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1.
Curr Med Res Opin ; 40(4): 567-574, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38407177

RESUMO

OBJECTIVE: To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. METHODS: Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. RESULTS: Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. CONCLUSION: In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions.


Type 2 diabetes is a disease of elevated blood sugar levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type of medication used to treat type 2 diabetes that work on GLP-1 receptors in the body. Semaglutide and dulaglutide are examples of GLP-1 RAs, which lower blood sugar and body weight. Tirzepatide is a newer medication, which works on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. It reduces blood sugar and body weight in people living with type 2 diabetes. Healthcare professionals and patients are interested in how switching medication from semaglutide or dulaglutide to tirzepatide might change blood glucose levels and body weight. However, because tirzepatide is a newer medication, there is not much information available on this aspect. Data from clinical trials of these medications were used to predict the effects of switching from semaglutide or dulaglutide to tirzepatide. These model-based simulations showed that switching to tirzepatide may further reduce HbA1c (a measure of blood sugar) and body weight. This may provide useful information to healthcare professionals and patients when making decisions about treatment with these medications.


Assuntos
Diabetes Mellitus Tipo 2 , Polipeptídeo Inibidor Gástrico , Receptor do Peptídeo Semelhante ao Glucagon 2 , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes , Fragmentos Fc das Imunoglobulinas , Proteínas Recombinantes de Fusão , Humanos , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas , Peso Corporal , Redução de Peso , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
2.
CPT Pharmacometrics Syst Pharmacol ; 13(3): 494-503, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38356317

RESUMO

Tirzepatide is a first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population-based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well-described by a two-compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half-life of tirzepatide was ~5 days and enabled sustained exposure with once-weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico , Receptor do Peptídeo Semelhante ao Glucagon 2 , Meia-Vida
3.
J Clin Endocrinol Metab ; 109(2): 361-369, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-37700637

RESUMO

CONTEXT: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Reação no Local da Injeção , Polipeptídeo Inibidor Gástrico/uso terapêutico , Anticorpos Neutralizantes , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1
4.
J Clin Pharmacol ; 59(2): 258-270, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30339268

RESUMO

Insulin replacement therapy is a fundamental treatment for glycemic control for managing diabetes. The engineering of insulin analogues has focused on providing formulations with action profiles that mimic as closely as possible the pattern of physiological insulin secretion that normally occurs in healthy individuals without diabetes. Hence, it may be helpful to practitioners to visualize insulin concentration profiles and associated glucose action profiles. Expanding on a previous analysis that established a pharmacokinetic (PK) model to describe typical profiles of insulin concentration over time following subcutaneous administration of various insulin formulations, the goal of the current analysis was to link the PK model to an integrated glucose-insulin (IGI) systems pharmacology model. After the pharmacokinetic-pharmacodynamic (PK-PD) model was qualified by comparing model predictions with clinical observations, it was used to project insulin (PK) and glucose (PD) profiles of common insulin regimens and dosing scenarios. The application of the PK-PD model to clinical scenarios was further explored by incorporating the impact of several hypothetical factors together, such as changing the timing or frequency of administration in a multiple-dosing regimen over the course of a day, administration of more than 1 insulin formulation, or insulin dosing adjusted for carbohydrates in meals. Visualizations of insulin and glucose profiles for commonly prescribed regimens could be rapidly generated by implementing the linked subcutaneous insulin PK-IGI model using the R statistical program (version 3.4.4) and a contemporary web-based interface, which could enhance clinical education on glycemic control with insulin therapy.


Assuntos
Glicemia/efeitos dos fármacos , Insulina/farmacologia , Insulina/farmacocinética , Adulto , Animais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Esquema de Medicação , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Pessoa de Meia-Idade , Modelos Biológicos
5.
J Clin Pharmacol ; 57(9): 1126-1137, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28394405

RESUMO

Insulin pharmacokinetics following subcutaneous administration were modeled, simulated, and displayed through an interactive and user-friendly interface to illustrate the time course of administered insulins frequently prescribed, providing a simple tool for clinicians through a straightforward visualization of insulin regimens. Pharmacokinetic data of insulin formulations with different onset and duration of action from several clinical studies, including insulin glargine, regular insulin, neutral protamine Hagedorn (NPH), insulin lispro, and premixed preparations of NPH with regular insulin (Mix 70/30), and insulin lispro protamine suspension with insulin lispro (Mix 50/50, Mix 75/25), were used to develop a predictive population pharmacokinetic model of insulins with consideration of factors such as insulin formulation, weight-based dosing, body-weight effect on volume of distribution, and administration time relative to meals, on the insulin time-action profile. The model-predicted insulin profile of each insulin was validated and confirmed to be comparable to observed data via an external validation method. Model-based simulations of clinically relevant insulin-dosing scenarios to cater to specific initial patient and prescribing conditions were then implemented with differential equations using the R statistical program (version 3.2.2). The R package Shiny was subsequently applied to build a web browser interface to execute and visualize the model simulation outputs. The application of insulin pharmacokinetic modeling enabled informative visualization of insulin time-action profiles and provided an efficient and intuitive educational tool to quickly convey and interactively explore many insulin time-action profiles to ease the understanding of insulin formulations in clinical practice.


Assuntos
Hipoglicemiantes/farmacocinética , Insulinas/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Insulinas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Drug Metab Dispos ; 43(3): 325-34, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25504564

RESUMO

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.


Assuntos
Transporte Biológico/fisiologia , Interações Medicamentosas/fisiologia , Glutamatos/metabolismo , Glutamatos/farmacocinética , Guanina/análogos & derivados , Rim/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/metabolismo , Área Sob a Curva , Linhagem Celular Tumoral , Feminino , Guanina/metabolismo , Guanina/farmacocinética , Células HeLa , Humanos , Ibuprofeno/metabolismo , Ibuprofeno/farmacocinética , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Pemetrexede
7.
J Pharmacokinet Pharmacodyn ; 40(1): 53-65, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23263772

RESUMO

Selecting dosing regimens for phase 2 studies for a novel glucokinase activator LY2599506 is challenging due to the difficulty in modeling and assessing hypoglycemia risk. A semi-mechanistic integrated glucose-insulin-glucagon (GIG) model was developed in NONMEM based on pharmacokinetic, glucose, insulin, glucagon, and meal data obtained from a multiple ascending dose study in patients with Type 2 diabetes mellitus treated with LY2599506 for up to 26 days. The series of differential equations from the NONMEM model was translated into an R script to prospectively predict 24-h glucose profiles following LY2599506 treatment for 3 months for a variety of doses and dosing regimens. The reduction in hemoglobin A1c (HbA1c) at the end of the 3-month treatment was estimated using a transit compartment model based on the simulated fasting glucose values. Two randomized phase 2 studies, one with fixed dosing and the other employing conditional dose titration were conducted. The simulation suggested that (1) Comparable HbA1c lowering with lower hypoglycemia risk occurs with titration compared to fixed-dosing; and (2) A dose range of 50-400 mg BID provides either greater efficacy or lower hypoglycemia incidence or both than glyburide. The predictions were in reasonable agreement with the observed clinical data. The model predicted HbA1c reduction and hypoglycemia risk provided the basis for the decision to focus on the dose-titration trial and for the selection of doses for the demonstration of superiority of LY2599506 to glyburide. The integrated GIG model represented a valuable tool for the evaluation of hypoglycemia incidence.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ativadores de Enzimas/uso terapêutico , Glucagon/metabolismo , Glucoquinase/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Administração Oral , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Feminino , Glucagon/sangue , Glucoquinase/sangue , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/sangue , Hipoglicemia/tratamento farmacológico , Hipoglicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Projetos de Pesquisa
8.
J Pharmacokinet Pharmacodyn ; 40(1): 67-80, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23263773

RESUMO

A proof of concept study was conducted to investigate the safety and tolerability of a novel oral glucokinase activator, LY2599506, during multiple dose administration to healthy volunteers and subjects with Type 2 diabetes mellitus (T2DM). To analyze the study data, a previously established semi-mechanistic integrated glucose-insulin model was extended to include characterization of glucagon dynamics. The model captured endogenous glucose and insulin dynamics, including the amplifying effects of glucose on insulin production and of insulin on glucose elimination, as well as the inhibitory influence of glucose and insulin on hepatic glucose production. The hepatic glucose production in the model was increased by glucagon and glucagon production was inhibited by elevated glucose concentrations. The contribution of exogenous factors to glycemic response, such as ingestion of carbohydrates in meals, was also included in the model. The effect of LY2599506 on glucose homeostasis in subjects with T2DM was investigated by linking a one-compartment, pharmacokinetic model to the semi-mechanistic, integrated glucose-insulin-glucagon system. Drug effects were included on pancreatic insulin secretion and hepatic glucose production. The relationships between LY2599506, glucose, insulin, and glucagon concentrations were described quantitatively and consequently, the improved understanding of the drug-response system could be used to support further clinical study planning during drug development, such as dose selection.


Assuntos
Ativadores de Enzimas/uso terapêutico , Glucagon/metabolismo , Glucoquinase/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Administração Oral , Adulto , Idoso , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Feminino , Glucagon/sangue , Glucoquinase/sangue , Humanos , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade
9.
Invest New Drugs ; 29(2): 323-31, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20091088

RESUMO

PURPOSE: To investigate the toxicity profile, activity, pharmacokinetics, and pharmacodynamics of pemetrexed in leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute leukemia were eligible. A phase I 3+3 design was implemented. Pemetrexed was infused intravenously (IV) over 25 min with vitamin supplementation. Courses were repeated every 3 to 4 weeks according to toxicity and efficacy. The starting dose of 900 mg/m² was escalated by approximately 33% until the dose-limiting toxicity (DLT) was determined. RESULTS: Twenty patients with acute myeloid (AML) or lymphocytic (ALL) leukemia received therapy. The main non-hematologic adverse event was liver dysfunction at several dose levels, including 2 DLTs at 3,600 mg/m². One patient with ALL (3,600 mg/m² dose level) achieved a partial response. Pemetrexed pharmacokinetics were linear with escalated dosing. Elevated plasma deoxyuridine was observed in a subset of patients following pemetrexed infusion, but was not correlated with dose levels. Changes in the nucleotide pools of circulating mononuclear cells were observed, but were variable. CONCLUSIONS: The recommended phase II dose of pemetrexed for future leukemia studies is 2,700 mg/m(2) IV over 25 min every 3 to 4 weeks with vitamin supplementation. Deoxyuridine levels did not increase with increasing pemetrexed dose, suggesting pemetrexed inhibition of thymidylate synthase (TS) may be saturated by the 900 mg/m² dose level. However, no firm conclusion can be made regarding TS saturation in tumor cells. While tolerable, pemetrexed monotherapy had limited activity in this highly refractory population. Exploration of pemetrexed in combination with other active agents in leukemia is a reasonable future endeavor.


Assuntos
Antineoplásicos/uso terapêutico , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Leucemia/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/farmacocinética , Guanina/uso terapêutico , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pemetrexede , Recidiva
10.
Clin Cancer Res ; 16(10): 2872-80, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20460481

RESUMO

PURPOSE: Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. EXPERIMENTAL DESIGN: Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. RESULTS: Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. CONCLUSIONS: No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.


Assuntos
Antineoplásicos/farmacocinética , Ascite/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glutamatos/farmacocinética , Guanina/análogos & derivados , Mesotelioma/tratamento farmacológico , Derrame Pleural Maligno/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Ascite/etiologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Glutamatos/efeitos adversos , Glutamatos/sangue , Guanina/efeitos adversos , Guanina/sangue , Guanina/farmacocinética , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pemetrexede , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Derrame Pleural Maligno/etiologia , Neoplasias Pleurais/complicações , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/patologia
11.
Clin Cancer Res ; 15(1): 346-54, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19118064

RESUMO

PURPOSE: The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. EXPERIMENTAL DESIGN: An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m(2) administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B(12), and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. RESULTS: Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the "typical" Western patient receiving 500 mg/m(2) pemetrexed +/- vitamin supplementation were 2.74 x 10(9)/L and 1.70 x 10(9)/L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m(2) pemetrexed with vitamin supplementation was 2.66 x 10(9)/L. Values for the 1,000 mg/m(2) dose with vitamin supplementation were 1.91 x 10(9)/L and 1.34 x 10(9)/L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. CONCLUSIONS: The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.


Assuntos
Ácido Fólico/uso terapêutico , Glutamatos/efeitos adversos , Glutamatos/farmacologia , Glutamatos/farmacocinética , Guanina/análogos & derivados , Neutropenia/induzido quimicamente , Vitamina B 12/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/farmacologia , Povo Asiático , Suplementos Nutricionais , Feminino , Guanina/efeitos adversos , Guanina/farmacocinética , Guanina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Pemetrexede , Fatores de Tempo , População Branca
12.
Clin Cancer Res ; 13(9): 2675-83, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17473199

RESUMO

PURPOSE: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. PATIENTS AND METHODS: Patients received a 10-min infusion of 600 to 14,00 mg/m(2) pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. RESULTS: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m(2) were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. CONCLUSIONS: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m(2) in LPT patients and 800 mg/m(2) in HPT patients, irrespective of the type of vitamin supplementation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Guanina/análogos & derivados , Complexo Vitamínico B/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Ácido Fólico/uso terapêutico , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/farmacocinética , Humanos , Infusões Parenterais , Masculino , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pemetrexede , Complexo Vitamínico B/uso terapêutico
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