Transplant patients at high risk of invasive mold infections receive voriconazole for prophylaxis. Large variability in voriconazole exposure with a fixed dosing regimen was observed. Low exposure of voriconazole predisposes patients for infection. High concentrations are associated with toxicity.
The objectives are to characterize the pharmacokinetics of voriconazole in transplant patients, to identify factors associated with the variability in the pharmacokinetics, and to develop adequate dosing guidelines for transplant patients.
Liver, lung and pediatric bone marrow transplant (BMT) patients were enrolled. Multiple blood samples were collected within one dosing interval (totally 75 full pharmacokinetic profiles). Voriconazole plasma concentrations were measured using HPLC. Non-compartmental analysis was performed using WinNonlin. Population pharmacokinetic models were developed using NONMEM. Covariate models were built using a forward addition and reverse removal approach. Precision of parameter estimation was evaluated by bootstrapping. Adequate dosing regimens were developed using Monte Carlo simulations.
There was a good correlation between AUCo-∞ and trough voriconazole plasma concentrations. Bioavailability of voriconazole is substantially reduced in lung transplant and BMT patients during the early post-transplant period. Pharmacokinetics of voriconazole is significantly associated with postoperative time, liver function and CYP2C19 genotype in liver transplant patients. Pharmacokinetics of voriconazole is significantly associated with postoperative time and cystic fibrosis in lung transplant patients. Pharmacokinetics of voriconazole is significantly associated with liver function in BMT patients. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability than non-CF patients. Donor characteristics had no significant correlation with pharmacokinetics of voriconazole in liver transplant patients. Bioavailability of voriconazole is similar between lung transplant and BMT patients. Compared to liver and lung transplant patients, BMT patients had significantly higher clearance and significantly lower volume of distribution.
In conclusion, weight-adjusted or fixed dosing regimens resulted in highly variable exposure of voriconazole in liver transplant, lung transplant and BMT patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), voriconazole dose can be individualized based on trough concentrations. Population analysis demonstrated inadequacy of oral administration of voriconazole and adequacy of intravenous administration during the first few post-operative days, followed by oral doses for optimal drug exposure.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11292010-053634 |
| Date | 10 January 2011 |
| Creators | Han, Kelong |
| Contributors | Robert Bies, Rakesh Goyal, Billy Day, Wen Xie, Raman Venkataramanan |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11292010-053634/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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