Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection

Abstract

The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these "poor absorbers" on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

Figures

Fig 1

Patient disposition. *, The patient did not wish to continue in the study for reasons unrelated to study treatment. †, Noncompliance with the study protocol. BID, twice daily; TID, three times daily.

Fig 2

Correlation between mean posaconazole plasma concentrations on days 2 and 8 (A) and days 3 and 8 (B) after multiple dosing of oral suspension (200 mg TID) (balanced data set, n = 49). R2, coefficient of determination. BID, twice daily; TID, three times daily.

Fig 3

Mean posaconazole plasma concentrations on days 2, 3, 8, and 15 after multiple dosing of oral suspension (200 mg TID, 400 mg BID, and 400 mg TID) (balanced data set, n = 49). Boxes represent the 25th, 50th, and 75th percentiles; whiskers represent the 5th and 95th percentiles; and circles represent outliers. BID, twice daily; TID, three times daily.

Fig 4

Mean posaconazole plasma concentrations across dose groups on days 3, 8, and 15 after multiple dosing of oral suspension (200 mg TID, 400 mg BID, and 400 mg TID), stratified by mean plasma concentration of 250 ng/ml on day 3 (balanced data set, n = 49). Although all patients received 200 mg posaconazole TID on days 1 through 8, the scatter plot identifies patients according to randomized dose group for ease of comparison. BID, twice daily; TID, three times daily.

Fig 5

Mean posaconazole plasma concentrations across dose groups on days 3, 8, and 15 after multiple dosing of oral suspension (200 mg TID, 400 mg BID, and 400 mg TID), stratified by mean plasma concentration of 250 ng/ml on day 8 (balanced data set, n = 49). Although all patients received 200 mg posaconazole TID on days 1 through 8, the scatter plot identifies patients according to randomized dose group for ease of comparison. BID, twice daily; TID, three times daily.