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1.
Ann Pharmacother ; 49(7): 784-9, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25862012

ABSTRACT

BACKGROUND: Dolutegravir (DTG; Tivicay; ViiV Healthcare, Research Triangle Park, NC) is an HIV-1-unboosted integrase inhibitor with no cytochrome P450 or uridine 5'diphosphate-glucuronosyltransferase inhibition or induction. As DTG is administered to HIV-1-infected women receiving oral contraceptives, assessing the potential for drug interactions was warranted. OBJECTIVE: To determine the impact of DTG on the pharmacokinetics (PK) and pharmacodynamics (PD) of a common oral contraceptive, norgestimate/ethinyl estradiol (NGM/EE; Ortho-Cyclen; Ortho-McNeil-Janssen Pharmaceuticals, Inc, Raritan, NJ). METHODS: This randomized, 2-period, double-blind, placebo-controlled study was conducted within 1 menstrual cycle at 1 clinical center in the United States; 16 women were enrolled. Participants received NGM 0.25 mg/EE 0.035 mg throughout the study. During days 1 to 10, they were randomized to receive twice-daily DTG 50 mg or matching placebo with food and switched to the other treatment during days 12 to 21. RESULTS: Ratios of area under the concentration-time curve from time 0 until end of the dosage interval (AUC0-τ), maximum plasma concentration, and concentration at the end of the dosage interval of norelgestromin with DTG treatment to the same PK parameters with placebo treatment were 0.975, 0.890, and 0.932, respectively; for EE, ratios were 1.03, 0.99, and 1.02, respectively. No significant differences in luteinizing hormone, follicle-stimulating hormone, and progesterone were detected on days 1, 10, 11, 21, and 22. DTG steady-state AUC0-τ was similar to historical data. No severe or grade 3/4 adverse events occurred. CONCLUSIONS: DTG had no effect on NGM/EE PK or PD. NGM/EE can be administered with DTG without dose adjustment.


Subject(s)
Contraceptives, Oral, Combined/pharmacokinetics , Ethinyl Estradiol/pharmacokinetics , HIV Integrase Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Norgestrel/analogs & derivatives , Adult , Double-Blind Method , Drug Combinations , Drug Interactions , Female , Follicle Stimulating Hormone/blood , Humans , Luteinizing Hormone/blood , Norgestrel/blood , Norgestrel/pharmacokinetics , Oxazines , Oximes/blood , Piperazines , Progesterone/blood , Pyridones
2.
J Infect Dis ; 209(4): 542-50, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-23983212

ABSTRACT

BACKGROUND: Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. METHODS: Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed. RESULTS: One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1-11) a median of 4.5 days (range, 1-7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. CONCLUSIONS: Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. CLINICAL TRIALS REGISTRATION: NCT01014988.


Subject(s)
Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Influenza, Human/drug therapy , Zanamivir/adverse effects , Zanamivir/pharmacokinetics , Administration, Intravenous , Adolescent , Adult , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Female , Hospitalization , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/virology , Male , Middle Aged , Treatment Outcome , Viral Load , Zanamivir/administration & dosage
3.
Eur J Clin Pharmacol ; 70(1): 29-35, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24096683

ABSTRACT

PURPOSE: Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG. METHODS: This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance. RESULTS: DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma. CONCLUSIONS: The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.


Subject(s)
HIV Integrase Inhibitors/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Renal Insufficiency/metabolism , Female , HIV Integrase Inhibitors/adverse effects , HIV Integrase Inhibitors/blood , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/blood , Humans , Male , Middle Aged , Oxazines , Piperazines , Pyridones
4.
Antimicrob Agents Chemother ; 57(9): 4394-7, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23817375

ABSTRACT

Prednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01425099.).


Subject(s)
HIV Integrase Inhibitors/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Prednisone/pharmacology , Adolescent , Adult , Aged , Area Under Curve , Drug Administration Schedule , Drug Interactions , Female , HIV Integrase Inhibitors/blood , Healthy Volunteers , Heterocyclic Compounds, 3-Ring/blood , Humans , Male , Middle Aged , Oxazines , Piperazines , Prednisone/blood , Pyridones
5.
Virus Res ; 325: 199039, 2023 02.
Article in English | MEDLINE | ID: mdl-36610656

ABSTRACT

Influenza infection causes substantial morbidity and mortality during seasonal epidemics and pandemics. Antivirals, including neuraminidase inhibitors, play an important role in the treatment of severely ill patients infected with influenza. Resistance is a key factor that can affect the efficacy of neuraminidase inhibitors (NAIs). It is a recommendation by regulatory authorities to monitor for resistance during the development of anti-influenza medications. An additional requirement by regulators is to examine amino acid sequences for minority species harbouring resistance substitutions. In a Phase III study of intravenous (IV) zanamivir respiratory samples were analysed for the presence of resistant quasi species using Next Generation Sequencing (NGS). In this study ten resistance substitutions, two of which were treatment emergent, were detected by NGS that otherwise would not have been detectable by Sanger sequencing. None of the substitutions were present at any other timepoints analysed. The effect these mutations have on clinical response is difficult to characterize; in fact, all patients from which these variants were isolated had a successful clinical outcome and the effect on clinical response was therefore likely minimal. Although NGS is becoming a routine method for nucleic acid sequencing and will detect substitutions previously undetected by Sanger sequencing, the value of this technique in identifying minority species with resistance substitutions that are clinically meaningful remains to be demonstrated, particularly with acute infections such as influenza.


Subject(s)
Influenza, Human , Zanamivir , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Resistance, Viral/genetics , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Influenza, Human/drug therapy , Neuraminidase/genetics , Oseltamivir/pharmacology , Zanamivir/pharmacology , Zanamivir/therapeutic use
6.
Lancet Respir Med ; 5(2): 135-146, 2017 02.
Article in English | MEDLINE | ID: mdl-28094141

ABSTRACT

BACKGROUND: Neuraminidase inhibitors are effective for the treatment of acute uncomplicated influenza. However, there is an unmet need for intravenous treatment for patients admitted to hospital with severe influenza. We studied whether intravenous zanamivir was a suitable treatment in this setting. METHODS: In this international, randomised, double-blind, double-dummy, phase 3 trial, we recruited patients aged 16 years or older with severe influenza admitted to 97 hospitals from 26 countries. We randomly assigned patients (1:1:1 stratified by symptom onset ≤4 days or 5-6 days) to receive 300 mg or 600 mg intravenous zanamivir, or standard-of-care (75 mg oral oseltamivir) twice a day for 5-10 days; patients were followed up for 28 days. The randomisation schedule, including stratification, was generated using GlaxoSmithKline's RandAll software. Patients, site study staff, and sponsor were masked to study treatment. The primary endpoint was time to clinical response-a composite of vital sign stabilisation and hospital discharge-in the influenza-positive population. The trial was powered to show an improvement of 1Ā·5 days or greater with 600 mg intravenous zanamivir. Pharmacokinetic, safety, and virology endpoints were also assessed. This trial is registered with ClinicalTrials.gov, number NCT01231620. FINDINGS: Between Jan 15, 2011, and Feb 12, 2015, 626 patients were randomly assigned to receive 300 mg intravenous zanamivir (n=201), 600 mg intravenous zanamivir (n=209), or 75 mg oral oseltamivir (n=205) twice a day; 11 patients discontinued the study before receiving any study treatment. 488 (78%) of 626 patients had laboratory-confirmed influenza. Compared with a median time to clinical response of 5Ā·14 days in the 600 mg intravenous zanamivir group, the median time to clinical response was 5Ā·87 days (difference of -0Ā·73 days, 95% CI -1Ā·79 to 0Ā·75; p=0Ā·25) in the 300 mg intravenous zanamivir group and 5Ā·63 days (difference of -0Ā·48 days, 95% CI -2Ā·11 to 0Ā·97; p=0Ā·39) in the oseltamivir group. Four patients with influenza A/H1N1pdm09 in the oseltamivir group developed H275Y resistance mutations. Adverse events were reported in 373 (61%) of treated patients and were similar across treatment groups; the most common adverse events (300 mg intravenous zanamivir, 600 mg intravenous zanamivir, oseltamivir) were diarrhoea (10 [5%], 15 [7%], 14 [7%]), respiratory failure (11 [5%], 14 [7%], 11 [5%]), and constipation (7 [3%], 13 [6%], 10 [5%]). 41 (7%) treated patients died during the study (15 [7%], 15 [7%], 11 [5%]); the most common causes of death were respiratory failure and septic shock. INTERPRETATION: Time to clinical response to intravenous zanamivir dosed at 600 mg was not superior to oseltamivir or 300 mg intravenous zanamivir. All treatments had a similar safety profile in hospitalised patients with severe influenza. FUNDING: GlaxoSmithKline.


Subject(s)
Antiviral Agents/administration & dosage , Hospitalization , Influenza, Human/drug therapy , Oseltamivir/administration & dosage , Zanamivir/administration & dosage , Administration, Intravenous , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Humans , Male , Middle Aged , Treatment Outcome , Young Adult
7.
Antiviral Res ; 134: 144-152, 2016 10.
Article in English | MEDLINE | ID: mdl-27568923

ABSTRACT

Intravenous zanamivir (IVZ) is a neuraminidase (NA) inhibitor (NAI) under investigation for the treatment of subjects hospitalised with influenza. The study included 130 symptomatic, hospitalised adults with influenza. Subjects received IVZ for 5-10 days. Viruses were cultured and analysed for susceptibility to zanamivir. Mean IC50s (nĀ =Ā 50) (Ā±SD) for influenza A/H1N1pdm09, A/H3N2 and influenza B were 0.20Ā Ā±Ā 0.06, 0.26Ā Ā±Ā 0.07 and 1.61Ā Ā±Ā 0.35Ā nM, respectively, and are comparable to data observed for sensitive isolates. A total of 185 NA and 180 haemagglutinin (HA) sequences were obtained from 123 subjects; the majority did not contain resistance substitutions. Four influenza A/H1N1pdm09 viruses from four subjects harboured NA resistance substitutions: three, Y155H, D199G and S247N, were present at Day 1 before IVZ exposure and the fourth, E119D/E, was detected at Post TreatmentĀ +5Ā Days but was not present at 5 other timepoints. Five subjects harboured virus with treatment-emergent NA substitutions not associated with resistance; N63D, V83A, W190C, M269K (A/H1N1pdm09) and R210K (A/H3N2). Viruses from fifteen subjects harboured HA resistance substitutions, (A/H1N1pdm09) one emerged during treatment: S162N (Day 5). Five viruses harboured treatment-emergent HA substitutions (A/H1N1pdm09) not associated with resistance: E81K, V108L, S164D, D168N and S185N. 10/92 subjects with A/H1N1pdm09 harboured a D222 HA substitution, which has been associated with increased virulence. The emergent substitutions are not associated with resistance but may have arisen due to selection pressure during IVZ treatment or by chance. In this study, there was evidence for resistance selection in a post treatment sample but the resistant variant did not persist in later visit samples.


Subject(s)
Administration, Intravenous , Genotype , Influenza A Virus, H3N2 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/genetics , Phenotype , Zanamivir/administration & dosage , Adult , Drug Resistance, Viral/genetics , Hemagglutinins/genetics , Hospitalization , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza A Virus, H3N2 Subtype/classification , Influenza A Virus, H3N2 Subtype/isolation & purification , Influenza, Human/drug therapy , Influenza, Human/virology , Inhibitory Concentration 50 , Neuraminidase/genetics , Sequence Analysis, DNA , Zanamivir/adverse effects , Zanamivir/pharmacology , Zanamivir/therapeutic use
9.
Clin Pharmacol Drug Dev ; 2(4): 342-348, 2013 Oct.
Article in English | MEDLINE | ID: mdl-26097786

ABSTRACT

This study evaluated dolutegravir pharmacokinetics (PK) in subjects with moderate hepatic impairment compared to matched, healthy controls. In this open-label, parallel-group study, eight adult subjects with moderate hepatic impairment (Child-Pugh Score 7-9) and eight healthy subjects matched for gender, age, and body mass index received a single dolutegravir 50-mg dose. Following dosing, 72-hour PK sampling was performed to determine total and unbound dolutegravir concentrations. PK parameters were calculated using non-compartmental analysis. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CIs) in subjects with hepatic impairment versus healthy subjects were generated by analysis of variance. Results showed that PK parameters of total plasma dolutegravir were similar between subject groups. The unbound fraction was higher in subjects with moderate hepatic impairment than in healthy subjects with GMR (90% CI) of 2.20 (1.62, 2.99) for unbound fraction at 3 hours post-dose and 1.76 (1.23, 2.51) for unbound fraction at 24 hours post-dose; this correlated with lower serum albumin concentrations and was not considered clinically significant. Dolutegravir was well tolerated in both groups; all adverse events were reported as minor. Although free fraction was increased, no dose adjustment is required for patients treated with dolutegravir who have mild to moderate hepatic impairment.

10.
J Burn Care Res ; 31(2): 365-8, 2010.
Article in English | MEDLINE | ID: mdl-20182379

ABSTRACT

The pathogenesis of Stevens-Johnson syndrome (SJS) remains obscure, but it has been associated with various infectious agents, including members of the herpesvirus family. We present the first report of high-level human herpesvirus-6 viremia at the onset of SJS, suggesting a possible new association. This finding supports the need for further investigation into the possible relationship between human herpesvirus-6 and SJS, which may illuminate the pathogenesis of SJS and bring us closer to achieving enhanced prevention and treatment of this rare disease.


Subject(s)
Herpesvirus 6, Human , Roseolovirus Infections/virology , Stevens-Johnson Syndrome/virology , Adolescent , Diagnosis, Differential , Female , Humans , Immunoglobulin G/therapeutic use , Middle Aged , Roseolovirus Infections/diagnosis , Roseolovirus Infections/drug therapy , Stevens-Johnson Syndrome/diagnosis , Stevens-Johnson Syndrome/drug therapy , Viremia/virology
12.
Infect Immun ; 74(9): 5161-8, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16926408

ABSTRACT

We applied an immunoscreening technique, in vivo-induced antigen technology (IVIAT), to identify immunogenic bacterial proteins expressed during human infection with Salmonella enterica serovar Typhi, the cause of typhoid fever. We were able to assign a functional classification to 25 of 35 proteins identified by IVIAT. Of these 25, the majority represent proteins with known or potential roles in the pathogenesis of S. enterica. These include proteins implicated in fimbrial structure and biogenesis, antimicrobial resistance, heavy metal transport, bacterial adhesion, and extracytoplasmic substrate trafficking as well as secreted hydrolases. The 10 remaining antigens represent proteins with unknown functions. Of the 35 identified antigens, four had no immunoreactivity when probed with control sera from individuals never exposed to serovar Typhi organisms; these four included PagC, TcfB, and two antigens of unknown function encoded by STY0860 and STY3683. PagC is a virulence factor known to be upregulated in vivo in S. enterica serovar Typhimurium infection of mice. TcfB is the major structural subunit of a fimbrial operon found in serovar Typhi with no homolog in serovar Typhimurium organisms. By examining differential immunoreactivities in acute- versus convalescent-phase human serum samples, we found specific anti-PagC and anti-TcfB immunoglobulin G responses in patients with serovar Typhi bacteremia. Serovar Typhi antigens identified by IVIAT warrant further evaluation for their contributions to pathogenesis, and they may have diagnostic, therapeutic, or preventive uses.


Subject(s)
Antigens, Bacterial/analysis , Bacterial Proteins/analysis , Membrane Proteins/analysis , Salmonella typhi/immunology , Typhoid Fever/immunology , Antigens, Bacterial/classification , Antigens, Bacterial/genetics , Bacterial Proteins/classification , Bacterial Proteins/genetics , Humans , Immunoassay , Immunoglobulin G/blood , Membrane Proteins/classification , Membrane Proteins/genetics , Salmonella typhi/genetics , Typhoid Fever/diagnosis
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