Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).

Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (P<0.001). Among the 78 patients (53.4%) in the ruxolitinib arm who achieved ⩾35% reductions in spleen volume at any time, the probability of maintaining response was 0.48 (95% confidence interval (CI), 0.35–0.60) at 5 years (median, 3.2 years). Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with ruxolitinib compared with BAT by intent-to-treat analysis (hazard ratio (HR)=0.67; 95% CI, 0.44–1.02; P=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18–1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits.

Key Points• Long-term analysis of the COMFORT-II Trial shows that ruxolitinib treatment results in durable reductions in splenomegaly and is well tolerated.• Patients randomized to ruxolitinib showed longer overall survival than those receiving the BAT.Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of ‡35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P 5 .009). This trial was registered at clinicaltrials.gov as #NCT00934544. (Blood. 2013;122(25):4047-4053)

The intrapulmonary pharmacokinetics of rifapentine were studied in 30 volunteers who received a single, oral dose of rifapentine (600 mg). Subgroups of five subjects each underwent bronchoscopy and bronchoalveolar lavage (BAL) at timed intervals following drug administration. Drug concentrations, including the concentration of the primary metabolite 25-desacetyl rifapentine, were determined in plasma, BAL fluid, and alveolar cells (AC) by high-pressure liquid chromatography. The concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The concentration-time data were fit to two-compartment (plasma) or one-compartment (AC and ELF) models. The peak concentrations in plasma, ELF, and AC, 26.2, 3.7, and 5.3 g/ml, respectively, occurred at 5, 5, and 7 h after drug administration, respectively. The half-lives and areas under the curve for plasma, ELF, and AC were 18.3 h and 520 g ⅐ h/ml, 20.8 h and 111 g ⅐ h/ml, and 13.0 h and 133 g ⅐ h/ml, respectively. Although the intrapulmonary rifapentine concentrations were less than the plasma rifapentine concentrations at all time periods, they remained above the proposed breakpoint for M. tuberculosis (0.5 g/ml) for the 48-h observation period. These data provide a pharmacokinetic rationale for extended-interval dosing. The optimum dosing regimen for rifapentine will have to be determined by controlled clinical trials.Rifapentine is an orally administered rifamycin derivative that has antituberculous activity and that is similar to rifampin (11,12,16,27). The MICs for sensitive strains are usually in the range of 0.03 to 0.12 mg/liter, and MICs for resistant strains are Ն8 mg/liter (15). Cross-resistance between rifapentine and rifampin is virtually complete (15). Cross-resistance between rifapentine and rifampin is virtually complete (15). Rifapentine has a longer elimination half-life than rifampin, allowing the possibility of less frequent (twice-or once-weekly) administration (17).There have been no previous reports of the intrapulmonary concentrations or pharmacokinetics of rifapentine in humans. The purpose of this study was to compare the concentrations of rifapentine in plasma, alveolar cells (ACs), and epithelial lining fluid (ELF) of normal volunteers and to compare the drug's pharmacokinetics in these three compartments. MATERIALS AND METHODSSubjects. The protocol was approved by the Human Research Committee of the University of California, San Francisco. Written informed consent was obtained from each subject by an experienced research nurse. Subjects were required to be 18 to 45 years of age. If the subjects were female, they were required to be nonlactating and not pregnant and to agree to use adequate contraception (e.g., barrier methods or abstinence) during the study and for 2 weeks following completion of the study. Women using oral contraceptives were required to agree to use a barrier method in addition for 1 month following the study. Subjects who were lactating or pregnant, had a history of intolerance to rifamycin dr...

The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 ؎ 1.60 g/ml [mean ؎ standard deviation; n ‫؍‬ 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 ؎ 3.50 g/ml) or ACs (2.61 ؎ 5.01 g/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 g/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 g/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 g/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.Isoniazid is an essential drug in the treatment of tuberculosis. For humans without tuberculosis who received a single 250-mg oral dose of isoniazid, elimination half-lives have been reported to be 1.2 and 3.3 h in fast and slow acetylators, respectively, and peak concentrations in plasma (at 1 h postdosing) have been reported to be 2.44 and 3.64 g/ml, respectively (25) 1993). However, this effect was not demonstrated in Kenyan patients, in whom concentrations in plasma were not different among individuals with or without AIDS or w...