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1.
Clin Pharmacol Drug Dev ; 10(9): 1054-1063, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33932130

RESUMO

Dabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation-positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open-label, fixed-sequence study in patients with BRAF V600 mutation-positive tumors. Repeat dabrafenib dosing resulted in a 2.56-fold increase in rosuvastatin maximum observed concentration (Cmax ), an earlier time to Cmax , but only a 7% increase in area under the concentration-time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax . No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase.


Assuntos
Imidazóis/farmacologia , Midazolam/farmacocinética , Oximas/farmacologia , Rosuvastatina Cálcica/farmacocinética , Adulto , Área Sob a Curva , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Feminino , Humanos , Imidazóis/administração & dosagem , Transportador 1 de Ânion Orgânico Específico do Fígado/efeitos dos fármacos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/efeitos dos fármacos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo
2.
Clin Cancer Res ; 25(24): 7294-7302, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31506385

RESUMO

PURPOSE: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers. PATIENTS AND METHODS: This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target. RESULTS: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily. CONCLUSIONS: In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imidazóis/uso terapêutico , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imidazóis/farmacocinética , Lactente , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias/genética , Neoplasias/patologia , Oximas/farmacocinética , Segurança do Paciente , Inibidores de Proteínas Quinases/farmacocinética , Distribuição Tecidual , Resultado do Tratamento
3.
Br J Cancer ; 120(10): 975-981, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30992546

RESUMO

BACKGROUND: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy. METHODS: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed. RESULTS: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks). CONCLUSIONS: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.


Assuntos
Aminopiridinas/administração & dosagem , Proteína-Tirosina Quinases de Adesão Focal/genética , Ácidos Hidroxâmicos/administração & dosagem , Neoplasias/tratamento farmacológico , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Idoso , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/farmacocinética , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Piridonas/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética
4.
Br J Clin Pharmacol ; 84(4): 764-775, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29243287

RESUMO

AIMS: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS: Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. RESULTS: Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, -1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg Cmax and AUC(0-∞) were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC(0-τ) with 300 mg BID was ≈ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was <5 msec (upper 90% CI, <10 msec). No unexpected toxicities occurred with supratherapeutic dosing. CONCLUSION: Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen.


Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Simulação por Computador , Relação Dose-Resposta a Droga , Eletrocardiografia Ambulatorial/métodos , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Neoplasias/genética , Neoplasias/patologia , Oximas/efeitos adversos , Oximas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
5.
Br J Haematol ; 170(1): 40-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25825041

RESUMO

There are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti-CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24.1 months vs. 6.8 months; time to next therapy was 14.8 months vs. 12.3 months; and progression-free survival was 7.4 months vs. 7.9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1-2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Vidarabina/análogos & derivados , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Retratamento , Vidarabina/farmacologia
6.
Drug Metab Dispos ; 41(12): 2215-24, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24097902

RESUMO

A phase I study was conducted to assess the metabolism and excretion of [(14)C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 µCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-high-performance liquid chromatography--tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy- and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned α to an alkyl (ethyl or t-butyl) side chain.


Assuntos
Carbono/metabolismo , Descarboxilação/fisiologia , Imidazóis/metabolismo , Neoplasias/metabolismo , Nitrogênio/metabolismo , Oximas/metabolismo , Administração Oral , Adulto , Fezes/química , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Adulto Jovem
7.
J Pharm Sci ; 102(9): 3100-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23608920

RESUMO

Dabrafenib is a small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF V600 mutation-positive melanoma. This clinical, open-label, two-cohort (n = 14 per cohort), randomized study was designed to evaluate the effect of drug substance particle size, and food on the plasma pharmacokinetics of a single oral dose of dabrafenib in patients with BRAF V600 mutation-positive solid tumors. In addition, an exploratory cross-cohort comparison of the relative bioavailability of single-dose dabrafenib administered in gelatin and hydroxypropyl methylcellulose (HPMC) capsules was performed. Higher bioavailability was noted with nonmicronized drug substance (larger particle size), under fasting conditions, and with HPMC capsules. Initial dissolution results at pH 1.2 showed higher dissolution of gelatin relative to HPMC capsules inconsistent with clinical data. Subsequent in vitro dissolution studies were conducted in fasted-state simulated gastric fluid over a 24-h period and showed that HPMC capsules reached a higher percentage of dabrafenib dissolved than gelatin capsules. The presence of HPMC is believed to inhibit precipitation of dabrafenib as the freebase, thereby maintaining a supersaturated solution over an extended period of time. Dabrafenib has been administered in pivotal clinical studies on an empty stomach using micronized drug substance in HPMC capsules.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Imidazóis/administração & dosagem , Imidazóis/sangue , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Oximas/sangue , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Cápsulas/química , Estudos de Coortes , Jejum , Feminino , Humanos , Derivados da Hipromelose , Masculino , Melanoma/genética , Metilcelulose/análogos & derivados , Metilcelulose/química , Pessoa de Meia-Idade , Tamanho da Partícula , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/genética
8.
Drug Metab Dispos ; 41(6): 1179-86, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23482500

RESUMO

Sorafenib is an orally active tyrosine kinase inhibitor used in the treatment of renal and hepatocellular carcinoma. This study was designed to establish whether transport proteins are involved in the hepatic uptake of sorafenib and to determine the extent of biliary excretion of sorafenib and its metabolites in human hepatocytes. Initial uptake was assessed in freshly isolated, suspended human hepatocytes in the presence of inhibitors and modulators. [(14)C]Sorafenib (1 µM) uptake at 4°C was reduced by about 61-63% of the uptake at 37°C, suggesting a high degree of passive diffusion. Hepatocyte uptake of [(14)C]sorafenib was not Na(+) dependent or influenced by the organic anion transporter 2 inhibitor ketoprofen. However, initial [(14)C]sorafenib hepatocyte uptake was reduced by 46 and 30% compared with control values in the presence of the organic anion transporting polypeptide inhibitor rifamycin SV and the organic cation transporter (OCT) inhibitor decynium 22, respectively. [(14)C]Sorafenib (0.5-5 µM) uptake was significantly higher in hOCT1-transfected Chinese hamster ovary cells compared with mock cells, and inhibited by the general OCT inhibitor, 1-methyl-4-phenylpryidinium. OCT1-mediated uptake was saturable with a Michaelis-Menten constant of 3.80 ± 2.53 µM and a V(max) of 116 ± 42 pmol/mg/min. The biliary excretion index and in vitro biliary clearance of sorafenib (1 µM) in sandwich-cultured human hepatocytes were low (∼11% and 11 ml/min/kg, respectively). Results suggest that sorafenib uptake in human hepatocytes occurs via passive diffusion, by OCT1, and by organic anion transporting polypeptide(s). Sorafenib undergoes modest biliary excretion, predominantly as a glucuronide conjugate(s).


Assuntos
Hepatócitos/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Adulto , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Feminino , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/metabolismo , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe
9.
Br J Pharmacol ; 161(5): 1059-69, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20977456

RESUMO

BACKGROUND AND PURPOSE: Imatinib is a clinically important inhibitor of tyrosine kinases that are dysregulated in chronic myelogenous leukaemia and gastrointestinal stromal tumours. Inter-individual variation in imatinib pharmacokinetics is extensive, and influences drug safety and efficacy. Hepatic cytochrome P450 (CYP) 3A4 has been implicated in imatinib N-demethylation, but the clearance of imatinib decreases during prolonged therapy. CYP3A phenotype correlates with imatinib clearance at the commencement of therapy, but not at steady state. The present study evaluated the possibility that multiple CYPs may contribute to imatinib oxidation in liver. EXPERIMENTAL APPROACH: Imatinib biotransformation in human liver microsomes (n= 20) and by cDNA-expressed CYPs was determined by LC-MS. Relationships between imatinib N-demethylation and other drug metabolizing CYPs were assessed. KEY RESULTS: N-desmethylimatinib formation was correlated with microsomal oxidation of the CYP3A4 substrates testosterone (ρ= 0.60; P < 0.01) and midazolam (ρ= 0.46; P < 0.05), and the CYP2C8 substrate paclitaxel (ρ= 0.58; P < 0.01). cDNA-derived CYPs 2C8, 3A4, 3A5 and 3A7 supported imatinib N-demethylation, but 10 other CYPs were inactive; in kinetic studies, CYP2C8 was a high-affinity enzyme with a catalytic efficiency ∼15-fold greater than those of CYPs 3A4 and 3A5. The CYP3A inhibitors ketoconazole and troleandomycin, and the CYP2C8 inhibitors quercetin and paclitaxel decreased imatinib oxidation. From molecular modelling, the imatinib structure could be superimposed on a pharmacophore for CYP2C8 substrates. CONCLUSIONS AND IMPLICATIONS: CYP2C8 and CYPs 3A contribute to imatinib N-demethylation in human liver. The involvement of CYP2C8 may account in part for the wide inter-patient variation in imatinib pharmacokinetics observed in clinical practice.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP3A/metabolismo , Piperazinas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/metabolismo , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Benzamidas , Cromatografia Líquida , Citocromo P-450 CYP2C8 , Inibidores do Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Mesilato de Imatinib , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Oxirredução , Espectrometria de Massas em Tandem
10.
Br J Clin Pharmacol ; 70(3): 400-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20716241

RESUMO

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The anticancer agent irinotecan is a prodrug that is hydrolyzed by hepatic carboxylesterase to its active and toxic metabolite SN-38 and oxidized by CYP3A4 to its inactive metabolite APC. Irinotecan therapy is complicated by co-administered drugs that inhibit CYP3A4 and decrease APC formation and that indirectly increase SN-38 formation. Dose adjustment in cancer patients with liver disease has been recommended. WHAT THIS STUDY ADDS: In microsomal fractions from patients with severe hepatic dysfunction both APC and SN-38 formation were decreased due to down-regulation of CYP3A4 and carboxylesterase enzymes. Thus relative SN-38 : APC formation was preserved. In some fractions the SN-38:APC ratio was increased, thus providing a possible explanation for clinical reports of increased SN-38 exposure in some patients with liver dysfunction. Close monitoring of SN-38 formation in patients with severe liver disease is warranted. AIMS: Dose modification with the anticancer agent irinotecan is recommended in patients with severe liver dysfunction. This study evaluated the impact of liver disease on the relative formation of phase I products of irinotecan biotransformation in human microsomes in vitro. METHODS: Microsomes from subjects with normal liver function and liver dysfunction (n=20) were assessed for irinotecan biotransformation and the expression of cytochrome P450 (CYP) 3A4 and carboxylesterase (CES) enzymes. RESULTS: Liver disease down-regulated CYP3A4 expression (median 33% of control, range 0-126%, P<0.05) and impaired CYP3A4-dependent oxidation of irinotecan to the inactive 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) (median 0.2, range 0-1.21 pmol mg protein(-1) min(-1) compared with median 0.66, range 0-2.35 in control, P<0.01). CES-mediated hydrolysis of irinotecan to 7-ethyl-10-hydroxycamptothecin (SN-38) was also impaired in liver disease (median 8.38, range 0-20.7 pmol mg protein(-1) min(-1) compared with median 13.3, range 0-28.9 in control, P<0.05). In seven of 20 liver disease microsomes neither metabolite was detected but in three the SN-38:APC ratio was high (41-68) compared with the remaining 10 samples (ratio 11-36). CONCLUSIONS: Down-regulation of CYP3A4 in liver disease decreased APC formation from irinotecan. SN-38 production was decreased and CES1 and 2 were down-regulated in most samples. However, in a subset of disease samples SN-38 production was relatively high because CYP3A4 activity was markedly impaired. This may account for clinical reports of increased SN-38 exposure in some patients with liver disease. Dose adjustments in cancer patients with liver disease who receive irinotecan are important and circulating SN-38 concentrations should be monitored closely.


Assuntos
Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Carboxilesterase/metabolismo , Hepatopatias/metabolismo , Microssomos Hepáticos/metabolismo , Biotransformação/efeitos dos fármacos , Camptotecina/farmacocinética , Doença Crônica , Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Humanos , Irinotecano
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