimination is carried out mainly by biliary excretion. Initial total clearance values demonstrated 95.32% variation coefficient, while total clearance values corrected to weight or body surface area presented similar variation coefficients, respectively 88.74% and 89.84%. The detailed pharmacokinetics study of doxorubicin and its metabolite doxorubicinol made it possible to calculate, for the first time in humans, the hepatic extraction ratio (E = 0.63), categorising doxorubicin as an intermediate hepatic-extraction-ratio drug

Effect of chronic hepatitis C on the activity of the main cytochrome P450 isoforms and membrane transporters on patients with different stages of hepatic fibrosis

A hepatite C crônica é uma infecção do fígado, o principal órgão envolvido na distribuição, metabolismo e eliminação de fármacos. Neste estudo, investigamos participantes com hepatite C crônica (n = 28), genótipos 1 e 3 do vírus da hepatite C, um dia antes do início do tratamento com agentes antivirais de ação direta (Fase 1) e até 30 dias após a avaliação da resposta virológica sustentada (Fase 2), alocados nos Grupos 1 (n = 15; F0/F1 e F2, fibrose hepática leve a moderada) e 2 (n = 13; F3 e F4, estágios avançados de fibrose/cirrose hepática) quanto à atividade das isoformas do citocromo P450 (CYP) e transportadores de membrana utilizando um coquetel de fármacos marcadores. Os participantes receberam, nas Fases 1 e 2, uma cápsula gelatinosa por via oral contendo cafeína (10 mg), losartana (2 mg), fexofenadina (10 mg), omeprazol (2 mg), metoprolol (10 mg), rosuvastatina (2 mg) e metformina (50 mg). Os fármacos inalterados e seus metabólitos em plasma foram analisados por LC-MS/MS em amostras de plasma coletadas 4 h (cálculo de razões metabólicas) ou no intervalo 0-48 h (cálculo de área sob a curva concentração plasmática vs. tempo; AUC) após a administração do coquetel. Os dados foram apresentados como médias geométricas ou medianas e intervalo de confiança de 90% das razões entre as Fases 1 e 2 ou entre os Grupos 1 e 2, empregando os testes t, Wilcoxon ou MannWhitney. A atividade da CYP2C19 (5-hidroxiomeprazol/omeprazol) foi reduzida em 37% [razão 1,63 (1,32-2,00), p < 0,01)] na Fase 1 para os participantes do Grupo 1, enquanto a atividade da CYP3A (omeprazol-sulfona/ omeprazol) foi reduzida em 64% [razão 1,46 (1,08-1,98), p < 0,05] na Fase 1 somente para o Grupo 2. A atividade do OATP1B1 & BCRP (AUC da rosuvastatina) foi reduzida nos Grupos 1 e 2, respectivamente, em 25% [razão 0,75 (0,53-0,82), p < 0,01)] e 31% [razão 0,69 (0,46-0,85), p < 0,05)] na Fase 1 quando comparada à Fase 2. As atividades da CYP1A2 (paraxantina/cafeína), CYP2C9 (E-3174/losartana) e CYP2D6 (alfa-hidroximetoprolol/metoprolol) foram reduzidas, respectivamente, em 57% [razão 0,43 (0,28-0,66), p < 0,01)], 52% [razão 0,48 (0,31-0,72), p < 0,01)] e 54% [razão 0,46 (0,26-0,82), p < 0,05)] no Grupo 2 quando comparadas ao Grupo 1 na Fase 1. As atividades da CYP1A2 e CYP2C19 foram reduzidas, respectivamente, em 57% [razão 0,43 (0,28-0,65), (p < 0,01)] e 43% [razão 0,57 (0,36-0,91), p < 0,05)] no Grupo 2 quando comparadas ao Grupo 1 na Fase 2. A atividade de OATP1B1 & BCRP foi reduzida nas Fases 1 e 2, respectivamente em 49% [razão 1,51 (1,17-2,20), p < 0,05)] e 61% [razão 1,39 (1,16-2,02), p < 0,01)] no Grupo 2 quando comparada ao Grupo 1. A atividade da P-gp (AUC da fexofenadina) não diferiu entre os Grupos 1 e 2 em ambas as fases ou entre as Fases 1 e 2 em ambos os grupos. Assim, o presente estudo reforça que a administração de medicamentos de baixo índice terapêutico, substratos de todas as isoformas CYP investigadas e de OATP1B1 & BCRP, deve levar em consideração a fase do tratamento e o estágio da hepatite C crônica.Chronic hepatitis C is a hepatic infection, the main organ involved in drug distribution, metabolism, and elimination of drugs. In this study, we investigated participants with chronic hepatitis C (n = 28), hepatitis C virus genotypes 1 and 3, one day before the beginning of the treatment with direct-acting antiviral agents (Phase 1) and up to 30 days after the assessment of the sustained virologic response (Phase 2), allocated in Groups 1 (n = 15; F0/F1 and F2, mild to moderate hepatic fibrosis) and 2 (n = 13; F3 and F4, advanced stages of hepatic fibrosis/cirrhosis) for the activity of cytochrome P450 (CYP) isoforms and membrane transporters applying a cocktail of probe drugs. In both Phases 1 and 2, participants received an oral gelatine capsule containing caffeine (10 mg), losartan (2 mg), fexofenadine (10 mg), omeprazole (2 mg), metoprolol (10 mg), rosuvastatin (2 mg), and metformin (50 mg). The unchanged drugs and their metabolites were analysed by LC-MS/MS in plasma samples collected at 4 h (determination of metabolic ratios) or in the range of 0-48 h (area under the plasma concentration vs time curve; AUC) after the cocktail administration. Data were presented as geometric means or medians and 90% confidence intervals of the ratios between Phases 1 and 2, or between Groups 1 and 2, applying t, Wilcoxon, or Mann-Whitney tests. CYP2C19 (5-hydroxyomeprazole/ omeprazole) activity was reduced by 37% [ratio 1.63 (1.32-2.00), p < 0.01)] in Phase 1 for Group 1, while CYP3A (omeprazole-sulfone/omeprazole) activity was reduced by 64% [ratio 1.46 (1.08-1.98), p < 0.05] in Phase 1 only for Group 2. OATP1B1 & BCRP activity (rosuvastatin AUC) was reduced in Groups 1 and 2, respectively, by 25% [ratio 0.75 (0.53-0.82), p < 0.01)] and 31% [ratio 0.69 (0.46-0.85), p < 0.05)] in Phase 1 when compared to Phase 2. The activities of CYP1A2 (paraxanthine/caffeine), CYP2C9 (E-3174/losartan), and CYP2D6 (alpha-hydroxymetoprolol/metoprolol) were reduced, respectively, by 57% [ratio 0.43 (0.28-0.66), p < 0.01)], 52% [ratio 0.48 (0.31-0.72), p < 0.01)], and 54% [ratio 0.46 (0.26-0.82), p < 0.05)] in Group 2 when compared to Group 1 in Phase 1. CYP1A2 and CYP2C19 activities were reduced, respectively, by 57% [ratio 0.43 (0.28-0.65), (p < 0,01)] and 43% [ratio 0.57 (0.36-0.91), p < 0.05)] in Group 2 when compared to Group 1 in Phase 2. OATP1B1 & BCRP activity was reduced in Phases 1 and 2, respectively, by 49% [ratio 1.51 (1.17-2.20), p < 0.05)] and 61% [ratio 1.39 (1.16-2.02), p < 0.01)] in Group 2 when compared to Group 1. The activity of P-gp (fexofenadine AUC) did not differ between Groups 1 and 2 in either phase or between Phases 1 and 2 in either group. Thus, the present study reinforces that the administration of drugs with low therapeutic indexes, substrates of any of the assessed CYP isoforms or OATP1B1 & BCRP, should consider the evolution of the treatment and the stage of chronic hepatitis C