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1.
Artigo em Inglês | MEDLINE | ID: mdl-31655295

RESUMO

Hereditary angioedema (HAE) is caused by deficiency or dysfunction in the C1 inhibitor (C1-INH) protein. C1-INH replacement therapy is used to treat patients with HAE to restore the missing or dysfunctional protein. In vitro studies showed that C1-INH inhibits prekallikrein activation and bradykinin formation in a dose-dependent manner when added to the plasma of patients with HAE. HAE is highly variable in clinical presentation, and early studies suggested that there was not a clear relationship between functional C1-INH levels and disease activity. Later, a threshold of approximately 40% functional C1-INH was identified, above which patients' risk of an attack was diminished. Long-term prophylaxis with plasma-derived C1-INH effectively reduces attack frequency and severity. Pharmacokinetic modeling shows that functional C1-INH levels are associated with the relative risk of having an attack. Subcutaneous administration of C1-INH results in consistently high levels of functional C1-INH activity, whereas intravenous administration results in periods of low trough functional C1-INH activity before the next scheduled dose, increasing the risk of an angioedema attack. These studies suggest that measurement of functional C1-INH activity may be useful as a biomarker of the risk of an attack in patients with HAE who are receiving long-term prophylaxis with plasma-derived C1-INH.

2.
J Allergy Clin Immunol Pract ; 7(6): 1793-1802.e2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30772477

RESUMO

BACKGROUND: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). OBJECTIVE: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). METHODS: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). RESULTS: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. CONCLUSIONS: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

3.
Allergy Asthma Proc ; 39(5): 365-370, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30107868

RESUMO

BACKGROUND: The first subcutaneous (SC) C1-esterase inhibitor concentrate (C1-INH) was approved by the U.S. Food and Drug Administration in June 2017 as routine prophylaxis to prevent hereditary angioedema attacks in adolescents and adults at a dose of 60 IU/kg twice weekly based on the phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) trial. OBJECTIVE: This article aimed to evaluate the relationship of the C1-INH (SC) dose regimens tested in the COMPACT trial (40 IU/kg and 60 IU/kg twice weekly) and the occurrence of adverse events (AEs). METHODS: Patients were instructed to record any AEs in their e-diary daily. Safety and tolerability were assessed based on reported AEs, including injection-site reactions (ISRs); unsolicited AEs (AEs other than ISRs); serious AEs; thrombotic, thromboembolic, anaphylactic, hypersensitivity, sepsis, and bacteremia events; inhibitory antibodies to C1-INH; and clinically significant abnormalities in laboratory assessments. Information on ISRs was specifically solicited. RESULTS: No relationship between the dose of C1-INH (SC) and the incidence of ISRs or unsolicited AEs was observed. The proportion of injections followed by at least one ISR was 12% with C1-INH (SC) 40 IU/kg versus 5% with 60 IU/kg and 6% with placebo. No ISRs were serious or led to treatment discontinuation, and all resolved. There were no anaphylaxis, thromboembolic, sepsis, or bacteremia events reported during treatment with C1-INH (SC). All hypersensitivity AEs were nonserious, and the majority were assessed as being unrelated to treatment. No inhibitory antibodies to C1-INH were observed. CONCLUSION: C1-INH (SC) is safe and well tolerated with no dose-dependent safety concerns, as demonstrated in the COMPACT trial.Clinical trial NCT01912456, www.clinicaltrials.gov.

4.
Clin Exp Allergy ; 48(10): 1325-1332, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29998524

RESUMO

BACKGROUND: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. OBJECTIVE: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA® ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. METHODS: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. RESULTS: C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour-1 , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (Ctrough ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in Ctrough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher Ctrough levels than IV dosing.

5.
CPT Pharmacometrics Syst Pharmacol ; 7(3): 158-165, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29316335

RESUMO

Subcutaneous C1-inhibitor (HAEGARDA, CSL Behring), is a US Food and Drug Administration (FDA)-approved, highly concentrated formulation of a plasma-derived C1-esterase inhibitor (C1-INH), which, in the phase III Clinical Studies for Optimal Management in Preventing Angioedema with Low-Volume Subcutaneous C1-inhibitor Replacement Therapy (COMPACT) trial, reduced the incidence of hereditary angioedema (HAE) attacks when given prophylactically. Data from the COMPACT trial were used to develop a repeated time-to-event model to characterize the timing and frequency of HAE attacks as a function of C1-INH activity, and then develop an exposure-response model to assess the relationship between C1-INH functional activity levels (C1-INH(f)) and the risk of an attack. The C1-INH(f) values of 33.1%, 40.3%, and 63.1% were predicted to correspond with 50%, 70%, and 90% reductions in the HAE attack risk, respectively, relative to no therapy. Based on trough C1-INH(f) values for the 40 IU/kg (40.2%) and 60 IU/kg (48.0%) C1-INH (SC) doses, the model predicted that 50% and 67% of the population, respectively, would see at least a 70% decrease in the risk of an attack.

6.
N Engl J Med ; 376(12): 1131-1140, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28328347

RESUMO

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).


Assuntos
Proteína Inibidora do Complemento C1/administração & dosagem , Angioedema Hereditário Tipos I e II/prevenção & controle , Adulto , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Angioedema Hereditário Tipos I e II/classificação , Humanos , Injeções Subcutâneas , Masculino , Risco , Autoadministração , Índice de Gravidade de Doença
7.
Cancer Chemother Pharmacol ; 71(5): 1219-29, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23455451

RESUMO

PURPOSE: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions. METHODS: Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach. RESULTS: PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib. CONCLUSIONS: The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.


Assuntos
Antineoplásicos/farmacocinética , Modelos Biológicos , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacocinética , Sirolimo/análogos & derivados , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cromatografia Líquida/métodos , Interações de Medicamentos , Everolimo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Compostos de Fenilureia/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/farmacocinética , Sorafenibe , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual
8.
Cancer Chemother Pharmacol ; 71(5): 1231-40, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23455452

RESUMO

PURPOSE: Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy, but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways. We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling pancreatic cancer cell growth. We investigated whether everolimus, an mTOR inhibitor, and sorafenib, a multi-kinase inhibitor, would together inhibit growth of low-passage, patient-derived pancreatic cancer xenografts in mice more efficaciously than either agent alone. METHODS: Tumor volume progression was measured following treatment with both drugs as single agents, in combination, and at multiple doses. Pharmacokinetics in tumors and other tissues was also assessed. Pharmacodynamic interactions were evaluated quantitatively. RESULTS: A 5-week regimen of daily oral doses of 10 mg/kg sorafenib and 0.5 mg/kg everolimus, alone and in combination, did not achieve significant tumor growth inhibition. Higher doses (20 mg/kg of sorafenib and 1 mg/kg of everolimus) inhibited tumor growth significantly when given alone and caused complete inhibition of growth when given in combination. Tumor volume progression was described by a linear growth model, and drug effects were described by Hill-type inhibition. Using population modeling approaches, dual-interaction parameter estimates indicated a highly synergistic pharmacodynamic interaction between the two drugs. CONCLUSIONS: The results indicate that combinations of mTOR and multi-kinase inhibitors may offer greater efficacy in pancreatic cancer than either drug alone. Drug effects upon tumor stromal elements may contribute to the enhanced anti-tumor efficacy.


Assuntos
Antineoplásicos/farmacologia , Niacinamida/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sirolimo/análogos & derivados , Animais , Antineoplásicos/administração & dosagem , Progressão da Doença , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Everolimo , Humanos , Camundongos , Camundongos SCID , Modelos Biológicos , Terapia de Alvo Molecular , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Neoplasias Pancreáticas/patologia , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Sorafenibe , Serina-Treonina Quinases TOR/antagonistas & inibidores , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
AAPS J ; 15(1): 78-84, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23054975

RESUMO

Everolimus targets the mammalian target of rapamycin, a kinase that promotes cell growth and proliferation in pancreatic cancer. Sorafenib inhibits the Raf-mitogen-activated protein kinase, vascular endothelial growth factor, and platelet-derived growth factor pathways, thus inhibiting cell growth and angiogenesis. Combinations of these two agents are under evaluation for therapy of several cancers. This study examined the effects of everolimus and sorafenib on proliferation of the pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Cell growth inhibition was evaluated in vitro for a range of concentrations of the drugs alone and in combination. Maximum inhibition capacity (I (max)) and potency (IC(50)) were determined. The data were analyzed to characterize drug interactions using two mathematical analysis techniques. The Ariens noncompetitive interaction model and Earp model were modified to accommodate alterations in the inhibition parameters of one drug in the presence of another. Sorafenib alone inhibited growth of both cell lines completely (I (max) = 1), with an IC(50) of 5-8 µM. Maximal inhibition by everolimus alone was only 40% (I (max) = 0.4) in both cell lines, with an IC(50) of 5 nM. Slight antagonistic interaction occurred between the drugs; both analytic methods estimated the interaction term Ψ as greater than 1 for both cell lines. The in vitro data for two pancreatic cancer cell lines suggest that a combination of these two drugs would be no more efficacious than the individual drugs alone, consistent with the drug interaction analysis that indicated slight antagonism for growth inhibition.


Assuntos
Antineoplásicos/farmacologia , Niacinamida/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Sirolimo/análogos & derivados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Interações de Medicamentos , Everolimo , Humanos , Niacinamida/farmacologia , Neoplasias Pancreáticas/patologia , Sirolimo/farmacologia , Sorafenibe
10.
Pharm Res ; 30(3): 707-13, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23151723

RESUMO

PURPOSE: Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of hematopoietic cells by targeting the mammalian target of rapamycin (mTOR). Sorafenib is a multikinase inhibitor that inhibits cell proliferation by arresting cells in the G0-G1 phase of the cell cycle. These agents are under investigation as combination therapy for various cancers. Because the two drugs individually inhibit lymphocyte proliferation, this study examined the effects of everolimus and sorafenib on lymphocyte proliferation in order to anticipate possible immunosuppression. METHODS: Inhibition of lymphocyte proliferation was evaluated ex vivo over a range of concentrations of these drugs, alone and in combination. Data analysis, using a population approach to characterize interactions, employed the Ariens noncompetitive interaction model, which was modified to accommodate interactions of the two drugs. RESULTS: Everolimus alone caused partial inhibition of lymphocyte proliferation, with a mean IC(50) of 4.5 nM for females and 10.5 nM in males. Sorafenib alone caused complete inhibition, with a mean IC(50) of 11.4 µM and no difference between genders. CONCLUSION: The population estimate for the interaction term was greater than 1, suggesting that the two drugs exert slight antagonism in terms of inhibition of lymphocyte proliferation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Imunossupressores/farmacologia , Linfócitos/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sirolimo/análogos & derivados , Adulto , Combinação de Medicamentos , Interações de Medicamentos , Everolimo , Feminino , Humanos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Niacinamida/farmacologia , Sirolimo/farmacologia , Sorafenibe
11.
J Pharmacokinet Pharmacodyn ; 36(5): 381-405, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19697107

RESUMO

This study derives and assesses modified equations for Indirect Response Models (IDR) for normalizing data for baseline values (R (0)) and evaluates different methods of utilizing baseline information. Pharmacodynamic response equations for the four basic IDR models were adjusted to reflect a ratio to, a change from (e.g., subtraction), or percent change relative to baseline. The original and modified IDR equations were fitted individually to simulated data sets and compared for recovery of true parameter values. Handling of baseline values was investigated using: estimation (E), fixing at the starting value (F1), and fixing at an average of starting and returning values of response profiles (F2). The performance of each method was evaluated using simulated data with variability under various scenarios of different doses, numbers of data points, type of IDR model, and degree of residual errors. The median error and inter-quartile range relative to true values were used as indicators of bias and precision for each method. Applying IDR models to normalized data required modifications in writing differential equations and initial conditions. Use of an observed/baseline ratio led to parameter estimates of k (in) = k (out) and inability to detect differences in k (in) values for groups with different R (0), whereas the modified equations recovered the true values. An increase in variability increased the %Bias and %Imprecision for each R (0) fitting method and was more pronounced for 'F1'. The overall performance of 'F2' was as good as that of 'E' and better than 'F1'. The %Bias in estimation of parameters SC(50) (IC(50)) and k (out) followed the same trend, whereas use of 'F1' or 'F2' resulted in the least bias for S (max) (I (max)). The IDR equations need modifications to directly assess baseline-normalized data. In general, Method 'E' resulted in lesser bias and better precision compared to 'F1'. With rich datasets including sufficient information on the return to baseline, Method 'F2' is reasonable. Method 'E' offers no significant advantage over 'F1' with datasets lacking information on the return to baseline phase. Handling baseline responses properly is an essential aspect of applying pharmacodynamic models.


Assuntos
Modelos Estatísticos , Farmacocinética , Farmacologia/estatística & dados numéricos , Algoritmos , Simulação por Computador , Interpretação Estatística de Dados , Humanos , Funções Verossimilhança , Software
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