Doris J. Rouse

Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients

ABSTRACT PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (± standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (±0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (±0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.

Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects

ABSTRACT PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compounds MIC is between 0.015 and 0.25 μg/ml for drug-sensitive strains and between 0.03 and 0.53 μg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 μg/ml (1,500-mg dose) in the single-dose study and 3.8 μg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.

Chlorhexidine vaginal and neonatal wipes in home births in Pakistan - A Randomized controlled trial

OBJECTIVE: To assess tolerance and safety of 0.6% chlorhexidine vaginal and neonatal wipes to improve perinatal outcomes in home deliveries in Pakistan and the ability of traditional birth attendants and project staff to perform a randomized trial of this intervention. METHODS: Focus groups of pregnant and nonpregnant women and in-depth interviews of traditional birth attendants explored barriers to the use of chlorhexidine wipes. Then, a study was performed of women delivering at home attended by traditional birth attendants. Consenting women were randomly assigned to receive either 0.6% chlorhexidine or saline vaginal and neonatal wipes. Women and their infants were followed up on postpartum days 7, 14, and 28. Acceptability and tolerance of vaginal and neonatal wipes, as well as maternal and neonatal outcomes, were assessed. RESULTS: The focus groups and interviews indicated that the chlorhexidine intervention would be acceptable to women and their providers. Of the 213 eligible pregnant women approached, 203 (95%) gave informed consent and were enrolled and allocated to groups. Traditional birth attendants had no difficulty administering chlorhexidine vaginal and neonatal wipes in a home setting. Of the 203 births, 103 (51%) of whom received 0.6% chlorhexidine, there were no allergic reactions, vaginal itching, burning, or requests for study termination. Follow-up at 28 days postpartum was more than 95%. Although this study was not powered to show significant differences in neonatal outcomes between treatment groups, the lower rates of some neonatal adverse clinical outcomes in the chlorhexidine group were encouraging. CONCLUSION: Use of 0.6% chlorhexidine vaginal and neonatal wipes for the prevention of neonatal infection is well-tolerated and seems safe. A trial of this intervention by traditional birth attendants in a home-delivery setting is feasible. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00121394 LEVEL OF EVIDENCE: I

Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

ABSTRACT This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0–t), and AUC extrapolated to infinity (AUC0–inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0–t, and AUC0–inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0–t, and AUC0–inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.)

Evaluation of Pharmacokinetic Interaction between PA-824 and Midazolam in Healthy Adult Subjects

ABSTRACT This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC0–t, AUC0–∞, and Cmax for midazolam and 1-hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of Cmax, AUC0–t, and AUC0–∞ parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The Cmax of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs.

NASA spinoffs to bioengineering and medicine

Through the active transfer of technology, the National Aeronautics and Space Administration (NASA) Technology Utilization (TU) Program assists private companies, associations, and government agencies to make effective use of NASAs technological resources to improve U.S. economic competitiveness and to provide societal benefit. Aerospace technology from areas such as digital image processing, space medicine and biology, microelectronics, optics and electrooptics, and ultrasonic imaging have found many secondary applications in medicine. Examples of technology spinoffs are briefly discussed to illustrate the benefits realized through adaptation of aerospace technology to solve health care problems. Successful implementation of new technologies increasingly requires the collaboration of industry, universities, and government, and the TU Program serves as the liaison to establish such collaborations with NASA. NASA technology is an important resource to support the development of new medical products and techniques that will further advance the quality of health care available in the U.S. and worldwide.

Interventions to reduce neonatal mortality: a mathematical model to evaluate impact of interventions in sub‐Saharan Africa

To determine which interventions would have the greatest impact on reducing neonatal mortality in sub‐Saharan Africa in 2012.

Maternal and Neonatal Directed Assessment of Technologies (MANDATE): Methods and Assumptions for a Predictive Model for Maternal, Fetal, and Neonatal Mortality Interventions

MANDATE is a mathematical model designed to estimate the relative impact of different interventions on maternal, fetal, and neonatal lives saved in sub-Saharan Africa and India. A key advantage is that it allows users to explore the contribution of preventive interventions, diagnostics, treatments, and transfers to higher levels of care to mortality reductions, and at different levels of penetration, utilization, and efficacy. MANDATE is a mathematical model designed to estimate the relative impact of different interventions on maternal, fetal, and neonatal lives saved in sub-Saharan Africa and India. A key advantage is that it allows users to explore the contribution of preventive interventions, diagnostics, treatments, and transfers to higher levels of care to mortality reductions, and at different levels of penetration, utilization, and efficacy. Maternal, fetal, and neonatal mortality disproportionately impact low- and middle-income countries, and many current interventions that can save lives are often not available nor appropriate for these settings. Maternal and Neonatal Directed Assessment of Technologies (MANDATE) is a mathematical model designed to evaluate which interventions have the greatest potential to save maternal, fetal, and neonatal lives saved in sub-Saharan Africa and India. The MANDATE decision-support model includes interventions such as preventive interventions, diagnostics, treatments, and transfers to different care settings to compare the relative impact of different interventions on mortality outcomes. The model is calibrated and validated based on historical and current rates of disease in sub-Saharan Africa and India. In addition, each maternal, fetal, or newborn condition included in MANDATE considers disease rates specific to sub-Saharan Africa and India projected to intervention rates similar to those seen in high-income countries. Limitations include variance in quality of data to inform the estimates and generalizability of findings of the effectiveness of the interventions. The model serves as a valuable resource to compare the potential impact of multiple interventions, which could help reduce maternal, fetal, and neonatal mortality in low-resource settings. The user should be aware of assumptions in evaluating the model and interpret results accordingly.