Therapeutic drug monitoring of posaconazole in allogeneic hematopoietic stem cell transplantation patients who develop gastrointestinal graft-versus-host disease.

Posaconazole (PCZ) is the latest triazole antifungal agent that has been approved for prophylaxis of invasive aspergillosis in high-risk immunocompromised patients, such as allogeneic hematopoietic stem cell transplantation patients, who develop graft-versus-host disease (GVHD). PCZ has high interindividual variability with regard to its plasma drug trough concentrations (C(min)). Moreover, the concentration-efficiency relationship remains to be better characterized in prophylaxis. To determine the variability factors in plasma drug concentrations, the PCZ C(min) and clinical parameters (localization of GVHD, presence of diarrhea, and diagnosis of invasive aspergillosis) were collected retrospectively in 29 consecutive allogeneic hematopoietic stem cell transplantation patients who developed GVHD and were receiving prophylactic PCZ (200 mg, 3 times/day, for ≥7 days). Blood samples were analyzed at steady state to determine the PCZ C(min) by liquid chromatography-tandem mass spectrometry. The average PCZ C(min) was 1.28 ± 0.82 mg/liter (mean ± standard deviation; n = 292 dosages), with an intraindividual variability of 49% and an interindividual variability of 64%. Twenty percent of C(min)s were below 0.7 mg/liter, which is considered the threshold of efficacy by the Food and Drug Administration. The patients who had gastrointestinal (GI) GVHD experienced a 24% reduction in the posaconazole C(min), compared with those with other localizations of GVHD. This decrease reached 33% when patients presented with diarrhea due to GI GVHD or an infectious etiology. PCZ C(min)s were 26% lower when invasive aspergillosis was declared. These data demonstrate that GI disturbances affect drug concentrations. Thus, therapeutic monitoring of PCZ can be used to detect low drug concentrations, possibly resulting in a lack of efficacy of invasive aspergillosis prophylaxis.

Methodological aspects of crossover and maximum fat-oxidation rate point determination.

AIM: Indirect calorimetry during exercise provides two metabolic indices of substrate oxidation balance: the crossover point (COP) and maximum fat oxidation rate (LIPOXmax). We aimed to study the effects of the analytical device, protocol type and ventilatory response on variability of these indices, and the relationship with lactate and ventilation thresholds. METHODS: After maximum exercise testing, 14 relatively fit subjects (aged 32+/-10 years; nine men, five women) performed three submaximum graded tests: one was based on a theoretical maximum power (tMAP) reference; and two were based on the true maximum aerobic power (MAP). Gas exchange was measured concomitantly using a Douglas bag (D) and an ergospirometer (E). RESULTS: All metabolic indices were interpretable only when obtained by the D reference method and MAP protocol. Bland and Altman analysis showed overestimation of both indices with E versus D. Despite no mean differences between COP and LIPOXmax whether tMAP or MAP was used, the individual data clearly showed disagreement between the two protocols. Ventilation explained 10-16% of the metabolic index variations. COP was correlated with ventilation (r=0.96, P<0.01) and the rate of increase in blood lactate (r=0.79, P<0.01), and LIPOXmax correlated with the ventilation threshold (r=0.95, P<0.01). CONCLUSION: This study shows that, in fit healthy subjects, the analytical device, reference used to build the protocol and ventilation responses affect metabolic indices. In this population, and particularly to obtain interpretable metabolic indices, we recommend a protocol based on the true MAP or one adapted to include the transition from fat to carbohydrate. The correlation between metabolic indices and lactate/ventilation thresholds suggests that shorter, classical maximum progressive exercise testing may be an alternative means of estimating these indices in relatively fit subjects. However, this needs to be confirmed in patients who have metabolic defects.

Exhaled nitric oxide in single and repetitive prolonged exercise.

This study was performed to determine the influence of single and repetitive exercise on nitric oxide (NO) concentration in the lung. Exhaled NO concentration (FE(NO)) was measured during a constant-flow exhalation manoeuvre (170 ml x s(-1), against a 10 cmH2O resistance) in healthy individuals (a) during and after a 100-min square-wave exercise of between 25 and 60% of maximal power output (n = 18) and (b) before and after five successive prolonged exercises (90-120 min, 75-85% of maximal heart rate) separated by 48 or 24 h (n = 8). The FE(NO0.170) was decreased during and after the 100-min exercise test (mean +/- s(x): 58.5 +/- 3.7% and 76.7 +/- 5.2% of resting value at 90 min of exercise and 15 min post-exercise, respectively; P < 0.05). The five successive exercise sessions induced a similar post-exercise FE(NO0.170) decrement (73.1 +/- 2.9% of resting value 15 min post-exercise), while basal FE(NO0.170) values were not different between the five sessions (P > 0.05). These results suggest that prolonged exercise induces a reduction in NO concentration within the lung that lasts for several minutes after the end of exercise. However, repetitive exercises (at least every 24 h) allow complete NO recovery from one session to another. The implication of such a decrease in NO availability within the lung remains to be clarified.