RESUMO
Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.
Assuntos
Eletrocardiografia , Fluoroquinolonas , Moxifloxacina , Humanos , Adulto , Masculino , Eletrocardiografia/efeitos dos fármacos , Método Duplo-Cego , Feminino , Pessoa de Meia-Idade , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/farmacocinética , Moxifloxacina/efeitos adversos , Moxifloxacina/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Adulto Jovem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Compostos Aza/efeitos adversos , Compostos Aza/farmacocinética , DesoxiadenosinasRESUMO
Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.
Assuntos
Antagonistas do Receptor Purinérgico P2X , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Adolescente , Esquema de Medicação , Meia-Vida , Sulfonamidas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , BenzenossulfonamidasRESUMO
This double-blind study evaluated the cardiac safety of amiselimod. Healthy adults (n = 190) were randomized (2:1:1) to receive (1) oral placebo (day -1), followed by oral amiselimod (days 1-26), which was upwardly titrated from 0.4 to 1.6 mg once daily to achieve steady-state concentrations comparable with 0.4 (therapeutic) and 0.8 mg (supratherapeutic) once daily, and placebo (day 27); (2) placebo (day -1), oral moxifloxacin 400 mg (day 1; positive control), followed by placebo (days 1-27); or (3) placebo (days -1 to 26), followed by moxifloxacin 400 mg (day 27). No participant had a corrected QT interval by Fredericia (QTcF) >500 milliseconds or a change from baseline (dQTcF) >60 milliseconds. The upper limits of the 90%CIs for the differences in least-squares mean difference in dQTcF between amiselimod and placebo on days 13 and 26 were <10 milliseconds. Area under the concentration-time curve from 0 to 23.5 hours after dosing and maximum plasma concentration of amiselimod and amiselimod-P (active metabolite) at steady-state concentrations for the 0.8-mg dose on day 26 were approximately double that observed with the 0.4-mg dose on day 13. All adverse events were mild to moderate in severity, and no deaths occurred. Amiselimod did not have any clinically relevant effect on the QTcF interval.
Assuntos
Fluoroquinolonas , Síndrome do QT Longo , Adulto , Humanos , Moxifloxacina/efeitos adversos , Fluoroquinolonas/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Eletrocardiografia , Método Duplo-Cego , Voluntários SaudáveisRESUMO
BACKGROUND: GP2017 is an adalimumab biosimilar. The objective of this study is to compare the pharmacokinetics (PK) of GP2017 in its approved formulation and GP2017-high concentration formulation (HCF) in a randomized, double-blind, two-arm PK bridging study. RESEARCH DESIGN AND METHODS: Healthy male subjects received a single 40 mg subcutaneous injection of either GP2017-HCF (n = 162) or GP2017 (n = 168). PK, safety, and immunogenicity were assessed over 72 days post-injection. RESULTS: The 90% confidence intervals [CIs] of geometric mean ratios between GP2017-HCF and GP2017 for Cmax, AUC0-inf, AUC0-360 and AUC0-last were within the pre-defined margin of 0.80 to 1.25; thus, PK comparability between GP2017-HCF and GP2017 was demonstrated. Subgroup analysis of PK comparability by anti-drug antibody (ADA) subpopulation showed that the 90% CIs of geometric mean ratios between GP2017-HCF and GP2017 for Cmax, AUC0-inf, AUC0-360 and AUC0-last were within the margin of 0.80 to 1.25 in ADA-positive and ADA-negative subjects. The proportions of subjects with positive ADA responses and with neutralizing antibodies were comparable between the GP2017-HCF and GP2017 groups. GP2017-HCF and GP2017 were well tolerated, and there were no reports of deaths or other serious adverse events. CONCLUSION: Results show PK comparability between GP2017-HCF and GP2017 and comparable safety and tolerability.
RESUMO
BACKGROUND: Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis virus-based COVID-19 vaccine candidate. METHODS: In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo. In Part 1, younger (18-54 years) and, in Part 2, older (≥55 years) adults seronegative for SARS-CoV-2 nucleocapsid received one of four V590 dose levels (5.00 × 105; 2.40 × 106; 1.15 × 107; or 5.55 × 107 plaque-forming units [pfu]) or placebo. In Part 3, a single V590 dose level (5.55 × 107 pfu) or placebo was administered to younger SARS-CoV-2 seropositive adults. Primary endpoints included adverse events (AEs) and for Parts 1 and 2 anti-SARS-CoV-2 serum neutralising antibody responses measured by 50% plaque reduction neutralisation (PRNT50) assay at Day 28. Registration NCT04569786 [P001-02]. FINDINGS: 232 participants were randomised and 219 completed the study. In seronegative participants, anti-SARS-CoV-2 spike-specific antibody responses to V590 were low and comparable to placebo across the lower dose levels. At the highest dose level (5.55 × 107 pfu), anti-SARS-CoV-2 spike-specific PRNT50 was 2.3-fold higher than placebo. The most frequently reported AEs were injection-site pain (38.4%), headache (15.1%) and fatigue (13.4%). INTERPRETATION: V590 was generally well-tolerated. However, Day 28 anti-SARS-Cov-2 spike-specific antibody responses in seronegative participants following a single intramuscular administration of V590 were not sufficient to warrant continued development. FUNDING: The study was funded by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Método Duplo-Cego , Humanos , Pandemias/prevenção & controle , SARS-CoV-2 , VacinasRESUMO
This single 60-mg dose, 4-period crossover study assessed the effect of food and formulation change on navtemadlin (KRT-232) pharmacokinetics (PK) and macrophage inhibitory cytokine-1 (MIC-1) pharmacodynamics. Healthy subjects (N = 30) were randomized to 3 treatment sequences, A: new tablet, fasted (reference, dosed twice); B: new tablet, 30 minutes after a high-fat meal (test 1); C: old tablet, fasted (test 2). PK/pharmacodynamic parameters were measured over 0 to 96 hours. Adverse events were mild without any discontinuations. No serious adverse events or deaths occurred. In treatment A, navtemadlin mean (coefficient of variation) maximum concentration (Cmax ) was 525 (66) ng/mL, at median time to maximum concentration (tmax ) of 2 hours. Mean (coefficient of variation) area under the plasma concentration-time curve from time 0 to time t (AUC0-t ) was 3392 (63.3) ng ⢠h/mL, and arithmetic mean terminal half-life was 18.6 hours. Acyl glucuronide metabolite (M1)/navtemadlin AUC0-t ratio was 0.2, and urine excretion of navtemadlin was negligible. After a meal (B vs A), navtemadlin tmax was delayed by 1 hour. Geometric least squares means ratios (90%CI) for navtemadlin Cmax and AUC0-t were 102.7% (87.4-120.6) and 81.4% (76.2-86.9), respectively. Old vs new tablet fasted formulations (C vs A) had geometric least squares means ratios (90%CI) of 78.4% (72.0-85.3) for Cmax and 85.9% (80.5-91.7) for AUC0-t . MIC-1 Cmax and AUC were comparable across groups; tmax was delayed relative to navtemadlin tmax by ≈8 hours. Navtemadlin AUC0-t and MIC-1 AUC0-t correlated significantly. In conclusion, navtemadlin can be administered safely with or without food; the new formulation does not affect navtemadlin PK. The 60-mg navtemadlin dose elicited a reproducible and robust MIC-1 response that correlated well with navtemadlin exposure, indicating that murine double minute 2 target engagement leads to p53 activation.
Assuntos
Interações Alimento-Droga , Proteínas Proto-Oncogênicas c-mdm2 , Humanos , Administração Oral , Estudos Cross-Over , Citocinas , Voluntários Saudáveis , Macrófagos , ComprimidosRESUMO
BACKGROUND: Amiselimod is a selective sphingosine 1-phosphate receptor modulator in development for inflammatory bowel disease. It is converted to its active metabolite, amiselimod phosphate (amiselimod-P), and has a long half-life and slow accumulation to steady state. We evaluated a multiple-dose titration regimen to determine the plasma pharmacokinetic (PK) profile of amiselimod and amiselimod-P at steady state for the 0.4 mg QD therapeutic dose on day 13 and for the 0.8 mg QD supratherapeutic dose on day 26. We also investigated the pharmacodynamic (PD) effect of amiselimod on absolute lymphocyte counts (ALCs). METHODS: A randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design assessed amiselimod and amiselimod-P. Healthy adults received a single dose of placebo followed by oral amiselimod, which was upwardly titrated in doses ranging from 0.4 to 1.6 mg QD to rapidly achieve steady-state concentrations for the 0.4 mg QD and 0.8 mg QD doses within a 28-day treatment period. The PK parameters of amiselimod and amiselimod-P (on days 1, 13 and 26) included the geometric mean (geometric coefficient of variation percentage [CV%]) maximum plasma concentration (Cmax), median (minimum, maximum) time to Cmax (Tmax), geometric mean (geometric CV%) area under the concentration-time curve (AUC) from time 0 to the last measurable concentration, and geometric mean (geometric CV%) AUC from time 0 to 23.5 hours post dose (AUC0-23.5). Multidose PD were evaluated by changes in ALCs. RESULTS: The PK population included 95 amiselimod-treated participants and the PD population included 190 participants who received amiselimod or placebo. On day 13, the steady-state AUC and Cmax for amiselimod 0.4 mg QD increased by 10-fold for amiselimod and by 4-fold for amiselimod-P compared with day 1. On day 26, the steady-state AUC0-23.5 and Cmax for amiselimod 0.8 mg QD increased by 1.9-fold for amiselimod and by 1.8-fold for amiselimod-P compared with day 13. The median Tmax of plasma amiselimod and amiselimod-P were similar on all 3 days and were reached at 11 to 12 hours post dose for amiselimod and at 10 hours post dose for amiselimod-P. The mean ALCs for amiselimod exhibited a gradual decrease from pre-dose (1.681 × 103/uL) to a nadir of 0.424 × 103/uL on day 27. CONCLUSION: The abbreviated amiselimod dosing titration regimen reached steady state within 14 days for the therapeutic 0.4 mg QD regimen and within 26 days for the supratherapeutic 0.8 mg QD regimen; expected decreases in ALCs were observed following amiselimod.
RESUMO
AIMS: To assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT-4101, a potent, selective, orally bioavailable, small-molecule by (a) evaluating the dose-response of single FT-4101 doses (3, 6 and 9 mg) on hepatic de novo lipogenesis (DNL) in healthy participants (Study 1) and (b) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks of FT-4101 dosing in patients with non-alcoholic fatty liver disease (NAFLD; Study 2). MATERIALS AND METHODS: In Study 1, three sequential cohorts of healthy men (n = 10/cohort) were randomized to receive a single dose of FT-4101 (n = 5/cohort) or placebo (n = 5/cohort) followed by crossover dosing after 7 days. Hepatic DNL was assessed during fructose stimulation from 13 C-acetate incorporation. In Study 2, men and women with NAFLD (n = 14) randomly received 12 weeks of intermittent once-daily dosing (four cycles of 2 weeks on-treatment, followed by 1 week off-treatment) of 3 mg FT-4101 (n = 9) or placebo (n = 5). Steady-state DNL based on deuterated water labelling, hepatic steatosis using magnetic resonance imaging-proton density fat fraction and sebum lipids and circulating biomarkers were assessed. RESULTS: Single and repeat dosing of FT-4101 were safe and well tolerated. Single FT-4101 doses inhibited hepatic DNL dose-dependently. Twelve weeks of 3 mg FT-4101 treatment improved hepatic steatosis and inhibited hepatic DNL. Decreases in sebum sapienate content with FT-4101 at week 11 were not significant compared to placebo and rebounded at week 12. Biomarkers of liver function, glucose and lipid metabolism were unchanged. CONCLUSIONS: Inhibition of FASN with 3 mg FT-4101 safely reduces hepatic DNL and steatosis in NAFLD patients.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Lipogênese , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.
Assuntos
Tetrodotoxina/administração & dosagem , Adolescente , Adulto , Método Duplo-Cego , Eletrocardiografia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Injeções Subcutâneas , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Tetrodotoxina/efeitos adversos , Tetrodotoxina/sangue , Tetrodotoxina/farmacocinética , Adulto JovemRESUMO
The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single-dose, double-blind (relebactam only), randomized, placebo- and positive-controlled, 3-period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open-label positive control), and IV placebo. Least squares mean and 2-sided 90% confidence interval for change from baseline in population-derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population-derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150-mg supratherapeutic dose (4.6-fold above the 250-mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a ß-lactamase inhibitor in antimicrobial therapy.
Assuntos
Moxifloxacina , Compostos Azabicíclicos , Estudos Cross-Over , Voluntários Saudáveis , Frequência Cardíaca , HumanosRESUMO
AIMS: Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics. METHODS: Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults. RESULTS: Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar. CONCLUSIONS: Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified.
Assuntos
Medicamentos Biossimilares , Adulto , Medicamentos Biossimilares/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Filgrastim , Voluntários Saudáveis , Humanos , Polietilenoglicóis/efeitos adversosRESUMO
Rezafungin is a new echinocandin in development for treatment of candidemia and invasive candidiasis, and for prophylaxis of invasive fungal infections. Rezafungin is the first echinocandin to undergo definitive QT/QTc study. This phase 1, single-center, randomized, double-blind trial was conducted to assess effects of intravenous rezafungin vs intravenous placebo (with moxifloxacin as positive control) on the QT interval of the electrocardiogram, corrected for heart rate by Fridericia's formula (QTcF), in healthy adults. Therapeutic (600 mg) and supratherapeutic (1400 mg) rezafungin doses were selected to achieve exposures 2.5-fold higher than produced by the highest dose used in a phase 2 trial (400 mg once weekly). The primary end point was change in QTcF from baseline (ΔQTcF) as a function of plasma concentration, assessed by comparing upper bounds of the 2-sided 90% confidence interval. The estimated mean ΔΔQTcF at the mean plasma concentrations for the rezafungin doses had upper bounds <10 milliseconds, within the upper bound of the 2-sided 90% confidence interval. Intravenous rezafungin up to 1400 mg in a single dose did not prolong QT interval and had no apparent effect on repolarization or QRS duration. Electrocardiogram results showed no clinically significant effects of concern. These findings support the continued development of rezafungin.
Assuntos
Antifúngicos/efeitos adversos , Equinocandinas/efeitos adversos , Eletrocardiografia , Adulto , Antifúngicos/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Equinocandinas/administração & dosagem , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/etiologia , Masculino , Pessoa de Meia-Idade , Moxifloxacina/administração & dosagem , Moxifloxacina/efeitos adversos , Adulto JovemRESUMO
AG10 is a novel, potent, and selective oral transthyretin (TTR) stabilizer being developed to treat TTR amyloidosis (ATTR). This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics (ex vivo stabilization) of orally administered AG10 in healthy adult volunteers. Both mutant and wild-type ATTR are underdiagnosed diseases with limited therapeutic options. As TTR amyloidogenesis is initiated by dissociation of TTR tetramers destabilized due to inherited mutations or aging, AG10 is designed to treat the disease at its source. Four single and three multiple ascending dose levels of AG10 or matching placebo were orally administered. Safety and tolerability were assessed by vital signs, electrocardiogram, adverse events, and clinical laboratory tests. Pharmacokinetics were measured using a validated bioanalytical assay. Pharmacodynamics were assessed via three pharmacodynamic assays of TTR stabilization. AG10 was uniformly well tolerated, and no safety signals of clinical concern were observed. Pharmacokinetic observations included time to maximum concentration <1 hour, dose-dependent maximum concentration and area under the plasma concentration-time curve, low intersubject variability, and half-life â¼25 hr. Complete (>90%) stabilization of TTR was observed across the entire dosing interval at steady state on the highest dose tested. Serum TTR levels, an in vivo reflection of TTR stabilization by AG10, increased from baseline following 12 days of dosing. AG10 appears to be safe and well tolerated in healthy adult volunteers and can completely stabilize TTR across the dosing interval, establishing clinical proof of concept. Based on these data, AG10 has the potential to be a safe and effective treatment for patients with either mutant or wild-type ATTR.
Assuntos
Benzoatos , Pirazóis , Administração Oral , Adolescente , Adulto , Neuropatias Amiloides Familiares , Benzoatos/efeitos adversos , Benzoatos/sangue , Benzoatos/farmacocinética , Benzoatos/farmacologia , Método Duplo-Cego , Jejum/metabolismo , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Albumina/análise , Pirazóis/efeitos adversos , Pirazóis/sangue , Pirazóis/farmacocinética , Pirazóis/farmacologia , Adulto JovemRESUMO
OBJECTIVE: Letermovir is an inhibitor of the terminase complex of cytomegalovirus (CMV) used as prophylactic therapy in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. As the combination oral contraceptive (COC) levonorgestrel/ethinyl estradiol (LNG/EE) may be coadministered in this target transplant population, the effects of letermovir on the pharmacokinetics (PK) of LNG and EE were investigated. MATERIALS AND METHODS: This was a phase I, open-label, fixed-sequence, two-period study conducted in healthy women (18 - 65 years old) of non-childbearing potential (protocol number: MK-8228 035). On day 1 of period 1, participants received a single dose of COC (LNG 0.15 mg/EE 0.03 mg). Following a 7-day washout, oral letermovir 480 mg was administered once-daily on days 1 - 12 of period 2, with a single dose of COC coadministered on day 8. Blood samples were collected to determine LNG and EE PK, and safety was assessed. RESULTS: The AUC0-∞ geometric mean ratios (90% confidence intervals) for COC + letermovir/COC alone were 1.36 (1.30, 1.43) for LNG and 1.42 (1.32, 1.52) for EE, indicating that letermovir coadministration increased COC exposure. Coadministration had no clinically-meaningful effect on Cmax, tmax, or apparent terminal T1/2 for either LNG or EE. All treatments were generally well tolerated. CONCLUSION: Letermovir coadministration with COC resulted in an increase in LNG and EE exposure in healthy adult women; however, levels were within the established safety margins. There was no decrease in LNG or EE exposure with no apparent risk of contraceptive failure on coadministration of letermovir and COC.â©.
Assuntos
Acetatos/farmacologia , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Quinazolinas/farmacologia , Adolescente , Adulto , Idoso , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Patupilone is a microtubule-targeted cytotoxic agent with clinical efficacy, but causes diarrhoea in more than 80% of patients. The efficacy and tolerability of patupilone delivered continuously by subcutaneous (s.c.) mini-pumps [(mini-pump dose (MPD)] or by intravenous bolus administration [intravenous bolus dose (IVBD)] were compared preclinically to determine whether the therapeutic index could be improved. The antiproliferative potency in vitro of patupilone was determined by measuring total cell protein. Tumours were grown s.c. in rats (A15) or nude mice (KB31, KB8511) or intracranially in nude mice (NCI-H460-Luc). Efficacy was monitored by measuring tumour volumes, bioluminescence or survival. Toxicity was monitored by body weight and/or diarrhoea. Total drug levels in blood, plasma, tissues or dialysates were quantified ex-vivo by liquid chromatography-mass spectroscopy/mass spectroscopy. Patupilone was potent in vitro with GI50s of 0.24-0.28 nmol/l and GI90s of 0.46-1.64 nmol/l. In rats, a single IVBD of patupilone dose dependently inhibited the growth of A15 tumours, but also caused dose-dependent body weight loss and diarrhoea, whereas MPD achieved similar efficacy, but no toxicity. In mice, MPD showed efficacy similar to that of IVBD against KB31 and KB8511 tumours, but with reduced toxicity. In a mouse intracranial tumour model, IVBD was more efficacious than MPD, consistent with patupilone concentrations in the brain. MPD provided constant plasma levels, whereas IVBD had very high C0/Cmin ratios of 70-280 (rat) or 8000 (mouse) over the dosing cycle. Overall, the correlation of plasma and tumour levels with response indicated that a Cave of at least GI90 led to tumour stasis. Continuous low concentrations of patupilone by MPD increased the therapeutic index in s.c. rodent tumour models compared with IVBD by maintaining efficacy, but reducing toxicity.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Epotilonas/administração & dosagem , Bombas de Infusão , Neoplasias Experimentais/tratamento farmacológico , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Epotilonas/sangue , Epotilonas/uso terapêutico , Feminino , Humanos , Infusões Subcutâneas , Injeções Intravenosas , Camundongos , Camundongos Nus , Microdiálise , Neoplasias Experimentais/sangue , Neoplasias Experimentais/patologia , Ratos , Especificidade da Espécie , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Oral contraceptive pills (OCPs) are an important element of hepatitis C virus (HCV) treatment in women of childbearing potential. These studies evaluated the safety and pharmacokinetic interactions between elbasvir (EBR) and grazoprevir (GZR) and ethinyl estradiol/levonorgestrel (EE/LNG). METHODS: Both studies were open-label, single-site, two-period, fixed-sequence, one-way interaction studies. In period 1, subjects received one tablet of EE/LNG (0.03 mg/0.15 mg). In period 2, subjects received EBR (50 mg once daily) for 13 days or GZR (200 mg once daily) for 10 days, with one tablet of EE/LNG on day 7 (GZR group) or 10 (EBR group). Each study enrolled 20 healthy, nonsmoking adult females. RESULTS: There was no clinically meaningful effect of multiple doses of EBR or GZR on the pharmacokinetics of EE or LNG. Geometric mean ratios (GMRs) for AUC0-∞ and Cmax in the presence and absence of EBR were 1.01 and 1.10 for EE and 1.14 and 1.02 for LNG, with 90% confidence intervals (CIs) that were contained in the interval [0.80, 1.25]. Similarly, the AUC0-∞ and Cmax GMRs in the presence and absence of GZR were 1.10 and 1.05 for EE and 1.23 and 0.93 for LNG, respectively. The 90% CIs for EE AUC0-∞ and for EE and LNG Cmax were contained in the interval [0.80, 1.25]; however, the 90% CI for the LNG AUC0-∞ [1.15, 1.32] slightly exceeded the upper bound. CONCLUSIONS: These results suggest that EBR/GZR can be co-administered to female patients with HCV of childbearing potential who are on OCPs to prevent pregnancy.
Assuntos
Antivirais/farmacocinética , Benzofuranos/farmacocinética , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/administração & dosagem , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacocinética , Levanogestrel/administração & dosagem , Quinoxalinas/farmacocinética , Adolescente , Adulto , Idoso , Amidas , Antivirais/farmacologia , Benzofuranos/farmacologia , Carbamatos , Ciclopropanos , Interações Medicamentosas , Feminino , Humanos , Imidazóis/farmacologia , Pessoa de Meia-Idade , Quinoxalinas/farmacologia , Sulfonamidas , Adulto JovemRESUMO
Two studies (ROADMAP and ORIENT) evaluating the renoprotective effects of olmesartan medoxomil (OM) in patients with type 2 diabetes suggested OM is associated with increased cardiovascular mortality. We conducted a thorough QTc study to evaluate the effects of OM on cardiac repolarization. A randomized, double-blind, phase 1 study was conducted per E14 Guidance to assess the effects of single doses of OM therapeutic dose (40 mg), OM supratherapeutic dose (160 mg), placebo, or moxifloxacin (MOXI; 400 mg) on QTc in 56 healthy subjects. The primary endpoint was the baseline-adjusted, placebo-corrected QTc interval using Fridericia's formula (ΔΔQTcF) for OM and MOXI. Assay sensitivity was concluded if lower limit of 1-sided 95%CI > 5 milliseconds of ΔΔQTcF for MOXI. No threshold pharmacologic effect for OM was concluded if upper limit of 1-sided 95%CI <10 milliseconds for ΔΔQTcF at any timepoint. Pharmacokinetics, ECGs, and safety were assessed. Assay sensitivity was demonstrated. The largest upper limit of the 1-sided 95%CI for ΔΔQTcF was <5 milliseconds for OM. No clinically significant changes were observed in ECGs. Pharmacokinetics and safety profile were consistent with previous data. Therapeutic and supratherapeutic OM doses had no clinically significant effect on cardiac repolarization and were well tolerated.
Assuntos
Eletrocardiografia/efeitos dos fármacos , Coração/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Olmesartana Medoxomila/administração & dosagem , Adolescente , Adulto , Estudos Cross-Over , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug-drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0-inf , whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0-inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax , AUC0-24 , or AUC0-inf . In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.
Assuntos
Anilidas/administração & dosagem , Anilidas/farmacocinética , Cetoconazol/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Rifampina/farmacocinética , Tiazolidinedionas/farmacocinética , Anilidas/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Área Sob a Curva , Citocromo P-450 CYP2C8/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Meia-Vida , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Cetoconazol/administração & dosagem , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Piridinas/sangue , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Rifampina/administração & dosagem , Rosiglitazona , Tiazolidinedionas/sangueRESUMO
PURPOSE: The purpose of this study was to examine drug interactions between boceprevir, a hepatitis C virus NS3/4A protease inhibitor, and a combined oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE). METHODS: A single-center, open-label study was conducted in 20 healthy female volunteers. In three consecutive 28-day treatment periods, subjects received EE/NE (0.035 mg/1 mg; 21 days on, 7 days off). During period 3, subjects also received boceprevir (800 mg three times daily) for 28 days. RESULTS: Coadministration of boceprevir with EE/NE did not affect NE AUC0-24 but slightly reduced NE C max. Geometric mean ratios (GMRs) for NE AUC0-24 and C max with EE/NE alone and EE/NE plus boceprevir were 0.96 (90% confidence interval (CI), 0.87-1.06) and 0.83 (90% CI, 0.76-0.90). Coadministration of boceprevir with EE/NE reduced EE AUC0-24 and C max by 26 and 21%, with GMRs of 0.74 (90% CI, 0.68-0.80) and 0.79 (90% CI, 0.75-0.84). Boceprevir had no effect on mid-cycle luteinizing hormone (LH), follicle-stimulating hormone (FSH), or sex hormone-binding globulin levels, and progesterone concentrations remained <1 ng/ml during the luteal phase. Adverse events reported in this study were consistent with the well-established safety profile of boceprevir. CONCLUSION: Serum progesterone, LH, and FSH levels indicate that ovulation was suppressed during coadministration of boceprevir with EE/NE. Coadministration of boceprevir with combined oral contraceptives containing EE and ≥1 mg of NE is therefore unlikely to alter contraceptive effectiveness. The ovulation suppression activity of oral contraceptives containing lower doses of NE, and of other forms of hormonal contraception during coadministration with boceprevir, has not been established.
Assuntos
Anticoncepcionais Orais Combinados/farmacologia , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacologia , Etinilestradiol/farmacocinética , Noretindrona/farmacologia , Noretindrona/farmacocinética , Prolina/análogos & derivados , Inibidores de Proteases/farmacologia , Adolescente , Adulto , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Combinados/sangue , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/efeitos adversos , Etinilestradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Hepacivirus , Humanos , Hormônio Luteinizante/sangue , Noretindrona/efeitos adversos , Noretindrona/sangue , Progesterona/sangue , Prolina/efeitos adversos , Prolina/farmacologia , Inibidores de Proteases/efeitos adversos , Globulina de Ligação a Hormônio Sexual/análise , Adulto JovemRESUMO
The aim was to determine the potential of the allosteric mammalian target of rapamycin inhibitor, everolimus, to act in combination with cytotoxic anticancer compounds in vitro and in vivo. A concomitant combination in vitro showed no evidence of antagonism, but enhanced the antiproliferative effects (additive to synergistic) with cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, paclitaxel, and patupilone. Everolimus (1-5 mg/kg/d orally) was evaluated for antitumor activity in vivo alone or in combination with suboptimal cytotoxic doses using athymic nude mice bearing subcutaneous human H-596 lung, KB-31 cervical, or HCT-116 colon tumor xenografts. Everolimus monotherapy was very well tolerated and caused inhibition of tumor growth, rather than regression, and this was associated with a dose-dependent decline in tumor pS6 levels, a key downstream protein of mammalian target of rapamycin. At the doses used, the cytotoxics inhibited tumor growth and caused tolerable body-weight loss. Concomitant combinations of cisplatin, doxorubicin, paclitaxel, or patupilone with everolimus produced cooperative antitumor effects, in some cases producing regressions without clinically significant increases in toxicity. In contrast, combinations with gemcitabine and 5-fluorouracil were less well tolerated. Alternative administration schedules were tested for cisplatin, gemcitabine, or paclitaxel combined with everolimus: these did not dramatically affect cisplatin or gemcitabine activity or tolerability but were antagonistic for paclitaxel. Everolimus showed promising maintenance activity after treatment with doxorubicin or paclitaxel ceased. Overall, the results confirm that everolimus is an effective, well-tolerated suppressor of experimental human tumor growth, and although it did not show strong potentiation of efficacy, antitumor activity in vivo was increased without marked increases in toxicity, supporting clinical use of everolimus as a partner for conventional cytotoxics.