Plasma Concentrations of Posaconazole Administered via Nasogastric Tube in Patients in a Surgical Intensive Care Unit

Abstract

Abdominal surgery may affect intestinal absorption and the resulting levels of posaconazole in the blood. We measured plasma posaconazole levels in surgical intensive care unit (SICU) patients and tried to develop a predictive population pharmacokinetics model. A total of 270 samples from 15 patients receiving posaconazole via nasogastric tube were measured by high-performance liquid chromatography (HPLC). SICU patients showed lower plasma drug concentrations, a higher apparent clearance, and a higher volume of distribution than those in hematology patients, possibly due to poor absorption.T he use of posaconazole in patients with hematological malignancies has been published extensively (4,6,19,20). Although recipients of solid organs and patients undergoing major abdominal surgery are also at risk for developing invasive fungal infections, and case reports show the suitability of posaconazole for this population (14,15), no pharmacokinetic data on posaconazole are yet available for patients of a surgical intensive care unit (SICU). Application of posaconazole via nasogastric tube in healthy volunteers resulted in up to 20% decreased plasma drug concentrations (5), but this has not yet been studied in seriously ill patients with high APACHE II and SOAP II scores. It is not clear whether and to what extent posaconazole pharmacokinetics is affected in these patients.The aims of the prospective POLICE trial (posaconazole via gastric tube) were to determine posaconazole concentrations in SICU patients in order to control if sufficient concentrations are achieved and to develop a population pharmacokinetics (PopPK) model. Posaconazole concentrations were determined by reversedphase high-performance liquid chromatography with UV detection as previously published (16). PopPK modeling was performed using nonlinear mixed-effects modeling (NONMEM version VI) with the first-order conditional estimation (FOCE) method and INTERACTION option (3). The influence of the following candidate covariates was examined consecutively: body weight, body height, body mass index, sex, age, albumin, ␥-glutamyltransferase, glutamine-oxalacetic transaminase, glutamatepyruvate transaminase, and bilirubin.Two hundred seventy samples from 15 SICU patients who underwent extensive abdominal surgery were eligible for evaluation. They received posaconazole for prophylactic or therapeutic purposes, regardless of participation in the study. Demographic parameters are shown in Table 1.All patients received 200 mg posaconazole every 6 h (q6h) as absorption was considered saturable. Daily posaconazole doses were administered via nasogastric tube: only twice was a jejunal or duodenal tube used. Other medication was not restricted during posaconazole treatment. Each patient received pantoprazole intravenously (40 mg/day) to prevent development of stress ulcers.In transplant patients (n ϭ 6), immunosuppressive therapy was mostly performed with tacrolimus or cyclosporine. Enteral nutrition was either normocaloric or high energy (3.0 to 5.8 g fat/100 ml) an...

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

“…A study in healthy volunteers demonstrated a 24% reduction in posaconazole area under the plasma concentration-time curve when administered via NG tube (40), with clinical studies in patients also confirming a significant reduction in posaconazole exposure (7,41). The lack of significance of this covariate in the present study is likely due to the small number of patients who received posaconazole via NG tube in this analysis (n ϭ 8).…”

Pharmacokinetics and Pharmacodynamics of Posaconazole

“…When posaconazole is only administered orally, F cannot be estimated. In such studies apparent V d (V d /F) will be reported, which is inversely proportional to the value of F. Thus, the inter-individual variability in apparent V d observed in patients receiving oral posaconazole is significantly affected by the F. In healthy volunteers, the V d /F of the posaconazole suspension and the delayed-release tablet are about twice as high as the absolute V d that was determined upon intravenous injection [29], which could be explained by the reported value of 50% for F. A compartmental pharmacokinetic model developed for patients with persistent febrile neutropenia or refractory IFD showed that [38] Kohl et al [35] Storzinger et al [36] Vehreschild et al [37] Dolton et al [39] Petitcollin et al [40] Iersel et al [41] Boonsathorn et al [70] Merk et al [30] Year Four trial delayed-release tablet formulations, including tablet A, tablet B, tablet C, and tablet D (tablet D is the marked image) Table 1 (continued) Authors AbuTarif et al [38] Kohl et al [35] Storzinger et al [36] Vehreschild et al [37] Dolton et al [39] Petitcollin et al [40] Iersel et al [41] Boonsathorn et al [70] Merk et al [30] Residual error, %CV (%RSE) Proportional the V d /F of posaconazole suspension is 2447 L [27], which indicates a remarkably larger V d /F than for the healthy population (427 L under fed and 1450 L under fasted conditions) [50]. Four population pharmacokinetic studies using nonlinear mixed-effect modeling confirmed this finding in other hematological patients receiving posaconazole suspension [35,[37][38][39].…”

“…The two relevant parameters for oral absorption are the absorption rate constant (k a ), describing the rate of absorption, and bioavailability (F), describing the extent of absorption. The k a of the oral suspension was reported to be different in different patient groups and mostly ranged from 0.40 to 0.77 h −1 , which corresponds to an absorption halflife (t 1/2 ) between 0.90 and 1.7 h [35][36][37]. Both a slower absorption (absorption t 1/2 of 17.5 h) and a faster absorption (absorption t 1/2 of 0.55 h) with a delayed onset of absorption have been reported [38,39].…”

“…The markedly larger V d /F in the patient population might be in part due to the lower F caused by concomitant medication and multiple clinical factors. Patients from the surgical intensive care unit (SICU) exhibited the largest V d /F (5280 L, compared to 1100-2770 L in hematological patients), which might be mainly caused by poor absorption resulting from the application of nasogastric tubes and/or by increased distribution to peripheral tissue due to capillary leakage and edema [36].…”

Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals

“…Interestingly, highest mean posaconazole serum levels at steady-state of patients included into our study were measured for antifungal therapy of patients treated on an ICU. This result is noteworthy because recently published studies, analyzing critically ill patients, demonstrated serum levels of posaconazole oral solution below target values (Ray et al, 2011;Storzinger et al, 2012). This may have been caused by drug-drug interactions between posaconazole and other drugs administered during the ICU stay, which were not part of this analysis.…”