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2.
Br J Clin Pharmacol ; 86(11): 2182-2191, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32285955

RESUMO

AIMS: Single-dose pharmacokinetic (PK) studies in healthy subjects have been the design of choice for bioequivalence determination for decades. This preference has been recently extended to PK similarity studies of proposed biosimilars. However, PK similarity studies can be complicated by the effect of immunogenicity response on drug disposition. The impact is exacerbated when there is an imbalance in host-specific immunological characteristics of subjects between the test and reference groups. Such complications remain poorly understood. The purpose of this communication is to show that the impact of immunogenicity response on PK similarity determination can be critical, using adalimumab as an example. METHODS: Data for adalimumab concentrations and immunogenicity response over 10 weeks were obtained from 133 healthy subjects receiving a 40 mg dose of Humira® in a PK similarity study. Also, a population PK model with a mechanistic construct for delineating the interplay between adalimumab disposition and antidrug antibodies response was utilized to estimate via simulation the probability that a PK similarity study would fail in typical study settings. RESULTS: The simulations showed that the immunogenicity response can have a profound impact on the outcome of PK similarity determination. As such, the probability of failing to achieve the similarity conclusion increased to 51.9%, from 13.8% in the absence of immunogenicity response. CONCLUSION: This study provides a model-based framework for better understanding of how a PK similarity study can be optimally designed and for interpretation of the outcome of PK similarity determination when the drug disposition is affected in the presence of immunogenicity response.


Assuntos
Medicamentos Biossimilares , Preparações Farmacêuticas , Adalimumab/metabolismo , Método Duplo-Cego , Humanos , Equivalência Terapêutica
3.
AAPS J ; 22(2): 23, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900603

RESUMO

IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (Treg) and effector memory (TEM) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on TEM cells relative to Treg cells resulting in a non-monotonic dose-response relationship for the Treg:TEM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Células Secretoras de Insulina/efeitos dos fármacos , Modelos Biológicos , Receptores de Interleucina-17/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/administração & dosagem , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Dinâmica não Linear , Receptores de Interleucina-17/imunologia , Linfócitos T Reguladores/imunologia , Resultado do Tratamento
4.
J Endocr Soc ; 4(1): bvz015, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31993549

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) confers a very high risk of premature cardiovascular disease and is commonly caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) and very rarely in LDLR adaptor protein 1 (LDLRAP1) genes. OBJECTIVE: To determine the prevalence of pathogenic mutations in the LDLR, APOB, and PCSK9 in a cohort of subjects who met Simon Broome criteria for FH and compare the clinical characteristics of mutation-positive and mutation-negative subjects. METHODS: Ninety-three men and 107 women aged 19 to 80 years from lipid clinics in the United States and Canada participated. Demographic and historical data were collected, physical examination performed, and serum lipids/lipoproteins analyzed. Targeted sequencing analyses of LDLR and PCSK9 coding regions and exon 26 of APOB were performed followed by detection of LDLR deletions and duplications. RESULTS: Disease-causing LDLR and APOB variants were identified in 114 and 6 subjects, respectively. Of the 58 LDLR variants, 8 were novel mutations. Compared with mutation-positive subjects, mutation-negative subjects were older (mean 49 years vs 57 years, respectively) and had a higher proportion of African Americans (1% vs 12.5%), higher prevalence of hypertension (21% vs 46%), and higher serum triglycerides (median 86 mg/dL vs 122 mg/dL) levels. CONCLUSIONS: LDLR mutations were the most common cause of heterozygous FH in this North American cohort. A strikingly high proportion of FH subjects (40%) lacked mutations in known culprit genes. Identification of underlying genetic and environmental factors in mutation-negative patients is important to further our understanding of the metabolic basis of FH and other forms of severe hypercholesterolemia.

5.
JCI Insight ; 4(24)2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31852846

RESUMO

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Memória Imunológica/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-7/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Feminino , Humanos , Interleucina-7/imunologia , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do Tratamento
6.
Endocrine ; 62(2): 371-380, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30203123

RESUMO

PURPOSE: This first-in-human study assessed safety, immunogenicity, pharmacokinetics, and pharmacodynamics of RN909, a monoclonal antibody antagonist of the glucagon receptor, in type 2 diabetes (T2DM) subjects. METHODS: This study enrolled 84 T2DM subjects receiving stable metformin regimens. Forty-four subjects were randomized to receive single escalating doses of RN909 (0.3 to 6 mg/kg subcutaneously (SC), or 1 mg/kg intravenously (IV)), or placebo; 40 subjects were randomized to receive multiple escalating doses (50 to 150 mg SC) or placebo every 4 weeks for 12 weeks. RESULTS: RN909 was well tolerated; treatment-related elevated liver function tests (LFTs) were observed in 4/33 (12.1%) and 5/32 (15.6%) subjects treated with single and multiple doses, respectively, versus 1/10 (10%) and 0 in the respective placebo groups. RN909 dose-normalized AUCinf increased more than dose-proportionally following single SC doses, and after multiple doses, accumulation ratios ranged from 1.3 to 3.4. The incidence of antidrug antibodies (ADA) was 33% after single doses and 50% after multiple doses. RN909 produced dose-dependent, durable fasting plasma glucose (FPG)-lowering at day 29 (mean change -20.6 to -97.5 mg/dL) and day 85 (mean change; -27.2 to -43.5 mg/dL) after single and multiple doses, respectively. HbA1c also was reduced after single (mean change -0.30% to -1.44%), and multiple doses (-0.83% to -1.56%). CONCLUSION: RN909 was well tolerated after single and multiple doses in T2DM subjects, with diarrhea and elevated LFTs the most frequent adverse events. The appearance of ADA did not affect pharmacokinetics or efficacy. Robust lowering of FPG and HbA1c was observed.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Receptores de Glucagon/antagonistas & inibidores , Receptores de Glucagon/imunologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/imunologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Placebos , Adulto Jovem
7.
Expert Rev Clin Immunol ; 14(4): 329-336, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29504427

RESUMO

BACKGROUND: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US. METHODS: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios for PK parameters, Cmax, AUCT, and AUCinf, were within the 80.00-125.00% pre-specified equivalence window. RESULTS: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration-time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for Cmax, AUCT, and AUCinf were within 80.00-125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups. CONCLUSIONS: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles. TRIAL REGISTRATION: CT.gov identifier NCT01844804.


Assuntos
Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/farmacocinética , Infliximab/administração & dosagem , Infliximab/farmacocinética , Adolescente , Adulto , Medicamentos Biossimilares/efeitos adversos , Feminino , Humanos , Infliximab/efeitos adversos , Masculino , Pessoa de Meia-Idade
8.
Clin Ther ; 39(11): 2243-2259.e5, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29037448

RESUMO

PURPOSE: Monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) elicit significant reductions in serum LDL-C levels. However, little is known about their effects on lipoprotein particles. The purpose of this analysis was to evaluate the effect of PCSK9 inhibition with bococizumab (RN316/PF-04950615), a humanized monoclonal antibody to PCSK9, on LDL, VLDL, and HDL particle concentration and size in hypercholesterolemic subjects. METHODS: Data from 3 double-blind, placebo-controlled, randomized studies were analyzed. In study 1, a total of 67 hypercholesterolemic subjects received IV placebo or bococizumab 0.25, 0.5, 1, or 1.5 mg/kg weekly for 4 weeks. In studies 2 and 3, a total of 135 hypercholesterolemic subjects taking statins received IV placebo or bococizumab 0.25, 1, 3, or 6 mg/kg monthly for 12 weeks. Lipoprotein particle concentration and size were measured by using nuclear magnetic resonance spectroscopy. FINDINGS: Overall, the majority of subjects were men (51.9%) aged >50 years of age and of white ethnic origin. In total, 189 subjects with both baseline and 2-week posttreatment data were included in the analysis. After PCSK9 inhibition with bococizumab 0.5, 1, 1.5, 3, and 6 mg/kg, concentrations of total LDL, total small LDL, and small VLDL particles decreased significantly versus baseline and placebo (P < 0.05), whereas concentrations of HDL particles increased (P < 0.05). The size of the LDL, VLDL, and HDL particles increased after PCSK9 inhibition. Reductions in LDL-C and total LDL particle concentrations were highly correlated. IMPLICATIONS: The effect of inhibiting PCSK9 with bococizumab on lipoprotein particle concentration and size are consistent with the general mechanism of PCSK9 inhibitors in blocking PCSK9-mediated downregulation of LDL receptors. PCSK9 inhibition has the potential to provide a clinical benefit through the modulation of atherogenic lipoprotein particles in addition to LDL-C lowering, and this effect will likely be assessed in future analyses of data from cardiovascular outcomes trials of PCSK9 monoclonal antibodies that are currently being conducted. ClinicalTrials.gov identifiers: NCT01243151, NCT01342211, and NCT01350141.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Inibidores de PCSK9 , Adulto , Idoso , LDL-Colesterol/sangue , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
J Clin Pharmacol ; 57(7): 855-864, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28181260

RESUMO

Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies. First, simulations performed with this model demonstrated that the conventional method of the area-under-the-curve ratio for bioavailability determination underestimated the subcutaneous bioavailability of bococizumab due to its target-mediated disposition. Second, a covariate model component for statin effects on bococizumab PK/PD was characterized, including a description of the decreased baseline LDL-C, increased baseline PCSK9, and increased LDL-C lowering with concomitant use of statins. Last, the impact of the dosing regimens with and without a dose holiday on bococizumab's LDL-C-lowering effectiveness was shown to be predictable due to the well-characterized PK-PD relationship.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/farmacocinética , Modelos Biológicos , Pró-Proteína Convertase 9/imunologia , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Hipercolesterolemia/tratamento farmacológico , Ligação Proteica
10.
J Clin Pharmacol ; 49(6): 643-9, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19398602

RESUMO

Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate-binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs alpha and beta that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (C(max)) achieved at approximately 2 hours. The C(max) and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC(50) estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Ligação a DNA/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Adulto , Sistema Nervoso Central/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Receptores X do Fígado , Masculino , Pessoa de Meia-Idade , Receptores Nucleares Órfãos , Adulto Jovem
11.
Blood ; 103(5): 1807-14, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-14615373

RESUMO

Antibody-targeted chemotherapy with gemtuzumab ozogamicin (CMA-676, a CD33-targeted immunoconjugate of N-acetyl-gamma-calicheamicin dimethyl hydrazide [CalichDMH], a potent DNA-binding cytotoxic antitumor antibiotic) is a clinically validated therapeutic option for patients with acute myeloid leukemia (AML). Here, we describe the preclinical profile of another immunoconjugate of CalichDMH, CMC-544, targeted to CD22 expressed by B-lymphoid malignancies. CMC-544 comprises a humanized IgG4 anti-CD22 monoclonal antibody (mAb), G5/44, covalently linked to CalichDMH via an acid-labile 4-(4'-acetylphenoxy) butanoic acid (AcBut) linker. Both CMC-544 and unconjugated G5/44 bound human CD22 with subnanomolar affinity. CMC-544, but not unconjugated G5/44, exerted potent cytotoxicity against CD22+ B-cell lymphoma (BCL) cell lines (inhibitory concentration of 50%: 6-600 pM CalichDMH). CMC-544 caused a potent inhibition of growth of small but established BCL xenografts leading to cures (therapeutic index > 10). CMC-544 prevented the establishment of BCL xenografts and also caused regression of large BCLs (> 1.5 g tumor mass). In contrast, unconjugated CalichDMH, unconjugated G5/44, and an isotype-matched control conjugate, CMA-676, were ineffective against these BCL xenografts. Thus, CD22-targeted delivery of CalichDMH is a potent and effective preclinical therapeutic strategy for BCLs. The strong antitumor profile of CMC-544 supports its clinical evaluation as a treatment option for B-lymphoid malignancies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos B/biossíntese , Moléculas de Adesão Celular , Imunoconjugados/uso terapêutico , Lectinas/biossíntese , Linfoma de Células B/terapia , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Humanizados , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos B/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoglobulina G/metabolismo , Imunoterapia/métodos , Concentração Inibidora 50 , Inotuzumab Ozogamicina , Lectinas/metabolismo , Linfoma de Células B/metabolismo , Linfoma não Hodgkin/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Químicos , Transplante de Neoplasias , Ligação Proteica , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Fatores de Tempo
12.
Int J Pharm ; 250(1): 157-68, 2003 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-12480282

RESUMO

PURPOSE: Cosalane is a potent inhibitor of HIV replication with activity against a broad range of viral targets. However, oral bioavailability of this highly lipophilic compound is extremely poor (<1%). The purpose of this study is to screen a variety of permeation enhancers (cyclodextrin derivatives, cremophor EL, bile salts and mixed micelles) for their ability to enhance the transport of cosalane and its analogs/prodrugs across Caco-2 cell monolayers. METHODS: Cosalane and its different analogs/prodrugs were synthesized and their physicochemical properties were determined. Caco-2 cells were cultured at a density of 66,000 cells/cm(2) either on collagen coated clear polyester membranes or Transwell inserts. Side-bi-side diffusion cells and Transwell inserts were employed to study for the transport of cosalane and its analogs/prodrugs with various permeation enhancers across Caco-2 cell monolayers. RESULTS: Permeabilities of EH-3-39, EH-3-55 and EH-3-57 significantly improved compared to that of cosalane in the presence of bile salt, sodium desoxycholate. Among the various cyclodextrins studied, hydroxypropyl beta cyclodextrin (HP-beta-CD) and dimethyl beta cyclodextrin (DM-beta-CD) exhibited 22.3-fold and 19-fold permeability enhancement of cosalane respectively across Caco-2 cell monolayers. Sodium desoxycholate (10 mM) also showed a remarkable (105-fold) enhancement on the permeability of cosalane (P(app) 11.72+/-3.31 x 10(-6) cm/s) without causing any measurable cellular damage. Cremophor EL resulted in higher transport of 14C mannitol. The mechanism of enhancement effect can be mainly attributed to the alteration of membrane fluidity by cyclodextrin and opening of tight junctions by cremophor EL. CONCLUSIONS: Among the enhancers tested, 10 mM sodium desoxycholate and HP-beta-CD appear to be viable candidates for further development of an oral formulation of cosalane and its congeners.


Assuntos
Fármacos Anti-HIV/farmacocinética , Ácido Aurintricarboxílico/análogos & derivados , Ácido Aurintricarboxílico/farmacocinética , Glicerol/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Ácido Aurintricarboxílico/administração & dosagem , Ácido Aurintricarboxílico/química , Transporte Biológico , Células CACO-2 , Ciclodextrinas/administração & dosagem , Glicerol/administração & dosagem , Humanos , Permeabilidade , Solubilidade
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