RESUMEN
The phase 2, open-label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6- or 8-week regimen of simeprevir, daclatasvir and sofosbuvir in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early-stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early-stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty-eight patients were treated (6-week group: n = 59; 8-week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early-stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6-week group was viral relapse (11.9%; 7/59). One patient had on-treatment failure due to an early withdrawal (lost to follow-up due to incarceration). One patient with SVR12 in the 6-week group had a late viral relapse at post-treatment week 24. No clinically significant drug-drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct-acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment-naïve, HCV GT1-infected patients with early-stage fibrosis or compensated cirrhosis.
Asunto(s)
Antivirales/administración & dosificación , Genotipo , Hepacivirus/clasificación , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Simeprevir/administración & dosificación , Sofosbuvir/administración & dosificación , Adolescente , Adulto , Anciano , Antivirales/efectos adversos , Antivirales/farmacocinética , Carbamatos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Pirrolidinas , Simeprevir/efectos adversos , Simeprevir/farmacocinética , Sofosbuvir/efectos adversos , Sofosbuvir/farmacocinética , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Valina/análogos & derivados , Adulto JovenRESUMEN
Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct-acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment-naïve or treatment-experienced adults with Child-Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7-9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS-331007 (sofosbuvir metabolite) was 2.2-, 1.5-, 1.2- and 1.2-fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.
Asunto(s)
Antivirales/administración & dosificación , Insuficiencia Hepática/etiología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Simeprevir/administración & dosificación , Sofosbuvir/administración & dosificación , Adulto , Anciano , Antivirales/efectos adversos , Antivirales/farmacocinética , Carbamatos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Masculino , Persona de Mediana Edad , Pirrolidinas , Simeprevir/efectos adversos , Simeprevir/farmacocinética , Sofosbuvir/efectos adversos , Sofosbuvir/farmacocinética , Resultado del Tratamiento , Estados Unidos , Valina/análogos & derivadosRESUMEN
OBJECTIVES: HIV antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission and for maternal care. Physiological changes during pregnancy can affect pharmacokinetics. The impact of pregnancy was evaluated for once-daily (qd) darunavir/ritonavir. METHODS: HIV-1-infected pregnant women on an antiretroviral regimen that includes darunavir were enrolled in the study and further treated with darunavir/ritonavir 800/100 mg qd. Plasma concentrations were assessed over 24 h during the second and third trimesters and postpartum using a validated high-performance liquid chromatography tandem mass spectrometry assay for total darunavir and ritonavir, and using (14) C-darunavir-fortified plasma for unbound darunavir. Pharmacokinetic parameters were derived using noncompartmental analysis. Safety and antiviral response were assessed at all visits. RESULTS: Data were available for 16 women. The area under the plasma concentration-time curve from 0 to 24 h (AUC24h ) for total darunavir was 34-35% lower during pregnancy vs. postpartum. Unbound darunavir AUC24h was 20-24% lower during pregnancy vs. postpartum. The minimum plasma concentration of total and unbound darunavir was 32-50% and 13-38% lower, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 59% at baseline and increased to 87-100% during the trial; the CD4 count increased over time. One serious adverse event (gestational diabetes) was judged as possibly related to study medication. All 16 infants born to women remaining in the study at delivery were HIV-1 negative (two were premature). CONCLUSIONS: Total darunavir exposure decreased during pregnancy, but the decrease was less for unbound (active) darunavir. These changes are not considered clinically relevant. Darunavir/ritonavir 800/100 mg qd may therefore be a treatment option for HIV-1-infected pregnant women.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Darunavir/administración & dosificación , Darunavir/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Ritonavir/administración & dosificación , Ritonavir/farmacocinética , Adolescente , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Plasma/química , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
OBJECTIVES: Following antiretroviral therapy failure, patients are often treated with a three-drug regimen that includes two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. An alternative two-drug nucleoside-sparing regimen may decrease the pill burden and drug toxicities associated with the use of N(t)RTIs. The Intelence aNd pRezista Once A Day Study (INROADS; NCT01199939) evaluated the nucleoside-sparing regimen of etravirine 400 mg with darunavir/ritonavir 800/100 mg once-daily in HIV-1-infected treatment-experienced subjects or treatment-naïve subjects with transmitted resistance. METHODS: In this exploratory phase 2b, single-arm, open-label, multicentre, 48-week study, the primary endpoint was the proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at week 48 [confirmed virological response (CVR), non-virological failure (VF) censored]. Key secondary endpoints included assessments of changes from baseline to week 48 in viral load, immunological response, pharmacokinetics/pharmacodynamics, safety, tolerability, metabolic and bone markers and body fat. RESULTS: Forty-one of the 54 enrolled subjects completed the study. Adverse events (7%) and VF (7%) were the most common reasons for discontinuation. The week 48 CVR rate in the intent-to-treat (ITT) non-VF censored population was 89% (primary endpoint). Seven subjects experienced VF. Common adverse events were diarrhoea (15%), rash (15%) and upper respiratory tract infection (11%). Mild/moderate lipid elevations, minimal changes in limb fat distribution and bone mineral density and no clinically relevant changes in glucose metabolism were observed. CONCLUSIONS: Etravirine 400 mg and darunavir/ritonavir 800/100 mg as a two-drug once-daily regimen in treatment-experienced subjects or treatment-naïve subjects with transmitted resistance was virologically efficacious and well tolerated.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Piridazinas/administración & dosificación , Ritonavir/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , Anciano , Fármacos Anti-VIH/farmacocinética , Distribución de la Grasa Corporal , Densidad Ósea/efectos de los fármacos , Recuento de Linfocito CD4 , Darunavir , Esquema de Medicación , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Nitrilos , Piridazinas/farmacocinética , Pirimidinas , ARN Viral/efectos de los fármacos , Ritonavir/farmacocinética , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Carga Viral/efectos de los fármacosRESUMEN
OBJECTIVES: Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women. METHODS: HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using (14) C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis. RESULTS: Data were available for 14 women. The area under the plasma concentration-time curve from 0 to 12 h (AUC12h) for total darunavir was 17-24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43-86% and 10-14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73-90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature. CONCLUSIONS: Total darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.
Asunto(s)
Infecciones por VIH/metabolismo , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1 , Complicaciones Infecciosas del Embarazo/metabolismo , Ritonavir/farmacocinética , Sulfonamidas/farmacocinética , Adolescente , Adulto , Darunavir , Esquema de Medicación , Femenino , Sangre Fetal/química , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Humanos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Resultado del Embarazo , Ritonavir/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVES: PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (≥ 6 to < 12 years) and adolescents (≥ 12 to < 18 years) over 48 weeks. METHODS: In a phase II, open-label, single-arm study, 101 treatment-experienced patients (41 children; 60 adolescents) with screening viral load (VL) ≥ 500 HIV-1 RNA copies/mL received etravirine 5.2 mg/kg (maximum dose 200 mg) twice a day (bid) plus OBR. RESULTS: Sixty-seven per cent of patients had previously used efavirenz or nevirapine. At week 48, the most common treatment-related grade ≥ 2 adverse event (AE) was rash (13%); 12% experienced grade 3 AEs. Only two grade 4 AEs occurred (both thrombocytopaenia, not etravirine related). At week 48, 56% of patients (68% children; 48% adolescents) achieved a virological response (VL<50 copies/mL; intent-to-treat, noncompleter=failure). Factors predictive of response were adherence > 95%, male sex, low baseline etravirine weighted genotypic score and high etravirine trough concentration (C0h ). Seventy-six patients (75%) completed the trial; most discontinuations occurred because of protocol noncompliance or AEs (8% each). Sixty-five per cent of patients were > 95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean etravirine area under the plasma concentration-time curve over 12 h (AUC0-12h ; 5216 ng h/mL) and C0h (346 ng/mL) were comparable to adult target values. CONCLUSIONS: Results with etravirine 5.2 mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200 mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients.
Asunto(s)
Farmacorresistencia Viral/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Nevirapina/administración & dosificación , Piridazinas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adolescente , Área Bajo la Curva , Niño , Erupciones por Medicamentos , Farmacorresistencia Viral/inmunología , Femenino , Infecciones por VIH/epidemiología , Humanos , Masculino , Cumplimiento de la Medicación , Mutación , Nevirapina/farmacocinética , Nitrilos , Piridazinas/farmacocinética , Pirimidinas , Inhibidores de la Transcriptasa Inversa/farmacocinética , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVES: Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine. METHODS: This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given. RESULTS: Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co-administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study. CONCLUSIONS: Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution.
Asunto(s)
Artemisininas/farmacocinética , Etanolaminas/farmacocinética , Fluorenos/farmacocinética , Malaria/complicaciones , Piridazinas/farmacocinética , Ritonavir/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Arteméter , Artemisininas/administración & dosificación , Estudios Cruzados , Darunavir , Interacciones Farmacológicas , Etanolaminas/administración & dosificación , Fluorenos/administración & dosificación , VIH/efectos de los fármacos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Voluntarios Sanos , Humanos , Lumefantrina , Malaria/tratamiento farmacológico , Persona de Mediana Edad , Nitrilos , Piridazinas/administración & dosificación , Piridazinas/metabolismo , Pirimidinas , Ritonavir/administración & dosificación , Sulfonamidas/administración & dosificaciónRESUMEN
OBJECTIVE: Two open-label, randomized, cross-over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate. METHODS: Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co-administration of etravirine with tenofovir disoproxil fumarate on either days 1-8 or days 9-16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h. RESULTS: The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration-time curve from 0 to 12 h (AUC(12 h)) for etravirine co-administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61-0.79) and 0.81 (0.75-0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC(24 h) was 1.16 (1.09-1.23) in Study 1 and 1.15 (1.09-1.21) in Study 2. CONCLUSIONS: These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co-administered.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Organofosfonatos/farmacocinética , Piridazinas/farmacocinética , Adenina/administración & dosificación , Adenina/farmacocinética , Adolescente , Adulto , Fármacos Anti-VIH/administración & dosificación , Bélgica , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Nitrilos , Organofosfonatos/administración & dosificación , Piridazinas/administración & dosificación , Pirimidinas , Tenofovir , Adulto JovenRESUMEN
OBJECTIVES: TMC125-C227, an exploratory phase II, randomized, controlled, open-label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator-selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, protease inhibitor-naïve, HIV-1-infected patients. METHODS: Patients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs). RESULTS: In an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first-line NNRTI-failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal-, lipid- and liver-related events. CONCLUSIONS: In a PI-naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI-naïve patients with first-line virological failure on an NNRTI-based regimen. Baseline two-class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , VIH-1 , Piridazinas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adulto , Terapia Antirretroviral Altamente Activa/métodos , Recuento de Linfocito CD4 , Esquema de Medicación , Farmacorresistencia Viral/efectos de los fármacos , Métodos Epidemiológicos , Femenino , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Piridazinas/efectos adversos , Piridazinas/farmacocinética , Pirimidinas , ARN Viral , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/farmacocinética , Carga Viral , Adulto JovenAsunto(s)
Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Piridazinas/farmacocinética , Adulto , Femenino , Infecciones por VIH/virología , Humanos , Nitrilos , Embarazo , Piridazinas/efectos adversos , Pirimidinas , Resultado del TratamientoRESUMEN
An existing population pharmacokinetic model of darunavir in adults was updated using pediatric data from two studies evaluating weight-based, once-daily dosing of darunavir/ritonavir (ARIEL, NCT00919854 and DIONE, NCT00915655). The model was then used to provide once-daily dosing recommendations for darunavir/ritonavir in pediatric patients aged ≥3 to <12 years. The final model comprised two compartments with first-order absorption and apparent clearance dependent on the concentration of α1-acid glycoprotein. The recommended darunavir/ritonavir once-daily dosing regimens in children aged ≥3 to <12 years are: 35/7 mg/kg from 10 to <15 kg, 600/100 mg from 15 to <30 kg, 675/100 mg from 30 to <40 kg, and 800/100 mg for ≥40 kg. These doses should result in exposures similar to the adult exposure after treatment with darunavir/ritonavir 800/100 mg once daily, while minimizing pill burden and allowing a switch from suspension to tablet(s) as early as possible.
RESUMEN
OBJECTIVE: To quantitate intracellular concentrations of zidovudine and lamivudine triphosphate and explore relationships with virologic and immunologic responses to antiretroviral therapy. DESIGN: Eight antiretroviral-naive, HIV-infected persons with CD4 T cell counts > 100 x 10(6) cells/l, and HIV RNA in plasma > 5000 copies/ml participating in a prospective, randomized, open-label study of standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir. METHODS: Peripheral blood mononuclear cells and plasma were collected frequently throughout the study for quantitation of intracellular zidovudine triphosphate and lamivudine triphosphate concentrations, and zidovudine and lamivudine concentrations in plasma. CD4 T cells and HIV RNA in plasma (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks throughout the study. Relationships among intracellular and plasma concentrations, and CD4 T cells and HIV RNA in plasma were investigated with regression analyses. RESULTS: Significant relationships were observed between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate and the baseline level of CD4 cells. Lamivudine triphosphate concentrations were related in a linear manner to the apparent oral clearance of lamivudine from plasma. A direct linear relationship was found between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. The percent change in CD4 cells during therapy and the rate of decline in HIV RNA in plasma were related to the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. CONCLUSION: These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Citidina Trifosfato/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH , Lamivudine/uso terapéutico , Nucleótidos de Timina/uso terapéutico , Zidovudina/uso terapéutico , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/farmacocinética , Recuento de Linfocito CD4 , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/farmacocinética , Didesoxinucleótidos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Humanos , Lamivudine/análogos & derivados , Lamivudine/farmacocinética , Leucocitos Mononucleares/metabolismo , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral/análisis , Análisis de Regresión , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Nucleótidos de Timina/farmacocinética , Zidovudina/análogos & derivados , Zidovudina/farmacocinéticaRESUMEN
OBJECTIVE: To quantify unbound indinavir concentrations and characterize indinavir plasma protein binding in HIV-infected adults. DESIGN: Pharmacokinetic study in antiretroviral-naive, HIV-infected persons with CD4 T lymphocytes > 100 x 10(6) cells/L and HIV-RNA in plasma >5000 copies/ml at baseline who were participating in an open-label study of zidovudine, lamivudine and indinavir therapy. METHODS: Eight men underwent 8 h intensive pharmacokinetic studies for indinavir on two occasions 6 months apart. Unbound indinavir was separated by ultra-filtration, and unbound and total concentrations were quantified by a validated high-performance liquid chromatography method. RESULTS: Overall indinavir protein binding was 61+/-6%, with a range among the profiles of 54 to 70%. Indinavir binding was higher at the 8 h post-dose concentration compared with the 1 h post-dose concentration (66 versus 57%, P = 0.0006). CONCLUSIONS: The mean 61% protein binding for indinavir in these HIV-infected persons is similar to the in vitro report of 60%. However, the fraction bound was concentration-dependent, and considerable variability in binding was present among patients. Quantification of unbound protease inhibitor concentrations opens new avenues of research to advance our understanding of the pharmacologically-relevant moieties of antiretroviral agents and thereby the pharmacotherapy of HIV infection.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Indinavir/farmacocinética , Adulto , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Unión ProteicaRESUMEN
OBJECTIVE: This paper reviews the function of the mitochondria and the mechanisms by which nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) cause mitochondrial toxicity. BACKGROUND: Highly active antiretroviral therapy (HAART) reduces rates of morbidity and mortality due to HIV disease. However, long-term treatment with these drugs may be associated with adverse effects. Nucleoside and nucleotide analogues are potent inhibitors of HIV reverse transcriptase and have become the cornerstone of HAART. Unfortunately, these drugs have also been shown to inhibit cellular polymerases, most notably mitochondrial DNA polymerase gamma. RESULTS: Studies of the NRTIs in enzyme assays and cell cultures demonstrate the following hierarchy of mitochondrial DNA polymerase gamma inhibition: zalcitabine > didanosine > stavudine > lamivudine > zidovudine > abacavir. In vitro investigations have also documented impairment of the mitochondrial enzymes adenylate kinase and the adenosine diphosphate/adenosine triphosphate translocator. Inhibition of DNA polymerase gamma and other mitochondrial enzymes can gradually lead to mitochondrial dysfunction and cellular toxicity. The clinical manifestations of NRTI-induced mitochondrial toxicity resemble those of inherited mitochondrial diseases (ie, hepatic steatosis, lactic acidosis, myopathy, nephrotoxicity, peripheral neuropathy, and pancreatitis). Fat redistribution syndrome, or HIV-associated lipodystrophy, is another side effect attributed in part to NRTI therapy. The morphologic and metabolic complications of this syndrome are similar to those of the mitochondrial disorder known as multiple symmetric lipomatosis: suggesting that this too may be related to mitochondrial toxicity. The pathophysiology of less common adverse effects of nucleoside analogue therapy, such as diabetes, ototoxicity, and retinal lesions, may be related to mitochondrial dysfunction but have not been adequately studied. CONCLUSION: NRTls can block both HIV reverse transcriptase and mitochondrial DNA polymerase gamma. Inhibition of the latter enzyme is the most likely cause of the adverse effects associated with these drugs.
Asunto(s)
Fármacos Anti-VIH/toxicidad , Inhibidores de la Transcriptasa Inversa/toxicidad , Animales , Fármacos Anti-VIH/farmacología , Sinergismo Farmacológico , Humanos , Inhibidores de la Transcriptasa Inversa/farmacologíaRESUMEN
The 2nd International Workshop on Clinical Pharmacology of HIV Therapy was convened in Noordwijk, The Netherlands on April 2nd-4th, 2001. The purpose of this meeting was to present and discuss research related to antiretroviral drug interactions, drug distribution to sanctuary sites, pharmacokinetics, pharmacodynamics (i.e., the relationship between pharmacokinetics and efficacy, toxicity or drug resistance), inhibitory quotient (IQ) and therapeutic drug monitoring (TDM). There were 28 oral and 49 poster presentations accepted to this meeting. While most studies focused on protease inhibitors (PIs), insight into the pharmacology of non-nucleoside reverse transcriptase inhibitors (NNRTIs) was also gleaned. Herein, we highlight some of the research that was presented.
Asunto(s)
Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH/sangre , Farmacología Clínica/métodos , Terapia Antirretroviral Altamente Activa/métodos , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Ritonavir/sangre , Ritonavir/uso terapéuticoRESUMEN
The pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration of protease inhibitors are reviewed. Protease inhibitors are a novel class of drugs used for the treatment of human immunodeficiency virus (HIV) infection. Saquinavir, ritonavir, indinavir, and nelfinavir have been approved in the United States; several other agents are under development. Protease inhibitors selectively block HIV protease, an enzyme involved in the later stages of HIV replication. Various pharmacokinetic differences exist among these agents, including differences in bioavailability, protein binding, and drug interactions. The drugs undergo extensive hepatic metabolism; dosage adjustments should be considered for patients with hepatic dysfunction. Clinical trials have shown protease inhibitors to be effective in reducing HIV RNA levels and increasing CD4+ lymphocyte counts. When protease inhibitors are used in combination with other antiretroviral agents, an additional beneficial effect on these markers occurs. Adverse effects of saquinavir and nelfinavir include mild gastrointestinal disturbances such as diarrhea. Ritonavir is less well tolerated because of gastrointestinal disturbances and circumoral and peripheral paresthesia. Indinavir has been associated with nephrolithiasis and asymptomatic hyperbilirubinemia. The development of resistance to protease inhibitors may be related to suboptimal dosages, noncompliance, or partial compliance. Protease inhibitors are potent and highly selective agents that block a critical step in HIV replication. They are effective and relatively well tolerated, but they are expensive, have extensive drug interaction profiles, and require careful compliance with the prescribed regimen.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Adulto , Niño , Ensayos Clínicos como Asunto , Contraindicaciones , Inhibidores de la Proteasa del VIH/economía , Humanos , Indinavir/farmacocinética , Indinavir/uso terapéutico , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Saquinavir/farmacocinética , Saquinavir/uso terapéuticoRESUMEN
The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.