Posaconazole liquid vs tablet formulation in lung transplant recipients.

Posaconazole is an extended-spectrum triazole antifungal used in the treatment and prophylaxis of Aspergillus infections. It is available as oral suspension (POS-Liq) and delayed-release tablets (POS-Tab). The aim of this longitudinal, retrospective study was to compare the clinical effectiveness, toxicity and pharmacokinetics of POS-Liq vs POS-Tab in lung transplant recipients (LTx-recipients), who were treated with both formulations subsequently. Twenty-four consecutive LTx-recipients with 191 documented posaconazole trough levels (PTLs) for POS-Liq or POS-Tab were included. The administered daily doses were 300 mg for POS-Tab and 600 mg (prophylaxis) or 800 mg (therapy) for POS-Liq. Target PTLs were ≥700 ng/mL (prophylaxis) and ≥1250 ng/mL (therapy). The overall prophylactic and therapeutic response rates were 78% and 67%, respectively. No cases of hepatotoxicity or QT-prolongation were observed with either formulation. The achieved target PTLs were tripled under POS-Tab compared to POS-Liq with fewer risk factors for sub-therapeutic PTLs. Concomitant administration of POS-Tab significantly reduced the tacrolimus concentration-to-dose ratio (P = .001). We suggest the use of POS-Tab is appropriate for prophylaxis and therapy of Aspergillus infections in LTx-recipients, since POS-Tab displayed more reliable PTLs with no added adverse events. However, we recommend regular drug monitoring for POS-Liq and for therapy with POS-Tab and that immunosuppressant levels are monitored closely when the posaconazole formulation is switched.

Tablet dissolution affected by a moisture mediated solid-state interaction between drug and disintegrant.

PURPOSE: To investigate the cause for decrease in delavirdine mesylate 200 mg tablet dissolution upon exposure to high humidity. METHODS: Dissolution testing was performed using the USP 2 (paddle) apparatus. Water in tablets was measured by Karl Fischer titration. 13C CP/MAS NMR was used to identify and quantify delavirdine form changes in tablets. FT-IR spectroscopy was used to monitor delavirdine form change in tablets and component mixes, and to investigate a solid state reaction with the disintegrant. RESULTS: Dissolution extent of delavirdine mesylate 200 mg tablets was substantially decreased after exposure to high humidity. This effect is related to the amount of water present in the tablet matrix. 13C CP/ MAS NMR detected about 30% conversion from the mesylate salt of delavirdine to its free base form in the tablet matrix. FT-IR spectroscopy demonstrated that a solid state reaction occurs between the freed methanesulfonic acid and the carboxyl sites on the croscarmellose sodium disintegrant. CONCLUSIONS: Water is thought to act as both a reaction medium and a plasticizer for croscarmellose sodium, facilitating protonation of the carboxyl sites on the disintegrant. This reaction has the potential to occur for any acid salt of a free base. The limiting solubility of delavirdine free base formed in the tablets accounts for much of the decrease in the extent of dissolution. A change in inter-particle bonding can explain the reduction in tablet deaggregation during dissolution.

USP dissolution apparatus 3 (reciprocating cylinder): instrument parameter effects on drug release from sustained release formulations.

The United States Pharmacopoeia dissolution apparatus 3 (reciprocating cylinder) was evaluated with respect to effects of changes in instrument parameters on drug release rate from six hydrophilic matrix formulations and one coated-bead formulation. Reciprocation rate had the largest effect on time to 50% release for all matrix formulations. Top mesh size had an effect on release rate for those formulations having an erosion component to the drug release mechanism. Bottom mesh size had no effect on release rate. For the coated-bead formulation, no parameter had an effect on release rate. In an assessment of the hydrodynamics of the reciprocating cylinders, conditions equivalent to the 50 rpm paddle and 100 rpm basket were determined to be at the extreme low end of the available reciprocation rate range.

Diagnosis of pancreatic allograft rejection by measurement of urinary radioimmunoreactive insulin.

The accurate, early, and sensitive diagnosis of pancreatic allograft rejection is one of the major problems in clinical pancreas transplantation today. Pancreaticocystotomy is a popular technique for pancreas transplantation that permits simple and frequent urinary chemistry examinations. In this experiment, 20 mongrel dogs with a bladder-drained pancreatic transplant had serial monitoring of urinary amylase (UA) and urinary insulin (UI). The mean UI in the nonrejection state was 9.6 +/- 12 mIU/L. In eight dogs varying degrees of rejection were documented by histopathology. All three animals having severe acute rejection had high levels of IU (all greater than 300-800 mIU/L). Of the five animals with mild-to-moderate rejection, all had significant UI elevations to greater than 100 mIU/L but none had elevations above 200 mIU/L (P less than 0.05 for all groups). Ten animals were treated with prednisone, Imuran, and cyclosporine (CsA), and five of these dogs had good graft function for greater than 14 days, during which the mean UI was extremely low (11 +/- 6.4 mIU/L, P less than 0.05). These values were not significantly different from the 0-14-day values for three pancreas autotransplants with bladder drainage (8.9 +/- 7.2 mIU/L, P less than 0.05). All rejections were preceded by significant rises of UI occurring two to five days prior to rejection. In seven animals, early graft dysfunction (1-4 days) developed, with total graft necrosis by five days. This graft injury was presumably caused by preservation damage or early vascular thrombosis and was associated with early (1-4 days) marked elevations of the UI (greater than 300 mIU/L). None of the animals with grafts surviving to rejection at seven days or more had these early severe elevations, and thus these early UI rises are pathognomonic of graft damage. In contrast, UA and lipase showed inconsistent association with rejection or early damage, although falls in UA generally occurred at or following the time of rejection. Marked daily variations in UA measurements were the most difficult aspect of UA monitoring. Serial electromagnetic flow probe studies of blood flow to the pancreas graft showed a good correlation between loss of blood flow and rises in UI associated with early graft injury. These results suggested that the UI assay gives a sensitive, early, accurate, and specific differential prediction of pancreas graft dysfunction. Specifically, the UI assay appears to be of value not only in the early differential diagnosis of graft injury and graft rejection, but also in the assessment of the severity of rejection.(ABSTRACT TRUNCATED AT 400 WORDS)