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1.
Cancer Chemother Pharmacol ; 78(6): 1131-1141, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27783139

ABSTRACT

PURPOSE: Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers. METHODS: Data were pooled from six clinical studies-serial pharmacokinetics from two healthy volunteer studies (n = 58) and sparse pharmacokinetics from four NSCLC studies (n = 152)-for a nonlinear mixed effects modeling (NONMEM v7.2) analysis. Demographics, smoking status, liver and renal function status, and Eastern Cooperative Oncology Group performance status were tested as covariates. RESULTS: There were 83 (40%) active smokers and 56 (27%) ex-smokers in the pooled dataset. Axitinib pharmacokinetics was adequately described with a linear, two-compartment model with a lagged first-order absorption. Final parameter estimates (inter-individual variability) were 16.1 L/h (59.1%) and 45.3 L (54.4%) for systemic clearance (CL) and central volume of distribution (Vc), respectively. Smoking status was found not to alter CL or Vc. Asian ethnicity and body weight were significant covariates for Vc, but were not considered clinically relevant since individual values of Vc for Asians were within the range of non-Asians. CONCLUSIONS: Based on this analysis, smoking status does not affect area under plasma concentration-time curve, and thus no dose adjustment is required for smokers.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Imidazoles/pharmacokinetics , Indazoles/pharmacokinetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacokinetics , Smoking/metabolism , Adult , Aged , Aged, 80 and over , Axitinib , Carcinoma, Non-Small-Cell Lung/metabolism , Female , Humans , Lung Neoplasms/metabolism , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological
2.
Br J Clin Pharmacol ; 77(3): 480-92, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23834452

ABSTRACT

AIMS: Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers. METHODS: Plasma concentration-time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19). RESULTS: A two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (Vc ), absorption rate constant (ka ) and absolute bioavailability (F) were 17.0 l h(-1) , 45.3 l, 0.523 h(-1) and 46.5%, respectively. With axitinib Form IV, ka and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected Vc , but the effect was within the estimated interindividual variability for Vc . CONCLUSIONS: The analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. Vc was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted.


Subject(s)
Angiogenesis Inhibitors/pharmacokinetics , Imidazoles/pharmacokinetics , Indazoles/pharmacokinetics , Models, Biological , Protein Kinase Inhibitors/pharmacokinetics , Adult , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/blood , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Axitinib , Biotransformation , Body Weight , Clinical Trials, Phase I as Topic , Cytochrome P-450 CYP2C19 , Drug Dosage Calculations , Female , Genotype , Glucuronosyltransferase/genetics , Glucuronosyltransferase/metabolism , Healthy Volunteers , Humans , Imidazoles/administration & dosage , Imidazoles/blood , Indazoles/administration & dosage , Indazoles/blood , Male , Middle Aged , Nonlinear Dynamics , Pharmacogenetics , Phenotype , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/blood , Young Adult
3.
Drug Metab Dispos ; 32(7): 689-98, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15205383

ABSTRACT

Metabolism and disposition of capravirine, a new non-nucleoside reverse transcriptase inhibitor, were studied in healthy male volunteers who were randomly divided into two groups (A and B) with five subjects in each group. Group A received a single oral dose of [(14)C]capravirine (1400 mg) and group B received multiple oral doses of ritonavir (100 mg), followed by a single oral dose of [(14)C]capravirine (1400 mg). Mean total recoveries of radioactivity for groups A and B were 86.3% and 79.0%, respectively, with a mean cumulative recovery in urine comparable with that in feces for both groups. Excretion of unchanged capravirine was negligible in urine and low in feces for both groups. The results suggest that capravirine was well absorbed, with metabolism as the principal mechanism of clearance. Capravirine underwent extensive metabolism to a variety of metabolites via oxygenations (mono-, di-, tri-, and tetra-) representing the predominant pathway, glucuronidation, and sulfation in humans. No useful plasma profiles of group A were obtained due to extremely low levels of plasma radioactivity. Analysis of group B plasma indicated that unchanged capravirine was the major radiochemical component, with three monooxygenated products and a glucuronide of capravirine as the major circulating metabolites. Nineteen metabolites were identified using liquid chromatography-multistage ion-trap mass spectrometry methodologies. In summary, coadministration of low-dose ritonavir (a potent CYP3A4 inhibitor) drastically decreased the levels of sequential oxygenated metabolites and markedly increased the levels of the parent drug and primary oxygenated metabolites overall in plasma, urine, and feces.


Subject(s)
Anti-HIV Agents/metabolism , Cytochrome P-450 Enzyme Inhibitors , Reverse Transcriptase Inhibitors/metabolism , Ritonavir/pharmacology , Administration, Oral , Anti-HIV Agents/blood , Carbon Radioisotopes , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A , Drug Interactions , Feces/chemistry , Humans , Imidazoles , Male , Reverse Transcriptase Inhibitors/blood , Spectrometry, Mass, Electrospray Ionization , Sulfur Compounds , Time Factors
4.
Semin Oncol ; 31(6 Suppl 13): 16-35, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15717736

ABSTRACT

Encapsulation of doxorubicin in polyethylene glycol-coated liposomes (Doxil/Caelyx [PLD]), was developed to enhance the safety and efficacy of conventional doxorubicin. The liposomes alter pharmacologic and pharmacokinetic parameters of conventional doxorubicin so that drug delivery to the tumor is enhanced while toxicity normally associated with conventional doxorubicin is decreased. In animals and humans, pharmacokinetic advantages of PLD include an increased area under the plasma concentration-time curve, longer distribution half-life, smaller volume of distribution, and reduced clearance. In preclinical models, PLD produced remission and cure against many cancers including tumors of the breast, lung, ovaries, prostate, colon, bladder, and pancreas, as well as lymphoma, sarcoma, and myeloma. It was also found to be effective as adjuvant therapy. In addition, it was found to cross the blood-brain barrier and induce remission in tumors of the central nervous system. Increased potency over conventional doxorubicin was observed and, in contrast to conventional doxorubicin, PLD was equally effective against low- and high-growth fraction tumors. The combination of PLD with vincristine or trastuzumab resulted in additive effects and possible synergy. PLD appeared to overcome multidrug resistance, possibly as the result of increased intracellular concentrations and an interaction between the liposome and P-glycoprotein function. On the basis of pharmacokinetic and preclinical studies, PLD, either alone or as part of combination therapy, has potential applications to treat a variety of cancers.


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Doxorubicin/administration & dosage , Animals , Antibiotics, Antineoplastic/pharmacokinetics , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cetuximab , Doxorubicin/pharmacokinetics , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Drug Synergism , Humans , Liposomes/pharmacokinetics , Models, Animal , Trastuzumab
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