RESUMO
Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells with demonstrated efficacy in phase 2 and 3. Temsavir is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate; its metabolism is mediated by esterase and CYP3A4 enzymes. Drugs that induce or inhibit CYP3A, P-glycoprotein, and BCRP may affect temsavir concentrations. Understanding potential drug-drug interactions (DDIs) following fostemsavir coadministration with antiretrovirals approved for HIV-1-infected treatment-experienced patients, including darunavir plus cobicistat (DRV/c) or DRV plus low-dose ritonavir (DRV/r) and etravirine, is clinically relevant. Open-label, single-sequence, multiple-dose, multicohort DDI studies were conducted in healthy participants (n = 46; n = 32). The primary objective was to assess the effects of DRV/r, etravirine, DRV/r plus etravirine, cobicistat, and DRV/c on temsavir systemic exposures; safety was a secondary objective. Compared with fostemsavir alone, coadministration with DRV/r increased the temsavir maximum observed plasma concentration (Cmax), area under the concentration-time curve in one dosing interval (AUCtau), and plasma trough concentration (Ctau) by 52%, 63%, and 88%, respectively, while etravirine decreased the temsavir Cmax, AUCtau, and Ctau by â¼50% each. DRV/r plus etravirine increased the temsavir Cmax, AUCtau, and Ctau by 53%, 34%, and 33%, respectively. Compared with fostemsavir alone, coadministration with cobicistat increased the temsavir Cmax, AUCtau, and Ctau by 71%, 93%, and 136%, respectively; DRV/c increased the temsavir Cmax, AUCtau, and Ctau by 79%, 97%, and 124%, respectively. Fostemsavir with all combinations was generally well tolerated. No dose adjustment is required for fostemsavir when coadministered with strong CYP3A inhibitors, P-glycoprotein inhibitors, and modest inducers, including regimens with DRV/r, DRV/c, cobicistat, etravirine, and DRV/r plus etravirine based on the therapeutic margin for temsavir (ClinicalTrials.gov registration no. NCT02063360 and NCT02277600).
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Pró-Fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Fármacos Anti-HIV/uso terapêutico , Estudos Clínicos como Assunto , Cobicistat/farmacocinética , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Voluntários Saudáveis , Humanos , Proteínas de Neoplasias , Nitrilas , Organofosfatos , Piperazinas , Pró-Fármacos/farmacologia , Pirimidinas , RitonavirRESUMO
AIMS: Regional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first-in-class attachment inhibitor that binds HIV-1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R-, S- and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered. METHODS: Study 206216 (NCT02666001) was a Phase I, open-label study, assessing the effect of FTR 600 mg (extended-release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non-HIV-infected participants on stable maintenance therapy with MET (40-120 mg; n = 16) or BUP plus naloxone (8-24 mg plus 2-6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales. RESULTS: Following coadministration with FTR, dose-normalized MET (R-, S- and total) exposures (maximum concentration in plasma, area under the plasma concentration-time curve over the dosing interval and concentration in plasma at 24 hours) increased 9-15% and BUP and norBUP exposures increased 24-39%. The 90% confidence interval ranges for MET (1.01-1.21) and BUP and norBUP (1.03-1.69) were within respective no-effect ranges (0.7-1.43 and 0.5-2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen. CONCLUSIONS: FTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Adulto , Fármacos Anti-HIV/uso terapêutico , Combinação Buprenorfina e Naloxona/farmacologia , Combinação Buprenorfina e Naloxona/uso terapêutico , Estudos Cross-Over , Interações Medicamentosas , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , HIV-1/isolamento & purificação , Humanos , Masculino , Metadona/farmacologia , Metadona/uso terapêutico , Pessoa de Meia-Idade , Antagonistas de Entorpecentes/uso terapêutico , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/complicações , Organofosfatos/farmacologia , Organofosfatos/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: GSK3532795 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor that targets HIV-1 Gag, inhibiting the final protease cleavage between capsid protein p24 and spacer protein-1, producing immature, noninfectious virions. METHODS: This was a phase 2a, randomized, dose-ranging multipart trial. In part A, subtype B-infected subjects received 5-120 mg GSK3532795 (or placebo) once daily for 10 days. In part B, subtype B-infected subjects received 40 mg or 80 mg GSK3532795 once daily with atazanavir (ATV) with or without (±) ritonavir (RTV) or standard of care (SOC) (tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and ATV/RTV 300 mg/100 mg) for 28 days. In part C, subtype C-infected subjects received 40 mg or 120 mg GSK3532795 once daily (or placebo) for 10 days. Endpoints included change in HIV-1 RNA from baseline on day 11 (parts A/C) or day 29 (part B). RESULTS: A >1 log10 median decline in HIV-1 RNA was achieved by day 11 in parts A and C and day 29 in part B at GSK3532795 doses ≥40 mg; part B subjects receiving GSK3532795 and ATV ± RTV achieved similar declines to those receiving SOC. Median of the maximum declines in HIV-1 RNA were similar for the 40-120 mg once-daily dose groups regardless of baseline Gag polymorphisms. There were no deaths, adverse events leading to discontinuation, or serious adverse events. CONCLUSIONS: GSK3532795 demonstrated potent antiviral activity against subtype B (monotherapy or with ATV ± RTV) and subtype C, and was generally well tolerated, which supported continued development of GSK3532795 in subjects with HIV-1 subtype B or subtype C. CLINICAL TRIALS REGISTRATION: NCT01803074.
Assuntos
Sulfato de Atazanavir , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV , Ritonavir , Adulto , Sulfato de Atazanavir/administração & dosagem , Sulfato de Atazanavir/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/uso terapêutico , Adulto JovemRESUMO
Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor approved worldwide for the treatment of HIV in adults and children over 3 years of age or weighing over 10 kg. Only recently EFV was approved in children over 3 months and weighing at least 3.5 kg in the United States and the European Union. The objective of this analysis was to support the selection of an appropriate dose for this younger pediatric population and to explore the impact of CYP2B6 genetic polymorphisms on EFV systemic exposures. A population pharmacokinetic (PPK) model was developed using data from three studies in HIV-1-infected pediatric subjects (n = 168) and one study in healthy adults (n = 24). The EFV concentration-time profile was best described by a two-compartment model with first-order absorption and elimination. Body weight was identified as a significant predictor of efavirenz apparent clearance (CL), oral central volume of distribution (VC), and absorption rate constant (Ka). The typical values of efavirenz apparent CL, VC, oral peripheral volume of distribution (VP), and Ka for a reference pediatric patient were 4.8 liters/h (4.5 to 5.1 liters/h), 84.9 liters (76.8 to 93.0 liters), 287 liters (252.6 to 321.4 liters), and 0.414 h(-1) (0.375 to 0.453 h(-1)), respectively. The final model was used to simulate steady-state efavirenz concentrations in pediatric patients weighing <10 kg to identify EFV doses that produce comparable exposure to adult and pediatric patients weighing ≥10 kg. Results suggest that administration of EFV doses of 100 mg once daily (QD) to children weighing ≥3.5 to <5 kg, 150 mg QD to children weighing ≥5 to <7.5 kg, and 200 mg QD to children weighing ≥7.5 to <10 kg produce exposures within the target range. Further evaluation of the impact of CYP2B6 polymorphisms on EFV PK showed that the identification of CYP2B6 genetic status is not predictive of EFV exposure and thus not informative to guide pediatric dosing regimens.
Assuntos
Fármacos Anti-HIV/farmacocinética , Benzoxazinas/farmacocinética , Citocromo P-450 CYP2B6/genética , Infecções por HIV/sangue , Modelos Estatísticos , Inibidores da Transcriptase Reversa/farmacocinética , Adolescente , Adulto , Alcinos , Fármacos Anti-HIV/sangue , Área Sob a Curva , Benzoxazinas/sangue , Disponibilidade Biológica , Peso Corporal , Pré-Escolar , Ensaios Clínicos como Assunto , Ciclopropanos , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Expressão Gênica , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Lactente , Masculino , Polimorfismo Genético , Inibidores da Transcriptase Reversa/sangueRESUMO
OBJECTIVES: To characterize the pharmacokinetics and inhibitory quotient (IQ) of atazanavir/ritonavir- and lopinavir/ritonavir-based regimens in HIV-infected, treatment-naive patients. METHODS: The CASTLE Study was a 96 week randomized study comparing 300 mg of atazanavir once daily with 400 mg of lopinavir twice daily, each with low-dose ritonavir (100 mg) plus tenofovir disoproxil fumarate/emtricitabine in HIV-infected, treatment-naive patients. A subset of patients participated in an intensive pharmacokinetic evaluation of the atazanavir regimen (n = 18) and the lopinavir regimen (n = 21) at week 4. (ClinicalTrials.gov NCT00272779) RESULTS: Atazanavir geometric mean (CV%) C(max), C(min) and AUC over the dosing interval were 2897 (46) ng/mL, 526 (57) ng/mL and 28â605 (46) ngâ·âh/mL, respectively, and for lopinavir they were 10â655 (51) ng/mL, 5944 (68) ng/mL and 90â946 (59) ngâ·âh/mL, respectively. The baseline protein binding-adjusted 90% effective concentration (PBA-EC(90)) was 16 (44) ng/mL for atazanavir and 173 (44) ng/mL for lopinavir. The median IQ (min, max), calculated as the ratio of C(min) to individual baseline PBA-EC(90), was 35 (4, 77) for atazanavir and 34 (11, 129) for lopinavir. The C(max) for ritonavir was 46% higher, while AUC(0-24) and C(min) were 16% and 72% lower in the atazanavir regimen compared with the lopinavir regimen. Tenofovir exposures were similar with both treatments. CONCLUSIONS: Atazanavir (300 mg once daily) and lopinavir (400 mg twice daily), each with low-dose ritonavir, achieved similar IQs in HIV-infected, treatment-naive patients. These results are supportive of the main clinical finding of the CASTLE Study, that the atazanavir/ritonavir-based regimen is non-inferior in antiviral efficacy to the lopinavir/ritonavir-based regimen in antiretroviral-naive subjects.
Assuntos
Lopinavir/farmacologia , Lopinavir/farmacocinética , Oligopeptídeos/farmacologia , Oligopeptídeos/farmacocinética , Piridinas/farmacologia , Piridinas/farmacocinética , Ritonavir/farmacologia , Ritonavir/farmacocinética , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade/métodos , Sulfato de Atazanavir , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Emtricitabina , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lopinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Organofosfonatos/administração & dosagem , Piridinas/administração & dosagem , Ritonavir/administração & dosagem , TenofovirRESUMO
BACKGROUND: Two clinical studies (PRINCE-1 and -2) in HIV-1-infected children assessed the safety, efficacy and pharmacokinetics of dual nucleos(t)ide reverse transcriptase inhibitor background therapy plus once-daily atazanavir (ATV) powder formulation boosted with ritonavir (ATV + RTV). Here, we present a combined analysis of ATV pharmacokinetics and pharmacodynamics across these studies. METHODS: Intensive 24-hour pharmacokinetic profiles at steady state compared ATV exposures (area under the concentration-time curve in one dosing interval) in 5 ATV + RTV baseline weight-band dosing categories, with historic data in adults receiving ATV + RTV 300/100 mg capsules. Repeated ATV Ctrough measurements over 48 weeks explored relationships between ATV composite Ctrough quartiles (CCQs) with virologic efficacy and key safety parameters. RESULTS: Of 146 children included in this combined analysis, 49.3% were male, 56.8% were Black/African American and 62.3% were antiretroviral experienced. Proportions with HIV-1 RNA <50 copies/mL at week 48 were 13/32, 24/32, 19/32 and 13/28 in the lowest through highest ATV CCQs, respectively. Mean changes from baseline in total bilirubin at week 48 were +0.3, +0.5, +0.6 and +1.0 mg/dL in the lowest through highest ATV CCQs, respectively. Corresponding proportions with adverse events of hyperbilirubinemia by week 48 were 1/36, 4/36, 5/36 and 13/35, respectively. Changes from baseline in total amylase or electrocardiogram parameters and adverse events of diarrhea did not vary by ATV CCQs. CONCLUSIONS: Weight-band dosing of ATV + RTV plus optimized dual nucleos(t)ide reverse transcriptase inhibitors in young HIV-1-infected children achieved similar ATV exposure to that in adults; no unexpected safety findings occurred, and with the exception of lower virologic suppression in the lowest ATV CCQ, there was no apparent trend in virologic suppression across ATV CCQs.
Assuntos
Fármacos Anti-HIV/farmacocinética , Sulfato de Atazanavir/farmacocinética , Inibidores da Protease de HIV/farmacocinética , Ritonavir/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Sulfato de Atazanavir/uso terapêutico , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Humanos , Lactente , Masculino , Ritonavir/uso terapêutico , Carga Viral/efeitos dos fármacosRESUMO
This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine.
Assuntos
Sulfato de Atazanavir/uso terapêutico , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Raltegravir Potássico/uso terapêutico , Ritonavir/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Cobicistat (COBI) is an alternative pharmacoenhancer to ritonavir. A fixed-dose combination (FDC) tablet containing atazanavir (ATV) and COBI has been developed for the treatment of HIV-1-infected patients. METHODS: This open-label, single-centre, single-dose, crossover study, randomized 64 healthy subjects to one of eight treatment sequences. Under light meal conditions, maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) to infinity (AUCINF) and AUC to the last measurable concentration (AUC0-T) for ATV and COBI administered as an FDC of ATV/COBI (300/150 mg) were compared to those following administration as separate agents given together; bioequivalence was concluded if the 90% CIs of the geometric mean ratios fell within the predetermined range of 0.80, 1.25. ATV and COBI pharmacokinetic parameters following administration as the FDC or as separate agents were also compared under fasted conditions. The effect of food (light and high-fat meals) on the pharmacokinetics of ATV and COBI for the FDC was also assessed. RESULTS: ATV and COBI administered in an FDC tablet were bioequivalent to the individual agents when given with a light meal. Under fasted conditions, pharmacokinetic parameters for ATV and COBI were similar for the individual components and the FDC. For the FDC, systemic exposure to ATV increased with a light meal compared to fasted conditions, and ATV concentration 24 h post-dose was similar with a light meal compared with a high-fat meal. CONCLUSIONS: ATV/COBI (300/150 mg) FDC tablet was bioequivalent to coadministration as separate agents with a light meal in healthy subjects. Clinicaltrials.gov identifier NCT01837719.
Assuntos
Sulfato de Atazanavir/farmacocinética , Cobicistat/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores da Protease de HIV/farmacocinética , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Equivalência Terapêutica , Adulto JovemRESUMO
BACKGROUND: AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years). METHODS: Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle. RESULTS: Thirty-seven subjects were treated. EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose values were generally suboptimal (<110 µM × h) in subjects younger than 3 years treated with oral solution; these subjects switched to capsule sprinkle. Twenty of 21 subjects younger than 3 years treated with capsule sprinkle achieved an EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose value >110 µM × h, although higher initial doses were administered in this age group. Interpatient variability in EFV exposure was high. By week 48, 77.8% and 63.0% of subjects achieved HIV-RNA <400 and <50 copies/mL, respectively. Median changes in log10 HIV-RNA and CD4 percentage from baseline were -3.18 copies/mL and +6%, respectively. Two (5.4%) patients discontinued because of adverse events (AEs). Serious AEs occurred in 20 (54.1%) subjects. Common AEs were diarrhea (49%), nasopharyngitis (35%) and pneumonia (30%). Overall, 43% of subjects with suboptimal EFV exposure at week 2 developed resistance. CONCLUSIONS: Once-daily EFV, given as capsule sprinkle, achieved target exposures in this study although doses were 2-3 times higher than Food and Drug Administration-approved doses for children younger than 3 years. These data are useful for dose selection modeling and simulation; however, Food and Drug Administration-approved doses should be used clinically. EFV + didanosine + FTC was efficacious with no new pediatric safety findings reported.
Assuntos
Benzoxazinas/uso terapêutico , Didanosina/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Alcinos , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Pré-Escolar , Ciclopropanos , Didanosina/administração & dosagem , Didanosina/farmacocinética , Emtricitabina/administração & dosagem , Emtricitabina/farmacocinética , Feminino , Infecções por HIV/epidemiologia , Humanos , Lactente , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Daclatasvir is a highly selective NS5A replication complex inhibitor currently in development for the treatment of chronic hepatitis C infection. Daclatasvir is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes. The primary objective of this study was to assess the effect of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate (Ortho Tri-Cyclen(®)). METHODS: In this open-label single-sequence study, 20 healthy female subjects received ethinyl estradiol and norgestimate for three cycles, with coadministration of daclatasvir in cycle 3. Pharmacokinetics of ethinyl estradiol and the active metabolites of norgestimate (norelgestromin and norgestrel) were assessed in cycles 2 and 3. RESULTS: Adjusted ratios of geometric means and 90% CIs were estimated for the maximum observed plasma concentration (ethinyl estradiol 1.11 [1.02, 1.20], norelgestromin 1.06 [0.99, 1.14] and norgestrel 1.07 [0.99, 1.16]) and area under the plasma concentration-time curve in one dosing interval (ethinyl estradiol 1.01 [0.95, 1.07], norelgestromin 1.12 [1.06, 1.17] and norgestrel 1.12 [1.02, 1.23]). CONCLUSIONS: Coadministration of daclatasvir resulted in no clinically relevant effects on exposure to ethinyl estradiol, norelgestromin or norgestrel.
Assuntos
Antivirais/administração & dosagem , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacocinética , Imidazóis/administração & dosagem , Norgestrel/análogos & derivados , Adolescente , Adulto , Antivirais/efeitos adversos , Carbamatos , Anticoncepcionais Orais Combinados/efeitos adversos , Esquema de Medicação , Combinação de Medicamentos , Interações Medicamentosas , Monitoramento de Medicamentos , Etinilestradiol/efeitos adversos , Feminino , Voluntários Saudáveis , Humanos , Imidazóis/efeitos adversos , Norgestrel/administração & dosagem , Norgestrel/efeitos adversos , Norgestrel/farmacocinética , Pirrolidinas , Valina/análogos & derivados , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: The combination of direct-acting antiviral agents in patients with chronic hepatitis C virus (HCV) infection has demonstrated clinical benefit; however, evaluation of potential drug-drug interactions is required prior to therapy. METHODS: An open-label study assessed the pharmacokinetics and tolerability of the HCV NS5A replication complex inhibitor daclatasvir and the HCV NS3 protease inhibitor asunaprevir when co-administered in healthy subjects. Daclatasvir 60 mg once daily and asunaprevir 600 mg twice daily were dosed for 7 days alone followed by combination dosing for 14 days at 30 mg once daily and 200 mg twice daily, respectively. Further assessments were provided comparing exposures from the current study with those from studies in HCV-infected patients receiving either the same or higher doses of daclatasvir or asunaprevir administered alone or together. RESULTS: Dose-normalized daclatasvir and asunaprevir morning exposures were comparable with control in healthy subjects, with geometric mean area under the concentration-time curve ratios of 1.202 (90 % CI 1.113-1.298) and 0.868 (90 % CI 0.726-1.038), respectively. In HCV patients daclatasvir and asunaprevir exposures were largely comparable, when administered together or alone. CONCLUSIONS: Additional data support the conclusion that there is no clinically meaningful interaction between daclatasvir and asunaprevir in either healthy subjects or HCV-infected patients, including those also receiving peginterferon-α/ribavirin, and that the combination of daclatasvir 60 mg once daily and asunaprevir 200 mg twice daily is generally well-tolerated.
Assuntos
Antivirais/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/farmacocinética , Isoquinolinas/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Área Sob a Curva , Carbamatos , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Pirrolidinas , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Valina/análogos & derivados , Adulto JovemRESUMO
BACKGROUND: Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy. METHODS: Three open-label studies were conducted in healthy subjects to assess potential interactions between the investigational first-in-class HCV NS5A replication complex inhibitor daclatasvir and representative antiretrovirals atazanavir/ritonavir, efavirenz and tenofovir disoproxil fumarate. RESULTS: Target exposure was that of 60 mg daclatasvir alone. Dose-normalized (60 mg) geometric mean ratios of daclatasvir AUCτ for 20 mg ± atazanavir/ritonavir (2.10 [90% CI 1.95, 2.26]) and 120 mg ± efavirenz (0.68 [0.60, 0.78]) showed less than the three-fold elevation and two-fold reduction, respectively, in systemic exposure predicted by prior interaction studies with potent inhibitors/inducers of CYP3A4. Daclatasvir dose adjustment to 30 mg once daily with atazanavir/ritonavir and 90 mg once daily with efavirenz is predicted to normalize AUCτ relative to the target exposure (geometric mean ratios 1.05 [0.98, 1.13] and 1.03 [0.90, 1.16], respectively). Atazanavir exposure (Cmax, AUCτ and C24 trough) and efavirenz Ctrough under coadministration were similar to historical data without daclatasvir. No clinically relevant interactions between daclatasvir and tenofovir disoproxil fumarate were observed for either drug, and no dosing adjustments were indicated. Daclatasvir was well tolerated in all three studies. CONCLUSIONS: The pharmacokinetic data support coadministration of daclatasvir with atazanavir/ritonavir, efavirenz and/or tenofovir. A Phase III study in HIV-HCV coinfection has commenced using the described dose modifications.
Assuntos
Fármacos Anti-HIV/farmacocinética , Imidazóis/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/farmacocinética , Adolescente , Adulto , Alcinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Carbamatos , Coinfecção , Ciclopropanos , Interações Medicamentosas , Feminino , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Pirrolidinas , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Tenofovir , Valina/análogos & derivados , Adulto JovemRESUMO
BACKGROUND: Women of childbearing age represent a growing proportion of people living with HIV. Preventing pregnancy is important in HIV-infected women receiving efavirenz as part of their antiretroviral therapy. METHODS: The effects of coadministration of efavirenz (600 mg once daily) on the pharmacokinetics (PK) of the active components (ethinyl estradiol [EE] and 17-deacetyl norgestimate [NGMN]) of Ortho Cyclen(®) (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) were investigated in 28 healthy HIV-negative women. The peak plasma concentration (C(max)), area under the concentration-time curve for a dosing interval (AUC([τ])), and lowest plasma concentration (C(min)) for EE and NGMN during cycles of treatment with Ortho Cyclen with and without coadministration of efavirenz were compared. Additionally, a post hoc exploratory analysis was conducted to assess the effect of efavirenz on the PK of an additional progestin, levonorgestrel (LNG). RESULTS: Exposures to EE were similar during coadministration of efavirenz and Ortho Cyclen to those during administration of Ortho Cyclen alone. Exposures to NGMN were substantially decreased following coadministration of efavirenz and Ortho Cyclen (adjusted geometric means for C(max), AUC([τ]) and C(min) decreased by 46%, 64% and 82%, respectively) compared with Ortho Cyclen alone. Consistent with NGMN, LNG exposures were decreased 80-86% by efavirenz. CONCLUSIONS: Although efavirenz had no significant effect on the PK of EE, exposures to the progestin components of Ortho Cyclen, NGMN and LNG, were substantially reduced. The results reinforce the need to use reliable methods of barrier contraception, even when taking oral contraceptives and efavirenz.