Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling.

BACKGROUND AND INTRODUCTION: The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose. METHODS: Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods. RESULTS: A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86-171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively. CONCLUSION: Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.

Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis.

Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log10(CFU). We also assessed the safety and pharmacokinetics of the study treatments. We found that bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1,200 mg QD (4.5%; 95% Bayesian confidence interval [BCI], 3.3 to 5.6), followed by 600 mg BD (4.1%; BCI, 2.5 to 5.7), 600 mg QD (4.1%; BCI, 2.9 to 5.3), 300 mg BD (3.3%; BCI, 1.9 to 4.7), 300 mg QD (2.3%; BCI, 1.1 to 3.5), and 1,200 mg TIW (2.2%; BCI, 1.1 to 3.3). Similar results were seen with bactericidal activity characterized by the daily rate of change in CFU count. Antimycobacterial activity correlated positively with plasma drug exposure and percentage time over MIC. There were no unexpected adverse events. All linezolid doses showed bactericidal activity. For the same total daily dose, once-daily dosing proved to be at least as effective as a divided twice-daily dose. An intermittent dosing regimen, with 1,200 mg given three times weekly, showed the least activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02279875.).

Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis.

BACKGROUND: Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. RESULTS: Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. CONCLUSIONS: The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.).

A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris.

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.

Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia.

OBJECTIVES: To summarize the 6-year clinical trial data with finasteride. Benign prostatic hyperplasia is a chronic and progressive disease and therefore assessment of long-term safety and efficacy is important. METHODS: The North American and International Phase III Finasteride trials enrolled symptomatic men with enlarged prostate glands. The initial 1-year placebo-controlled study was followed by a 5-year open-label extension. In total, 6-year finasteride data were available in 487 patients originally randomized to finasteride, and 5-year data were available on 238 patients originally randomized to placebo. RESULTS: After 6 years of treatment with finasteride 5 mg, the mean quasi-American Urological Association Symptom Score improved by 4.0 points, the median prostate volume decreased by 24%, and the mean maximal urinary flow rate increased by 2.9 mL/s (P <0.001 for all parameters). Long-term finasteride treatment was well tolerated, with a low incidence of drug-related sexual adverse events occurring during the first year and even fewer occurrences during the 5-year open extension. CONCLUSIONS: Treatment with finasteride leads to durable improvement in urinary tract symptoms, flow rate, and prostate volume, with no increase in the prevalence of drug-related adverse events over time.