RESUMO
BACKGROUND: Ezabenlimab (BI 754091) is a humanised monoclonal antibody targeting programmed cell death protein-1. We report results from open-label, dose-escalation/expansion, Phase I trials that evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics and antitumour activity of ezabenlimab at the recommended Phase II dose in patients with selected advanced solid tumours. STUDY DESIGN: Study 1381.1 (NCT02952248) was conducted in Canada, the United Kingdom and the United States. Study 1381.4 (NCT03433898) was conducted in Japan. Study 1381.3 (NCT03780725) was conducted in the Netherlands. The primary endpoints were: number of patients experiencing dose-limiting toxicities (DLTs) in the first cycle (dose escalation parts), number of patients with DLTs during the entire treatment period and objective response (dose expansion part of Study 1381.1). RESULTS: Overall, 117 patients received ezabenlimab intravenously every 3 weeks (80 mg, n = 3; 240 mg, n = 111; 400 mg, n = 3). No DLTs were observed and the MTD was not reached. Fifty-eight patients (52.3%) had grade ≥ 3 adverse events, most commonly anaemia (10.8%) and fatigue (2.7%). In 111 assessed patients treated with ezabenlimab 240 mg, disease control rate was 56.8% and objective response rate was 16.2%. Three patients had complete response; at data cut-off (November 2021) one remained in response and was still receiving ongoing treatment (duration of response [DoR]: 906 days). Partial responses occurred across several tumour types; DoR ranged from 67 to 757 days. CONCLUSIONS: Ezabenlimab was well tolerated and associated with durable antitumour activity in multiple solid tumours, comparable to other immune checkpoint inhibitors in similar patient populations and treatment settings.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Canadá , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
PURPOSE: Although lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [89Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration. METHODS: Patients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3). After baseline tumor biopsy and [18F]FDG-PET, patients were given 240 mg of BI 754091, followed 8 days later by administration of [89Zr]Zr-BI 754111 (37 MBq, 4 mg). PET scans were performed 2 h, 96 h, and 144 h post-injection. To investigate target specificity, a second tracer administration was given two weeks later, this time with pre-administration of 40 (N = 3) or 600 mg (N = 3) unlabeled BI 754111, followed by PET scans at 96 h and 144 h post-injection. Tumor immune cell infiltration was assessed by immunohistochemistry and RNA sequencing. RESULTS: Tracer uptake in tumors was clearly visible at the 4-mg mass dose (tumor-to-plasma ratio 1.63 [IQR 0.37-2.89]) and could be saturated by increasing mass doses (44 mg: 0.67 [IQR 0.50-0.85]; 604 mg: 0.56 [IQR 0.42-0.75]), demonstrating target specificity. Tumor uptake correlated to immune cell-derived RNA signatures. CONCLUSIONS: [89Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03780725. Registered 19 December 2018.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Humanos , Radioisótopos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Tomografia por Emissão de Pósitrons/métodos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Zircônio , Linhagem Celular TumoralRESUMO
Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus protease. It inhibits multiple cytochrome P-450 enzymes and multiple membrane transporters. The objective of this study was to evaluate the effect of steady-state faldaprevir on the pharmacokinetics (PK) of a single dose of atorvastatin or rosuvastatin. In this single-center, open-label, fixed-sequence crossover study, 33 healthy adult male and female volunteers were given either atorvastatin 10 mg (n = 16) or rosuvastatin 10 mg (n = 17) on day 1. Subjects subsequently received 240 mg twice daily of faldaprevir (loading dose) on day 5, followed by 240 mg faldaprevir once daily from day 6 to day 10, with an additional single dose of atorvastatin (10 mg) or rosuvastatin (10 mg) given on day 10. PK samples for the statins were collected on days 1-3 and days 10-12. Concomitant administration with faldaprevir led to approximately 9-fold and 34-fold increases in AUC0-∞ and Cmax , respectively, of atorvastatin and approximately 15-fold and 33-fold increases in AUC0-∞ and Cmax , respectively, of rosuvastatin, compared with the statins given alone. Exposure to the major metabolites (ortho-hydroxyatorvastatin and N-desmethylrosuvastatin) was increased to a similar magnitude as that of the parent compounds. The marked drug-drug interaction observed is most likely related to the inhibitory effects of faldaprevir on transporters, particularly hepatic uptake transporters such as OTAP1B1 and OATP1B3. Given the significant increase in exposure to statins in healthy volunteers, coadministration of faldaprevir with statins should be avoided.
Assuntos
Antivirais/farmacologia , Atorvastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Oligopeptídeos/farmacologia , Rosuvastatina Cálcica/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Tiazóis/farmacologia , Adulto , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Atorvastatina/efeitos adversos , Atorvastatina/análogos & derivados , Atorvastatina/sangue , Estudos Cross-Over , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Prolina/análogos & derivados , Pirimidinas/sangue , Quinolinas , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/sangue , Inibidores de Serina Proteinase/efeitos adversos , Sulfonamidas/sangue , Tiazóis/efeitos adversosRESUMO
OBJECTIVES: This study was conducted to investigate the effect of food and coadministration of omeprazole on the relative bioavailability (BA) of faldaprevir (FDV). METHODS: Fifteen healthy participants participated in this open-label, randomized, three-way cross-over study. Faldaprevir was administered as a 240 mg single dose during fasting state, following intake of a high-fat breakfast, or following omeprazole 40 mg q.d. dosing for 5 days. PK samples were collected on the day of faldaprevir administration. KEY FINDINGS: We found geometric mean (gMean) AUC0-∞ values for faldaprevir of 48 200, 37 900 and 36 000 ng h/ml under the fed, fasted and omeprazole coadministration conditions respectively. Similarly, gMean Cmax values for faldaprevir were 2600, 2030, 1920 ng/ml under the same respective conditions. The adjusted gMean ratio between the fed and fasted condition was approximately 120% for both AUC0-∞ and Cmax , while the ratio of omeprazole coadministration to fasted condition was approximately 94%. Faldaprevir was safe and well tolerated in the study. CONCLUSIONS: Administration of a single dose of 240 mg faldaprevir after high-fat breakfast led to a modest, clinically irrelevant increase in faldaprevir exposure, while coadministration of omeprazole did not influence faldaprevir exposure.
Assuntos
Antivirais/administração & dosagem , Antivirais/farmacocinética , Interações Alimento-Droga , Hepacivirus/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Omeprazol/administração & dosagem , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Adulto , Ácidos Aminoisobutíricos , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Hepacivirus/enzimologia , Humanos , Leucina/análogos & derivados , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Omeprazol/efeitos adversos , Prolina/análogos & derivados , Inibidores da Bomba de Prótons/efeitos adversos , Quinolinas , Fatores de Risco , Proteínas não Estruturais Virais/metabolismo , Adulto JovemRESUMO
The effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC(0-24,ss)), the steady-state maximum concentration of the drug in plasma (C(max,ss)), and the steady-state concentration of the drug in plasma at 24 h (C(24,ss)) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone- and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.).
Assuntos
Combinação Buprenorfina e Naloxona/farmacocinética , Metadona/farmacocinética , Oligopeptídeos/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Adulto , Ácidos Aminoisobutíricos , Buprenorfina/análogos & derivados , Buprenorfina/sangue , Combinação Buprenorfina e Naloxona/sangue , Interações Medicamentosas , Feminino , Humanos , Leucina/análogos & derivados , Masculino , Metadona/sangue , Pessoa de Meia-Idade , Oligopeptídeos/farmacologia , Prolina/análogos & derivados , Quinolinas , Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Tiazóis/farmacologia , Adulto JovemRESUMO
Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor. Faldaprevir is known to inhibit P-glycoprotein, CYP3A4, and UDP-glucuronosyltransferase 1A1. This study evaluated the effect of steady-state 240 mg faldaprevir on the pharmacokinetics (PK) of an oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG) in healthy premenopausal women. In period 1, subjects received EE/LNG once daily (QD) for 14 days. Blood samples were taken on days 1, 11, and 12, with intensive PK blood sampling for EE and LNG on day 13. In period 2, subjects received EE-LNG QD and 240 mg faldaprevir QD on days 14 to 21 (240 mg faldaprevir twice daily on day 14). Blood samples were taken on days 14, 19, and 20, with PK profiling samples obtained for EE and LNG on day 21. A total of 15/16 subjects completed the study. Overall, EE and LNG exposure (assessed by the area under the curve) was approximately 1.4-fold higher when EE and LNG were coadministered with faldaprevir than when administered alone. Median t1/2 (terminal half-life in plasma at steady state) values were prolonged for both EE (2.4 h longer) and LNG (4.7 h longer) when EE and LNG were coadministered with faldaprevir. The mean oral clearance and apparent volume of distribution of both EE and LNG were lower (â¼ 30%) when EE and LNG were coadministered with faldaprevir. Coadministration of faldaprevir and an oral contraceptive resulted in a moderate increase in exposure to both EE and LNG. However, this increase was not considered clinically meaningful, and no dose adjustment of oral contraceptives was deemed necessary. (This study has been registered at ClinicalTrials.gov under registration number NCT01570244.).
Assuntos
Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Oligopeptídeos/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Adolescente , Adulto , Ácidos Aminoisobutíricos , Área Sob a Curva , Bilirrubina/sangue , Anticoncepcionais Orais Combinados/administração & dosagem , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Etinilestradiol/sangue , Feminino , Meia-Vida , Humanos , Leucina/análogos & derivados , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Levanogestrel/sangue , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Prolina/análogos & derivados , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacocinética , Quinolinas , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Proteínas não Estruturais Virais/antagonistas & inibidores , Adulto JovemRESUMO
Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.).
Assuntos
Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacocinética , Insuficiência Renal/fisiopatologia , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Adulto , Idoso , Ácidos Aminoisobutíricos , Disponibilidade Biológica , Feminino , Meia-Vida , Hepatite C/tratamento farmacológico , Humanos , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Prolina/análogos & derivados , Quinolinas , Tiazóis/uso terapêuticoRESUMO
Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of ≥7 days: (A) twice-daily raltegravir (Days 1-3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2-5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUC(τ,ss) and C(max,ss), respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure.
Assuntos
Inibidores de Integrase de HIV/farmacocinética , Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Raltegravir Potássico/farmacocinética , Tiazóis/farmacologia , Adulto , Ácidos Aminoisobutíricos , Esquema de Medicação , Interações Medicamentosas/genética , Feminino , Genótipo , Glucuronosiltransferase/genética , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Voluntários Saudáveis , Humanos , Leucina/análogos & derivados , Masculino , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Prolina/análogos & derivados , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Quinolinas , Raltegravir Potássico/administração & dosagem , Raltegravir Potássico/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients. METHODS: In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated. RESULTS: Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined. CONCLUSIONS: No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Oligopeptídeos/farmacologia , Organofosfonatos/farmacologia , Inibidores de Proteases/farmacologia , Ritonavir/farmacologia , Sulfonamidas/farmacologia , Tiazóis/farmacologia , Adenina/farmacologia , Adenina/uso terapêutico , Adulto , Alcinos , Ácidos Aminoisobutíricos , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Benzoxazinas/uso terapêutico , Coinfecção , Ciclopropanos , Darunavir , Interações Medicamentosas , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Voluntários Saudáveis , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Prolina/análogos & derivados , Inibidores de Proteases/uso terapêutico , Quinolinas , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Tenofovir , Tiazóis/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: The POTENT trial compared the safety and efficacy of tipranavir/ritonavir (TPV/r) to darunavir/ritonavir (DRV/r), each with an optimized background regimen (OBR) in triple-class experienced HIV-1-infected patients with resistance to more than one protease inhibitor (PI). METHODOLOGY/PRINCIPAL FINDINGS: POTENT was a prospective, open-label study of triple-class (PI, non-nucleoside reverse transcriptase inhibitors [NNRTI], nucleoside reverse transcriptase inhibitors [NRTI]), treatment-experienced, HIV-positive patients. Subjects were randomized to either TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) on a genotype-guided, investigator-selected OBR. CD4+ counts and HIV viral loads were assayed at key timepoints. The primary endpoint was time to virologic failure (viral load ≥500copies/mL). POTENT was prematurely terminated due to slow enrollment. Thirty-nine patients were treated with either TPV/r (n = 19) or DRV/r (n = 20); 82% were male, 77% White, with mean age of 43.6 years. Mean baseline HIV RNA was 3.9 log(10) copies/mL. Median prior antiretrovirals was 11, with no prior raltegravir or maraviroc exposure. Raltegravir was the most common novel class agent in the OBRs (n = 14 TPV/r; n = 12 DRV/r). In both groups, patients achieved mean viral load decreases ≥2 log(10) copies/mL by week 8, and by week 12 mean CD4+ counts rose by 40-50 cells/mm3. Total observation time was 32 weeks. Drug-related adverse events were reported in 21% (TPV/r) and 25% (DRV/r) of patients. CONCLUSIONS/SIGNIFICANCE: TPV/r- and DRV/r-based regimens showed similar short-term safety and efficacy. These data support the use of next-generation PIs such as tipranavir or darunavir with novel class antiretroviral agents (integrase inhibitors, CCR5 antagonists, or fusion inhibitors).
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1 , Piridinas/administração & dosagem , Pironas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Darunavir , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/imunologia , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Piridinas/efeitos adversos , Pironas/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Carga Viral/imunologiaRESUMO
Three separate controlled, two-period studies with healthy volunteers assessed the pharmacokinetic interactions between tipranavir-ritonavir (TPV/r) in a 500/200-mg dose and 500 mg of clarithromycin (CLR), 100 mg of fluconazole (FCZ), or 150 mg of rifabutin (RFB). The CLR study was conducted with 24 subjects. The geometric mean ratios (GMR) and 90% confidence intervals (90% CI; given in parentheses) of the areas under the concentration-time curve (AUC), the maximum concentrations of the drugs in serum (C(max)), and the concentrations in serum at 12 h postdose (Cp12h) for multiple-dose TPV/r and multiple-dose CLR, indicating the effect of TPV/r on the CLR parameters, were 1.19 (1.04-1.37), 0.95 (0.83-1.09), and 1.68 (1.42-1.98), respectively. The formation of the metabolite 14-OH-CLR was decreased by 95% in the presence of TPV, and the TPV AUC increased 66% compared to that for human immunodeficiency virus (HIV)-negative historical controls. The FCZ study was conducted with 20 subjects. The GMR (and 90% CI) of the AUC, C(max), and Cp24h, indicating the effect of multiple-dose TPV/r on the multiple-dose FCZ parameters, were 0.92 (0.88-0.95), 0.94 (0.91-0.98), and 0.89 (0.85-0.92), respectively. The TPV AUC increased by 50% compared to that for HIV-negative historical controls. The RFB study was conducted with 24 subjects. The GMR (and 90% CI) of the AUC, C(max), and Cp12h for multiple-dose TPV/r and single-dose RFB, indicating the effect of TPV/r on the RFB parameters, were 2.90 (2.59-3.26), 1.70 (1.49-1.94), and 2.14 (1.90-2.41), respectively. The GMR (and 90% CI) of the AUC, C(max), and Cp12h of TPV/r and RFB with 25-O-desacetyl-RFB were 4.33 (3.86-4.86), 1.86 (1.63-2.12), and 2.76 (2.44-3.12), respectively. Coadministration of TPV with a single dose of RFB resulted in a 16% increase in the TPV Cp12h compared to that for TPV alone. In the general population, no dose adjustments are necessary for the combination of TPV/r and CLR or FCZ. Combining TPV/r with RFB should be done with caution, while toxicity and RFB drug levels should be monitored. Study medications were generally well-tolerated in these studies.