Amanda Peppercorn

Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: Results of a phase 1 study among healthy subjects

Background:Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV integrase inhibitor, dolutegravir (DTG). Methods:Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. Results:In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time–concentration curve (AUC0–24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (C&tgr;) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0–24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the C&tgr; was 0.70 (90% CI: 0.57 to 0.87). Conclusions:Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.

Increasing US rates of endocarditis with Staphylococcus aureus: 1999-2008.

Estimates of the incidence and impact of bacterial infective endocarditis (IE) have been limited by the infrequency of the disease. Administrative data analyses can provide important information across a broad range of hospitals and regions. We used a recent, nationally representative sample to estimate the incidence of hospitalizations for bacterial IE in the United States.

Safety and Pharmacokinetics of Intravenous Zanamivir Treatment in Hospitalized Adults With Influenza: An Open-label, Multicenter, Single-Arm, Phase II Study

Abstract Background.u2003Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. Methods.u2003Patients 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.u2003One 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.u2003Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. Clinical Trials Registrationu2003NCT01014988.

Pharmacokinetics of Single-Dose Dolutegravir in HIV-Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls

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 3u2009hours post‐dose and 1.76 (1.23, 2.51) for unbound fraction at 24u2009hours 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.

Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial

BACKGROUNDnNeuraminidase 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.nnnMETHODSnIn 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 GlaxoSmithKlines 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 1·5 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.nnnFINDINGSnBetween 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 5·14 days in the 600 mg intravenous zanamivir group, the median time to clinical response was 5·87 days (difference of -0·73 days, 95% CI -1·79 to 0·75; p=0·25) in the 300 mg intravenous zanamivir group and 5·63 days (difference of -0·48 days, 95% CI -2·11 to 0·97; p=0·39) 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.nnnINTERPRETATIONnTime 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.nnnFUNDINGnGlaxoSmithKline.

Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir

PurposeDolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects.MethodsThe first study was an open-label crossover where 12 subjects received DTG 50xa0mgxa0every 24 hours (q24h) for 5xa0days, followed by DTG 50xa0mg and EFV 600xa0mg q24h for 14xa0days. The second study was an open-label crossover where 18 subjects received DTG 50xa0mgxa0q24h for 5xa0days followed by TPV/r 500/200xa0mg every 12 hours (q12h) for 7xa0days and then DTG 50xa0mg q24h and TPV/r 500/200xa0mg q12h for a further 5xa0days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90xa0% confidence intervals were generated.ResultsThe combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75xa0% in DTG AUC(0–τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76xa0% in DTG AUC(0–τ), Cmax and Cτ, respectively.ConclusionsGiven the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50xa0mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.

Relative bioavailability of a paediatric granule formulation of the HIV integrase inhibitor dolutegravir in healthy adult subjects.

BACKGROUNDnThis study evaluated the pharmacokinetics of a granule formulation of dolutegravir developed as an alternative to tablets for use in paediatric populations.nnnMETHODSnA randomized, open-label study in healthy adults was carried out. Subjects received five treatments in a crossover design: a single dose of dolutegravir 50 mg as a tablet and dolutegravir 50 mg in 10 g of granule administered directly to mouth or mixed with purified water, water containing high cation concentrations or milk-based infant formula. Study treatments were separated by 7 days. Safety evaluations and serial pharmacokinetic sampling were done during each treatment period. A non-compartmental pharmacokinetic analysis was performed; geometric least-squares mean ratios and 90% CIs were generated for treatment comparison. Palatability was assessed by questionnaire.nnnRESULTSnPlasma dolutegravir exposures in all granule treatment arms exceeded those of tablet formulation. The mean area under the curve from time 0 to infinity (AUC(0-∞)) and maximum concentrations were 55-83% and 62-102% higher, respectively. Pharmacokinetics were similar when dolutegravir was mixed with purified or cation-containing water. Dolutegravir was well tolerated, with no withdrawals due to adverse events. Taste was rated acceptable for all treatments.nnnCONCLUSIONSnThe exposure of dolutegravir after administration of granule formulation alone, with different types of water and with milk formula, exceeded that of the tablet. The similarity of dolutegravir exposure seen with the granule formulation demonstrates that dolutegravir granule can be given without restriction on the type of liquid or can be administered directly to the mouth (for example, when potable water is not available).

Phenotypic and genotypic analysis of influenza viruses isolated from adult subjects during a phase II study of intravenous zanamivir in hospitalised subjects

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 (nxa0=xa050) (±SD) for influenza A/H1N1pdm09, A/H3N2 and influenza B were 0.20xa0±xa00.06, 0.26xa0±xa00.07 and 1.61xa0±xa00.35xa0nM, 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 Treatmentxa0+5xa0Days 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.

Intravenous Zanamivir in Hospitalized Patients With Influenza

This open-label study of IV zanamivir (an NA inhibitor for treatment of severe influenza in hospitalized children) suggests a positive risk/benefit profile. BACKGROUND: Children with severe influenza infection may require parenteral therapy if oral or inhaled therapies are ineffective or cannot be administered. Results from a study investigating intravenous (IV) zanamivir for the treatment of hospitalized infants and children with influenza are presented. METHODS: This phase II, open-label, multicenter, single-arm study assessed the safety of investigational IV zanamivir in hospitalized children with influenza. Safety outcomes included treatment-emergent adverse events (TEAEs), clinical laboratory measurements, and vital signs. Clinical outcomes, pharmacokinetics, and virologic efficacy data were collected as key secondary outcomes. RESULTS: In total, 71 children received treatment with investigational IV zanamivir (exposure comparable to 600 mg twice daily in adults). TEAEs and serious TEAEs (STEAEs) were reported in 51 (72%) and 15 (21%) patients, respectively. The mortality rate was 7%, and median durations of hospital and ICU stays were 6 and 7.5 days, respectively. No STEAEs or deaths were considered related to IV zanamivir treatment, and no patterns of TEAEs, laboratory abnormalities, or vital signs were observed. The mean zanamivir exposures from 34 patients with normal renal function who received 12 mg/kg, 14 mg/kg, or 600 mg of IV zanamivir ranged from 64.5 to 110 hour·µg/mL. The median change from baseline in the viral load was −1.81 log10 copies per mL after 2 days of treatment. CONCLUSIONS: The safety profile of IV zanamivir was favorable, with no drug-related STEAEs reported. The majority of children experienced virologic response and clinical improvement during the treatment course. Systemic zanamivir exposures in children were consistent with adults.

Safety, tolerability and pharmacokinetics of orally inhaled zanamivir: a randomized study comparing Rotacap/Rotahaler and Rotadisk/Diskhaler in healthy adults.

BACKGROUNDnDuring a pandemic, the need for available anti-influenza medications increases. There has been extensive use of the approved zanamivir Rotadisk/Diskhaler but no clinical data are available for administration by an alternative Rotacap/Rotahaler presentation.nnnMETHODSnIn this randomized three-way crossover study, each healthy adult received zanamivir 10 mg every 12 h for 5 days via Rotadisk/Diskhaler, via Rotacap/Rotahaler and placebo via Rotacap/Rotahaler, with a washout period between treatments. Safety assessments were conducted throughout the study and at follow-up. Serial blood samples for pharmacokinetic analysis were collected over a 12-h dose interval on day 5 of each treatment period. Pharmacokinetic parameters were compared using a mixed-effects model.nnnRESULTSnA total of 18 healthy adults were recruited and 17 subjects completed the study. A total of 20 adverse events (AEs) were reported (all grade 1) by nine subjects, with no AE reported ≥1× in any treatment group. Nasal congestion, reported by one subject in the zanamivir Rotadisk/Diskhaler group, was the only drug-related AE. No serious AEs or withdrawals due to AEs occurred during the study. There were no significant changes in clinical laboratory values, vital signs or spirometry. Serum zanamivir exposures were similar after administration via Rotacap/Rotahaler and Rotadisk/Diskhaler. Both oral inhalation presentations are likely to deliver similar zanamivir concentrations to sites of influenza infection in the respiratory tract.nnnCONCLUSIONSnThe safety and pharmacokinetic results from this study support the use of the Rotacap/Rotahaler presentation, potentially allowing an increased number of zanamivir treatment courses to be supplied in the event of an influenza pandemic.