Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection

Krishna, Gopal; Sansone-Parsons, Angela; Martinho, Monika; Kantesaria, Bhavna; Pedicone, Lisa D.

doi:10.1128/aac.00454-06

Cited by 146 publications

(108 citation statements)

References 30 publications

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“…In healthy volunteers, age, gender, and race or ethnicity do not have a clinically relevant effect on the pharmacokinetics of posaconazole (30). Similar plasma posaconazole concentrations have been observed in adult and pediatric patients with IFIs (18).…”

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confidence: 55%

Pharmacokinetics and Absorption of Posaconazole Oral Suspension under Various Gastric Conditions in Healthy Volunteers

Krishna¹,

Moton²,

Ma³

et al. 2009

Antimicrob Agents Chemother

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A four-part, randomized, crossover study with healthy subjects evaluated the effects of gastric pH, the dosing frequency and prandial state, food consumption timing, and gastric motility on the absorption of posaconazole. In part 1, a single dose (SD) of posaconazole (400 mg) was administered alone or with an acidic beverage or a proton pump inhibitor (PPI), or both. In part 2, posaconazole (400 mg twice daily and 200 mg four times daily) was administered for 7 days with and without a nutritional supplement (Boost). In part 3, an SD of posaconazole (400 mg) was administered while the subjects were fasting and before, during, and after a high-fat meal. In part 4, an SD of posaconazole (400 mg) and the nutritional supplement were administered alone, with metoclopramide, and with loperamide. Compared to the results obtained with posaconazole alone, administration with an acidic beverage increased the posaconazole maximum concentration in plasma (C max ) and the area under the concentration-time curve (AUC) by 92% and 70%, respectively, whereas a higher gastric pH decreased the posaconazole C max and AUC by 46% and 32%, respectively. Compared to the results obtained with posaconazole alone, posaconazole at 400 mg or at 200 mg plus the nutritional supplement increased the posaconazole C max and AUC by 65% and 66%, respectively, and by up to 137% and 161%, respectively. Administration before a high-fat meal increased the C max and the AUC by 96% and 111%, respectively, while administration during and after the meal increased the C max and the AUC by up to 339% and 387%, respectively. Increased gastric motility decreased the C max and the AUC by 21% and 19%, respectively. Strategies to maximize posaconazole exposure in patients with absorption difficulties include administration with or after a high-fat meal, with any meal or nutritional supplement, with an acidic beverage, or in divided doses and the avoidance of proton pump inhibitors.

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mentioning

confidence: 55%

Pharmacokinetics and Absorption of Posaconazole Oral Suspension under Various Gastric Conditions in Healthy Volunteers

Krishna¹,

Moton²,

Ma³

et al. 2009

Antimicrob Agents Chemother

Self Cite

315

290

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“…Several studies with febrile patients with neutropenia and/or invasive fungal infections have shown that when PSC is administered at the recommended dosage of 400 mg orally twice daily, the resulting human serum PSC levels are generally Ͻ1 g/ml (10,11,21). In a previous study with mice infected with R. microsporus (18), the serum PSC levels at 40 mg/kg were similar (Ͻ1 to 2 g/ml) to those obtained with the drug administered at the recommended dosage in humans.…”

Section: Discussionmentioning

confidence: 99%

Correlation between In Vitro Activity of Posaconazole and In Vivo Efficacy against Rhizopus oryzae Infection in Mice

Rodríguez

Pastor

Sutton

et al. 2010

Antimicrob Agents Chemother

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We have evaluated the in vitro activity of posaconazole (PSC) against 50 clinical strains of Rhizopus oryzae using a broth microdilution method, the Neo-Sensitabs tablet diffusion method, and minimal fungicidal concentration (MFC) determination. In general, PSC showed low MICs against this fungus, and the MICs correlated with the inhibition zone diameters. Most of the MFCs, however, were from 1 to 4 dilutions higher than their corresponding MICs. We then investigated the efficacies of several different doses of PSC in a murine model. All treatments began 24 h after challenge and lasted for 7 days. The drug was administered twice a day to mice infected with three strains that showed intermediate PSC susceptibility (MIC ‫؍‬ 2 g/ml) and three PSC-susceptible strains (MIC ‫؍‬ 0.25 g/ml). A dose of 10 mg/kg of body weight was ineffective, while doses of 20 and 30 mg/kg prolonged the survival of the mice. The 50 strains tested were segregated into two groups on the basis of the in vitro data. For the group with the most strains (85%), the strains had low PSC MICs, mice infected with the strains showed higher rates of survival (30 to 40%), and PSC was able to reduce the fungal load in the kidney and less regularly in the brain. For the second group (15% of the strains), the strains had intermediate PSC MICs, mice infected with the strains had lower survival rates (10 to 20%), and PSC treatment resulted in variable and no reductions in the fungal loads in the kidneys and brains, respectively.Infections caused by some fungi of the order Mucorales are highly invasive and potentially fatal, and they mainly affect patients with diabetes mellitus or hematological malignances (20). In a recent survey of the occurrence of Mucorales in clinical samples in the United States, approximately half of the isolates identified belonged to the species Rhizopus oryzae (2). Treatment of Mucorales infections is based on four critical factors: rapid diagnosis, removal of predisposing factors, surgical debridement, and appropriate antifungal therapy, with liposomal amphotericin B (LAMB) being the drug of choice (21). Although posaconazole (PSC) has been demonstrated to be less effective than LAMB for the treatment of human R. oryzae infections and its use is not recommended as the primary treatment, this drug is considered a reasonable option for patients who are refractory to or intolerant of polyenes (8, 22). PSC has been tested as salvage therapy in several clinical trials, 14 to 37% of the patients showed a complete response (8,22). However, even in such cases the actual role of this drug is difficult to assess, as most of these patients had previously been treated with AMB or their lipid formulations. It is also unknown whether these success rates were related to the patients' immune status and/or other conditions or to the susceptibility of the strains involved in these infections. Furthermore, in clinical trials in which PSC has been evaluated, the fungi involved were not identified to the species level, thereby making it impossible t...

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“…Posaconazole has been used as an alternative to AmB in treatment of S. vasiformis infections because of the toxicity of AmB (319,334) or in combination with other antifungals (Table 4) (162). Posaconazole's safety profile for children under the age of 13 years is limited (174,334).…”

Section: Vol 24 2011 Mucormycosis Caused By Unusual Mucormycetes 429mentioning

confidence: 99%

Mucormycosis Caused by Unusual Mucormycetes, Non-Rhizopus, -Mucor, and -Lichtheimia Species

2011

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SUMMARY Rhizopus , Mucor , and Lichtheimia (formerly Absidia ) species are the most common members of the order Mucorales that cause mucormycosis, accounting for 70 to 80% of all cases. In contrast, Cunninghamella , Apophysomyces , Saksenaea , Rhizomucor , Cokeromyces , Actinomucor , and Syncephalastrum species individually are responsible for fewer than 1 to 5% of reported cases of mucormycosis. In this review, we provide an overview of the epidemiology, clinical manifestations, diagnosis of, treatment of, and prognosis for unusual Mucormycetes infections (non- Rhizopus , - Mucor , and - Lichtheimia species). The infections caused by these less frequent members of the order Mucorales frequently differ in their epidemiology, geographic distribution, and disease manifestations. Cunninghamella bertholletiae and Rhizomucor pusillus affect primarily immunocompromised hosts, mostly resulting from spore inhalation, causing pulmonary and disseminated infections with high mortality rates. R. pusillus infections are nosocomial or health care related in a large proportion of cases. While Apophysomyces elegans and Saksenaea vasiformis are occasionally responsible for infections in immunocompromised individuals, most cases are encountered in immunocompetent individuals as a result of trauma, leading to soft tissue infections with relatively low mortality rates. Increased knowledge of the epidemiology and clinical presentations of these unusual Mucormycetes infections may improve early diagnosis and treatment.

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Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection

Cited by 146 publications

References 30 publications

Pharmacokinetics and Absorption of Posaconazole Oral Suspension under Various Gastric Conditions in Healthy Volunteers

Pharmacokinetics and Absorption of Posaconazole Oral Suspension under Various Gastric Conditions in Healthy Volunteers

Correlation between In Vitro Activity of Posaconazole and In Vivo Efficacy against Rhizopus oryzae Infection in Mice

Mucormycosis Caused by Unusual Mucormycetes, Non-Rhizopus, -Mucor, and -Lichtheimia Species

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