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1.
Artículo en Inglés | MEDLINE | ID: mdl-30745395

RESUMEN

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 µM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.


Asunto(s)
Interacciones Farmacológicas/fisiología , Piridonas/metabolismo , Triazoles/metabolismo , Animales , Transporte Biológico/fisiología , Línea Celular , Citocromo P-450 CYP3A/metabolismo , Perros , Células HEK293 , Hepatocitos/metabolismo , Humanos , Cinética , Células de Riñón Canino Madin Darby , Proteínas de Transporte de Membrana/metabolismo
2.
Artículo en Inglés | MEDLINE | ID: mdl-30782982

RESUMEN

Doravirine is a non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Due to the high prevalence of HIV-1 and hepatitis C virus (HCV) coinfection and coadministration of HIV-1 and HCV treatment, potential drug-drug interactions (DDIs) between doravirine and two HCV treatments were investigated in two phase 1 drug interaction trials in healthy participants. Trial 1 investigated the effect of multiple-dose doravirine and elbasvir + grazoprevir coadministration (N = 12), and trial 2 investigated the effect of single-dose doravirine and ledipasvir-sofosbuvir coadministration (N = 14). Doravirine had no clinically relevant effect on the pharmacokinetics of elbasvir, grazoprevir, ledipasvir, sofosbuvir, or the sofosbuvir metabolite GS-331007. Coadministration of elbasvir + grazoprevir with doravirine moderately increased doravirine area under the concentration-time curve from 0 to 24 h (AUC0-24), maximal concentration (Cmax), and concentration 24 h postdose (C24), with geometric least-squares mean ratio (GMR) with 90% confidence intervals (CI) of 1.56 (1.45, 1.68), 1.41 (1.25, 1.58), and 1.61 (1.45, 1.79), respectively. Doravirine AUC0-∞, Cmax, and C24 values increased slightly following coadministration with ledipasvir-sofosbuvir (GMR [90% CI] of 1.15 [1.07, 1.24], 1.11 [0.97, 1.27], and 1.24 [1.13, 1.36], respectively). The modest increases in doravirine exposure are not clinically meaningful based on the therapeutic profile of doravirine. Effects are likely secondary to cytochrome P450 3A and P-glycoprotein inhibition by grazoprevir and ledipasvir, respectively. Coadministration of doravirine with elbasvir + grazoprevir or ledipasvir-sofosbuvir was generally well tolerated. Clinically relevant DDIs are not expected to occur between doravirine and elbasvir-grazoprevir or ledipasvir-sofosbuvir at the therapeutic doses.


Asunto(s)
Antivirales/farmacocinética , Bencimidazoles/farmacocinética , Benzofuranos/farmacocinética , Fluorenos/farmacocinética , Imidazoles/farmacocinética , Piridonas/farmacocinética , Quinoxalinas/farmacocinética , Triazoles/farmacocinética , Adulto , Amidas , Carbamatos , Ciclopropanos , Interacciones Farmacológicas , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Sulfonamidas
3.
Artículo en Inglés | MEDLINE | ID: mdl-30783000

RESUMEN

Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.


Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Piridonas/farmacocinética , Triazoles/farmacocinética , Adolescente , Adulto , Anciano , Alquinos , Benzoxazinas/farmacocinética , Ciclopropanos , Interacciones Farmacológicas , Femenino , Humanos , Cetoconazol/farmacocinética , Masculino , Persona de Mediana Edad , Ritonavir/farmacocinética , Adulto Joven
4.
Xenobiotica ; 49(4): 422-432, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29557716

RESUMEN

Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [14 C]doravirine (350 mg, ∼200 µCi) trial (n = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (n = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials. Following oral [14 C]doravirine administration, all of the administered dose was recovered. The absorbed dose was eliminated primarily via metabolism. An oxidative metabolite (M9) was the predominant metabolite in excreta and was the primary circulating metabolite (12.9% of circulating radioactivity). Following IV administration, doravirine clearance and volume of distribution were 3.73 L/h (95% confidence intervals (CI) 3.09, 4.49) and 60.5 L (95% CI 53.7, 68.4), respectively. In vitro, doravirine is not highly bound to plasma proteins (unbound fraction 0.24) and has good passive permeability. The metabolite M9 was generated by cytochrome P450 3A (CYP3A)4/5-mediated oxidation. Doravirine was a P-gp substrate but P-gp efflux is not expected to play a significant role in limiting doravirine absorption or to be involved in the elimination of doravirine. In conclusion, doravirine is a low clearance drug, primarily eliminated by CYP3A-mediated metabolism.


Asunto(s)
Absorción Fisiológica , Piridonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Triazoles/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Intravenosa , Adulto , Humanos , Masculino , Metaboloma/efectos de los fármacos , Persona de Mediana Edad , Piridonas/sangre , Piridonas/química , Piridonas/orina , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/orina , Distribución Tisular , Triazoles/sangre , Triazoles/química , Triazoles/orina , Adulto Joven
5.
Artículo en Inglés | MEDLINE | ID: mdl-29891610

RESUMEN

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0-∞), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.).


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Riñón/metabolismo , Piridonas/farmacocinética , Insuficiencia Renal Crónica/sangre , Triazoles/farmacocinética , Anciano , Fármacos Anti-VIH/sangre , Área Bajo la Curva , Estudios de Casos y Controles , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón/patología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Piridonas/sangre , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/fisiopatología , Índice de Severidad de la Enfermedad , Triazoles/sangre
6.
Artículo en Inglés | MEDLINE | ID: mdl-30012772

RESUMEN

Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for preexposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence and, together with the potency of MK-8591, supports its consideration for extended-duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo Implants, administered subcutaneously, were studied in rodents and nonhuman primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models, as well as data generated in phase 1a (Ph1a) and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels, resulting in a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.


Asunto(s)
Desoxiadenosinas/uso terapéutico , Portadores de Fármacos/química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Animales , Fármacos Anti-VIH , Desoxiadenosinas/química , VIH-1/efectos de los fármacos , VIH-1/patogenicidad , Macaca mulatta , Masculino , Polímeros/química , Ratas , Ratas Wistar , Inhibidores de la Transcriptasa Inversa/química
7.
Artículo en Inglés | MEDLINE | ID: mdl-27872071

RESUMEN

Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.


Asunto(s)
Atorvastatina/farmacocinética , Piridonas/farmacocinética , Triazoles/farmacocinética , Adulto , Área Bajo la Curva , Atorvastatina/sangre , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridonas/sangre , Inhibidores de la Transcriptasa Inversa/farmacocinética , Triazoles/sangre
8.
Artículo en Inglés | MEDLINE | ID: mdl-27872069

RESUMEN

Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC0-24), maximum observed plasma concentration (Cmax), and observed plasma concentration at 24 h postdosing (C24) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC0-24, Cmax, and C24, respectively, by day 14 after efavirenz cessation. The doravirine C24 reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Benzoxazinas/farmacocinética , Piridonas/farmacocinética , Triazoles/farmacocinética , Adulto , Alquinos , Fármacos Anti-VIH/sangre , Benzoxazinas/sangre , Benzoxazinas/farmacología , Ciclopropanos , Interacciones Farmacológicas , Femenino , Cefalea/inducido químicamente , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Piridonas/efectos adversos , Piridonas/sangre , Triazoles/efectos adversos , Triazoles/sangre
9.
J Antimicrob Chemother ; 71(6): 1586-96, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27002074

RESUMEN

OBJECTIVES: Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission. METHODS: Long-acting raltegravir was administered subcutaneously to BALB/c, NSG (NOD-scid-gamma) and humanized BLT (bone marrow-liver-thymus) mice and rhesus macaques. Raltegravir concentration in peripheral blood and tissue was analysed. Suppression of HIV replication was assessed in infected BLT mice. Two high-dose HIV vaginal challenges were used to evaluate protection from HIV transmission in BLT mice. RESULTS: Two weeks after a single subcutaneous injection of long-acting raltegravir in BLT mice (7.5 mg) and rhesus macaques (160 mg), the plasma concentration of raltegravir was comparable to 400 mg orally, twice daily in humans. Serum collected from mice 3 weeks post-administration of long-acting raltegravir efficiently blocked HIV infection of TZM-bl indicator cells in vitro. Administration of long-acting raltegravir suppressed viral RNA in plasma and cervico-vaginal fluids of infected BLT mice, demonstrating penetration of active raltegravir into the female reproductive tract. Using transmitted/founder HIV we observed that BLT mice administered a single subcutaneous dose of long-acting raltegravir were protected from two high-dose HIV vaginal challenges 1 week and 4 weeks after drug administration. CONCLUSIONS: These preclinical results demonstrated the efficacy of long-acting raltegravir in preventing vaginal HIV transmission.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Transmisión de Enfermedad Infecciosa/prevención & control , Infecciones por VIH/prevención & control , Profilaxis Pre-Exposición/métodos , Raltegravir Potásico/administración & dosificación , Vagina/virología , Animales , Quimioprevención/métodos , Femenino , Infecciones por VIH/transmisión , Inyecciones Subcutáneas , Macaca mulatta , Ratones Endogámicos BALB C , Ratones SCID , Resultado del Tratamiento
10.
Bioorg Med Chem Lett ; 26(11): 2631-5, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27106707

RESUMEN

Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson's disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules.


Asunto(s)
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Tiofenos/farmacología , Administración Oral , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química
11.
Antimicrob Agents Chemother ; 58(11): 6790-806, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25182644

RESUMEN

Nonhuman primate models are needed for evaluations of proposed strategies targeting residual virus that persists in HIV-1-infected individuals receiving suppressive combination antiretroviral therapy (cART). However, relevant nonhuman primate (NHP) models of cART-mediated suppression have proven challenging to develop. We used a novel three-class, six-drug cART regimen to achieve durable 4.0- to 5.5-log reductions in plasma viremia levels and declines in cell-associated viral RNA and DNA in blood and tissues of simian immunodeficiency virus SIVmac239-infected Indian-origin rhesus macaques, then evaluated the impact of treatment with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA; Vorinostat) on the residual virus pool. Ex vivo SAHA treatment of CD4(+) T cells obtained from cART-suppressed animals increased histone acetylation and viral RNA levels in culture supernatants. cART-suppressed animals each received 84 total doses of oral SAHA. We observed SAHA dose-dependent increases in acetylated histones with evidence for sustained modulation as well as refractoriness following prolonged administration. In vivo virologic activity was demonstrated based on the ratio of viral RNA to viral DNA in peripheral blood mononuclear cells, a presumptive measure of viral transcription, which significantly increased in SAHA-treated animals. However, residual virus was readily detected at the end of treatment, suggesting that SAHA alone may be insufficient for viral eradication in the setting of suppressive cART. The effects observed were similar to emerging data for repeat-dose SAHA treatment of HIV-infected individuals on cART, demonstrating the feasibility, utility, and relevance of NHP models of cART-mediated suppression for in vivo assessments of AIDS virus functional cure/eradication approaches.


Asunto(s)
Antirretrovirales/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Acetilación/efectos de los fármacos , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Histonas/metabolismo , Macaca mulatta , ARN Viral/sangre , ARN Viral/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Carga Viral/efectos de los fármacos , Vorinostat
12.
Viruses ; 13(8)2021 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-34452431

RESUMEN

Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase-mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.


Asunto(s)
Desoxiadenosinas/metabolismo , Interacciones Farmacológicas , Preparaciones Farmacéuticas/metabolismo , Inhibidores de la Transcriptasa Inversa/metabolismo , Animales , Transporte Biológico , Sistema Enzimático del Citocromo P-450/metabolismo , Desoxiadenosinas/sangre , Perros , Infecciones por VIH/tratamiento farmacológico , Humanos , Técnicas In Vitro , Células de Riñón Canino Madin Darby , Proteínas de Transporte de Membrana/metabolismo , Ratones , Transportadores de Anión Orgánico/metabolismo , Conejos
13.
J Clin Pharmacol ; 61(3): 394-405, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32989795

RESUMEN

Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not been quantified in previous clinical studies, a physiologically based pharmacokinetic model was developed to investigate the change in M9 exposure when doravirine is coadministered with CYP3A inducers. Simulations demonstrated that although CYP3A induction increases doravirine clearance by up to 4.4-fold, M9 exposure is increased by only 1.2-fold relative to exposures for doravirine 100 mg once daily in the absence of CYP3A induction. Thus, a 2.4-fold increase in M9 exposure relative to the clinical dose of doravirine is anticipated when doravirine 100 mg twice daily is coadministered with rifabutin. In a subsequent clinical trial, doravirine and M9 exposures, when doravirine 100 mg twice daily was coadministered with rifabutin, were found to be consistent with model predictions using rifampin and efavirenz as representative inducers. These findings support the dose adjustment to doravirine 100 mg twice daily when coadministered with rifabutin.


Asunto(s)
Modelos Biológicos , Piridonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Rifabutina/farmacología , Triazoles/farmacocinética , Adulto , Alquinos/farmacología , Benzoxazinas/farmacología , Simulación por Computador , Ciclopropanos/farmacología , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Inductores del Citocromo P-450 CYP3A/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridonas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Rifabutina/administración & dosificación , Rifampin/farmacología , Triazoles/administración & dosificación , Adulto Joven
14.
Bioorg Med Chem Lett ; 20(14): 4065-8, 2010 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-20547452

RESUMEN

A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-L-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket.


Asunto(s)
Inhibidores de la Proteasa del VIH/farmacología , Lisina/análogos & derivados , Inhibidores de la Proteasa del VIH/química , Modelos Moleculares , Relación Estructura-Actividad
15.
Clin Pharmacol Drug Dev ; 9(2): 151-161, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31120195

RESUMEN

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor indicated for the treatment of HIV type 1 infection. A subset of people living with HIV receives methadone for the treatment of opioid addiction. The current study (NCT02715700) was an open-label, multiple-dose, drug interaction study in participants on a methadone maintenance program to investigate potential drug-drug interactions between doravirine and methadone. Participants received a stable methadone maintenance dose of 20 to 180 mg once daily for 14 days prior to day 1 and remained on their maintenance dose over days 1 through 7. On days 2 through 6, an oral dose of doravirine 100 mg was coadministered. For doravirine and methadone pharmacokinetic analysis, blood samples were collected before dosing through 24 hours after dosing. Fourteen participants were enrolled; all participants completed the study. For R-methadone, geometric least squares mean ratios (90% confidence intervals) for dose-normalized area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration ([methadone + doravirine]/methadone alone) were 0.95 (0.90-1.01), 0.95 (0.88-1.03), and 0.98 (0.93-1.03), respectively. For doravirine, based on a comparison with historical data, modest decreases in area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration were observed after coadministration of doravirine and methadone; geometric least squares mean ratios ([methadone + doravirine]/doravirine alone [90% confidence intervals]) were 0.74 (0.61-0.90), 0.80 (0.63-1.03), and 0.76 (0.63-0.91), respectively. Coadministration of doravirine and methadone was generally well tolerated. No serious adverse events occurred, and there were no discontinuations. In conclusion, coadministration of methadone and doravirine did not have a clinically meaningful effect on the pharmacokinetic profile of either agent.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Metadona/farmacocinética , Trastornos Relacionados con Opioides/tratamiento farmacológico , Piridonas/farmacocinética , Triazoles/farmacocinética , Adulto , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/sangre , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacología , Esquema de Medicación , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada/estadística & datos numéricos , Femenino , Humanos , Masculino , Metadona/administración & dosificación , Metadona/sangre , Metadona/farmacología , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Piridonas/administración & dosificación , Piridonas/sangre , Piridonas/farmacología , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/administración & dosificación , Triazoles/sangre , Triazoles/farmacología
16.
Clin Pharmacol Drug Dev ; 9(1): 107-114, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30973682

RESUMEN

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, type 2 diabetes mellitus is often treated with metformin. Perturbations of metformin absorption or elimination may affect its safety and efficacy profile; therefore, understanding potential drug-drug interactions between doravirine and metformin is important. An open-label, fixed-sequence, 2-period trial in healthy adults was conducted. Single-dose metformin 1000 mg was administered in period 1; in period 2, doravirine 100 mg was administered once daily on days 1 to 7, and single-dose metformin 1000 mg was administered on day 5. Plasma pharmacokinetics for metformin alone and coadministered with doravirine were assessed. Fourteen participants enrolled and completed the trial. Least-squares geometric mean ratios and 90% confidence intervals of metformin AUC0-∞ , and Cmax following coadministration of metformin and doravirine compared with metformin alone were 0.94 (0.88-1.00) and 0.94 (0.86-1.03), respectively; metformin Tmax and half-life were also minimally impacted. These data indicate that doravirine did not have a clinically relevant effect on the pharmacokinetics of metformin. Metformin alone and coadministered with doravirine was generally well tolerated. These data support coadministration of doravirine 100 mg and metformin 1000 mg without dose adjustment.


Asunto(s)
Hipoglucemiantes/farmacocinética , Metformina/farmacocinética , Piridonas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/farmacología , Adulto , Área Bajo la Curva , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Hipoglucemiantes/sangre , Masculino , Persona de Mediana Edad , Adulto Joven
17.
J Clin Pharmacol ; 59(8): 1093-1098, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30817001

RESUMEN

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus type 1 infection. Because of potential concomitant administration with acid-reducing agents, a drug-interaction trial was conducted to evaluate the potential impact of these types of medications on doravirine pharmacokinetics. In an open-label, 3-period, fixed-sequence trial, healthy adult participants received the following: period 1, a single dose of doravirine 100 mg; period 2, coadministration of a single dose of doravirine 100 mg and an antacid (1600 mg aluminum hydroxide, 1600 mg magnesium hydroxide, and 160 mg simethicone); period 3, 40 mg pantoprazole once daily on days 1-5 coadministered with a single dose of doravirine 100 mg on day 5. There was a minimum 10-day washout between periods. Plasma samples for pharmacokinetic evaluation were collected, and safety was assessed. Fourteen participants (8 male, 6 female) were enrolled, and 13 completed the trial. Geometric mean ratios (90% confidence intervals) for doravirine AUC0-inf , Cmax , and C24 for doravirine + antacid/doravirine were 1.01 (0.92-1.11), 0.86 (0.74-1.01), and 1.03 (0.94-1.12), respectively, and for doravirine + pantoprazole/doravirine were 0.83 (0.76-0.91), 0.88 (0.76-1.01), and 0.84 (0.77-0.92), respectively. Doravirine was generally well tolerated administered alone or with either of the acid-reducing agents. Coadministration of an aluminum/magnesium-containing antacid or pantoprazole did not have a clinically meaningful effect on doravirine pharmacokinetics, supporting the use of acid-reducing agents with doravirine.


Asunto(s)
Hidróxido de Aluminio/farmacología , Antiácidos/farmacología , Hidróxido de Magnesio/farmacología , Pantoprazol/farmacología , Inhibidores de la Bomba de Protones/farmacología , Piridonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Simeticona/farmacología , Triazoles/farmacocinética , Adulto , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad
18.
Toxicology ; 246(1): 63-72, 2008 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-18280627

RESUMEN

Administration of 0.4% clofibrate in the diet stimulated estradiol (E(2))-induced mammary carcinogenesis in the August-Copenhagen Irish (ACI) rat without having an effect on serum levels of E(2). This treatment stimulated by several-fold the NAD(P)H-dependent oxidative metabolism of E(2) and oleyl-CoA-dependent esterification of E(2) to 17beta-oleyl-estradiol by liver microsomes. Glucuronidation of E(2) by microsomal glucuronosyltransferase was increased moderately. In contrast, the activity of NAD(P)H quinone reductase 1 (NQO1), a representative monofunctional phase 2 enzyme, was significantly decreased in liver cytosol of rats fed clofibrate. Decreases in hepatic NQO1 in livers of animals fed clofibrate were noted before the appearance of mammary tumors. E(2) was delivered in cholesterol pellets implanted in 7-8-week-old female ACI rats. The animals received AIN-76A diet containing 0.4% clofibrate for 6, 12 or 28 weeks. Control animals received AIN-76A diet. Dietary clofibrate increased the number and size of palpable mammary tumors but did not alter the histopathology of the E(2)-induced mammary adenocarcinomas. Collectively, these results suggest that the stimulatory effect of clofibrate on hepatic esterification of E(2) with fatty acids coupled with the inhibition of protective phase 2 enzymes, may in part, enhance E(2)-dependent mammary carcinogenesis in the ACI rat model.


Asunto(s)
Clofibrato/toxicidad , Estradiol/agonistas , Hipolipemiantes/toxicidad , Neoplasias Mamarias Animales/inducido químicamente , Microsomas Hepáticos/efectos de los fármacos , Animales , Clofibrato/administración & dosificación , Dieta , Estradiol/sangre , Estradiol/metabolismo , Femenino , Hipolipemiantes/administración & dosificación , Neoplasias Mamarias Animales/patología , Microsomas Hepáticos/enzimología , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Ratas , Ratas Endogámicas ACI
19.
J Clin Pharmacol ; 58(8): 1044-1052, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29723418

RESUMEN

Doravirine is a nonnucleoside reverse transcriptase inhibitor in clinical development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretroviral therapies. The cytochrome P450 (CYP)3A-dependent metabolism of doravirine makes it susceptible to interactions with modulators of this pathway, including the antituberculosis treatment rifampin. Rifabutin, an alternative antibiotic used to treat tuberculosis, may have a lower-magnitude effect on CYP3A. The aim of this trial was to determine the effect of steady-state rifabutin on doravirine single-dose pharmacokinetics and tolerability. In this open-label, 2-period, fixed-sequence, drug-drug interaction study, healthy subjects received a single dose of doravirine 100 mg alone and coadministered on day 14 of once-daily administration of rifabutin 300 mg for 16 days. Plasma samples were taken to determine doravirine pharmacokinetics, and safety was monitored throughout. Dose adjustment of doravirine in the presence of coadministered rifabutin was explored through nonparametric superposition analysis. Rifabutin reduced doravirine area under the concentration-time curve from time zero to infinite and plasma drug concentration 24 hours postdose with geometric mean ratios ([rifabutin+doravirine]/[doravirine alone]) (90%CIs) of 0.50 (0.45-0.55) and 0.32 (0.28-0.35), respectively. Doravirine apparent clearance increased from 5.9 L/h without rifabutin to 12.2 L/h when coadministered. Doravirine pharmacokinetics with and without coadministered rifabutin were not equivalent. Nonparametric superposition analysis projected that administration of doravirine 100 mg twice daily with rifabutin will restore steady-state trough concentration values to efficacious levels associated with doravirine 100 mg once daily in the absence of CYP3A inducers. Doravirine may be coadministered with rifabutin when the doravirine dose frequency is increased from 100 mg once daily to 100 mg twice daily.

20.
Clin Drug Investig ; 37(7): 659-667, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28353169

RESUMEN

BACKGROUND AND OBJECTIVE: Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co-infected with human immunodeficiency virus. Rifampin demonstrates organic anion-transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration. The objective of this study was to evaluate the effects of co-administration of single and multiple doses of rifampin on doravirine pharmacokinetics. METHODS: In period 1 of this open-label, two-period, fixed-sequence study in healthy adults, subjects received single-dose doravirine 100 mg; blood samples for measuring plasma concentration were collected pre-dose and up to 72 h post-dose. In period 2, following a 7-day washout, subjects received doravirine 100 mg and rifampin 600 mg on day 1, rifampin 600 mg daily on days 4-18, with doravirine 100 mg co-administered on day 17; blood samples were collected pre-dose and up to 72 h post-dose on day 1 and up to 48 h post-dose on day 17. Safety assessments included adverse events, physical examinations, vital signs, and clinical laboratory measurements. RESULTS: Ten subjects completed the study. Doravirine area under the concentration-time curve from time zero extrapolated to infinity and plasma concentration at 24 h post-dose were comparable in the presence and absence of single-dose rifampin [geometric mean ratios (90% confidence intervals)] of 0.91 (0.78-1.06) and 0.90 (0.80-1.01), respectively. Doravirine maximum plasma concentration increased when co-administered with single-dose rifampin vs. doravirine alone, geometric mean ratio (90% confidence interval): 1.40 (1.21-1.63). Reductions in doravirine geometric mean ratios (90% confidence interval), area under the concentration-time curve from time zero extrapolated to infinity: 0.12 (0.10-0.15), plasma concentration at 24 h post-dose: 0.03 (0.02-0.04), maximum plasma concentration: 0.43 (0.35-0.52), and apparent terminal half-life were observed when co-administered with multiple-dose rifampin vs. doravirine administered alone. Doravirine was well tolerated. Adverse events were mild and resolved by study completion. CONCLUSIONS: Doravirine co-administration with single-dose rifampin indicated that inhibition of organic anion-transporting polypeptide uptake transporters and P-glycoprotein has little impact on doravirine pharmacokinetics. Long-term co-administration of rifampin or other strong CYP3A inducers with doravirine will likely reduce its efficacy.


Asunto(s)
Piridonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Rifampin/administración & dosificación , Triazoles/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adulto , Área Bajo la Curva , Citocromo P-450 CYP3A/metabolismo , Inductores del Citocromo P-450 CYP3A/farmacología , Semivida , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Rifampin/farmacología , Adulto Joven
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