Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers

Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.Rifapentine (RFP), a cyclopentyl rifamycin, is an orally administered drug registered by the Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis (TB). It exerts its antibacterial activity through inhibition of DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis (32). RFP has a microbiologically active metabolite, 25-desacetyl rifapentine (25-DRFP) (10). RFP has a long half-life (5, 17) and superior in vitro potency against M. tuberculosis in comparison with rifampin and rifabutin (10), making it an attractive candidate for shortening and simplifying antitubercular therapy.Currently, RFP is dosed at 600 mg either once weekly or twice weekly in human immunodeficiency virus (HIV)-negative patients with noncavitary TB (2). There is concern that the development of acquired rifamycin monoresistance (ARR), treatment failure, and relapse may be associated with intermittent dosing (4, 20), insufficient companion drug exposure (33), or low rifamycin concentrations (9, 21). RFP''s sterilizing effect has been shown to be dose dependent in murine studies which suggest that daily doses of RFP may reduce treatment duration to just 3 months (25, 26, 37), and higher doses of RFP are associated with improved early bactericidal activity in humans (29). Clinical trials are currently evaluating new antituberculosis regimens containing higher doses of RFP used intermittently or daily doses of RFP. Concomitant food has a marked effect on RFP absorption (6). The effect of food on systemic RFP exposure may therefore impact treatment activity and safety. The aim of this study was to investigate the effect of meals differing in fat and bulk content on the rate and extent of RFP absorption and 25-DRFP disposition. The study was designed to include meals comprising largely maize, a staple cereal in many parts of Africa and South America, and a light meal (i.e., a reconstituted powdered chicken soup). The study was conducted in 1999 shortly after the release of results from studies evaluating intermittent 600-mg doses of rifapentine, which displayed unacceptably high relapse rates in patients with lung cavities or immune suppression. It was therefore anticipated that future studies would evaluate higher doses of the drug.     

Effects of multiple daily injection therapy with Humalog mixtures versus separately injected insulin lispro and NPH insulin in adults with type I diabetes mellitus

BACKGROUND: Injection of insulin lispro (LP) before meals provides a more physiologic insulin activity profile than regular human insulin, but the relatively short duration of action of LP may allow the blood glucose (BG) level to increase during the late postprandial period (4-7 hours after meals) unless basal insulin is optimally replaced. One approach to basal insulin optimization has been to combine small doses of NPH with LP before meals. When used in a similar fashion, premixed, fixed-ratio insulin preparations containing LP and NPL (an LP-based intermediate-acting insulin) may provide the basis for an optimized basal-bolus insulin regimen. OBJECTIVE: This study assessed mean late postprandial glycemic control during treatment with a premixed formulation consisting of a high proportion of LP (75% LP/25% NPL; H) and a premixed formulation consisting of a medium proportion of LP (50% LP/50% NPL; M). The H/M formulation was given before meals and was compared with treatment with preprandial LP + NPH (LP + N) in patients with type 1 diabetes mellitus (DM). METHODS: This multicenter, randomized, open-label, 2-period crossover study was conducted at 4 centers in Italy and 1 center in France. Patients eligible for the study had type 1 DM, were > or = 18 years of age, and had a glycosylated hemoglobin (HbA(1c)) <150% of the upper limit of normal. Patients were randomly assigned to 1 of 2 treatment sequences: LP self-mixed with NPH before meals plus NPH alone at bedtime for 8 weeks (LP + N) followed by preprandial H or M, plus NPH alone at bedtime for 8 weeks (H/M), or the opposite sequence. Assessments included 8-point self-monitored BG profiles, HbA(1c), and hypoglycemia (any sign or symptom of hypoglycemia or BG < 3.0 mmol/L [<54.0 mg/dL]). The primary outcome measure was the late postprandial BG value, calculated as the mean of the combined prelunch (late postbreakfast), predinner (late postlunch), and bedtime (late postdinner) values. RESULTS: A total of 89 patients with type 1 DM were enrolled (44 men, 45 women; mean [SD] age, 38.3 [12.8] years; mean [SD] body weight, 70.8 [11.6] kg; mean [SD] body mass index, 24.6 [3.0] kg/m(2); mean [SD] duration of diabetes, 17.8 [10.5] years; mean HbA(1c), 7.9% [0.88%]). The mean (SD) late postprandial BG values were similar between treatments (8.9 [2.1] mmol/L [160.3 (37.8) mg/dL] for H/M vs 9.0 [1.8] mmol/L [162.1 (32.4) mg/dL] for LP + N), as were the end point HbA(1c) values (7.8% [0.9%] for H/M vs 7.9% [0.8%] for LP + N). The rate of hypoglycemia was significantly higher during treatment with H/M, primarily because of episodes occurring between 12 PM and 6 PM, but was relatively low in both groups (mean/median rate per patient per 30 days: 2.87/2.14 for H/M and 2.11/1.07 for LP + N; P < 0.05). CONCLUSIONS: In this population of patients with type 1 DM, preprandial H/M provided an effective alternative regimen for prandial and basal insulin replacement. Late postprandial BG control, an indicator of basal insulin sufficiency, was similar to that achieved with an intensified regimen of LP + N injected separately before meals, and the end point HbA(1c) was similar between the 2 treatments.     

Molecular Diagnosis of Fluoroquinolone Resistance in Mycobacterium tuberculosis

As a consequence of the use of fluoroquinolones (FQ), resistance to FQ has emerged, leading to cases of nearly untreatable and extensively drug-resistant tuberculosis. Mutations in DNA gyrase represent the main mechanism of FQ resistance. A full understanding of the pattern of mutations found in FQ-resistant (FQ^r) clinical isolates, and of their proportions, is crucial for improving molecular methods for the detection of FQ resistance in Mycobacterium tuberculosis. In this study, we reviewed the detection of FQ resistance in isolates addressed to the French National Reference Center for Mycobacteria from 2007 to 2012, with the aim of evaluating the performance of PCR sequencing in a real-life context. gyrA and gyrB sequencing, performed prospectively on M. tuberculosis clinical isolates, was compared for FQ susceptibility to 2 mg/liter ofloxacin by the reference proportion method. A total of 605 isolates, of which 50% were multidrug resistant, were analyzed. The increase in FQ^r strains among multidrug-resistant (MDR) strains during the time of the study was alarming (8% to 30%). The majority (78%) of the isolates with gyrA mutations were FQ^r, whereas only 36% of those with gyrB mutations were FQ^r. Only 12% of the FQ^r isolates had a single mutation in gyrB. Combined gyrA and gyrB sequencing led to >93% sensitivity for detecting resistance. The analysis of the four false-positive and the five false-negative results of gyrA and gyrB sequencing illustrated the actual limitations of the reference proportion method. Our data emphasize the need for combined gyrA and gyrB sequencing in the investigation of FQ susceptibility in M. tuberculosis and challenge the validity of the current phenotype-based approach as the diagnostic gold standard for determining FQ resistance.     

Intestinal over-expression of iron transporters induces iron overload in birds in captivity

Hereditary hemochromatosis (HH) is a frequent genetic disease of older subjects of northern European descent. It is characterized by increased iron absorption and severe iron overloading in parenchymal organs. A similar disturbance of iron metabolism occurs in specific animal species in captivity. To address the key features leading to high absorption and thus to iron overload in these animals, we have studied the two iron transport proteins DMT1 and Ireg1 in the best-known susceptible species, the mynah bird. Here, we show that these birds have a high expression of DMT1 in the duodenum and also a strikingly high expression of Ireg1 along the whole small intestine. We believe that the iron accumulation in susceptible species only occurs in captivity because of a genotypic adaptation to their natural environment, where contrary to captivity, dietary iron is hardly available. The Caucasian population carrying mutations leading to iron overload today may have also benefited from the genetic advantage of up-regulating iron transport millennia ago, when dietary iron was scarce.