Oral Bioavailability Of Ganciclovir Research Articles

Evaluation of valganciclovir pharmacokinetics in lung transplant recipients

Valganciclovir is commonly used for cytomegalovirus prevention after lung transplantation. The pharmacokinetic profile of valganciclovir in lung transplant patients has not been well described or linked to efficacy and safety. This prospective, randomized, crossover study determined the steady-state pharmacokinetic profile of 2 different doses of valganciclovir in lung transplant recipients and compared these profiles with intravenous ganciclovir. Ten patients were evaluated. Patients were 56.8 ± 3.4 years old and had a mean creatinine clearance of 69 ± 9 ml/min. Oral bioavailability of ganciclovir after administration of valganciclovir was 59%, and mean half-life was 3.73 ± 1.15 hours. The maximal concentration after intravenous 5 mg/kg ganciclovir was significantly higher than after 450 mg valganciclovir (8.37 ± 3.03 mg/liter vs. 5.3 ± 2.09 mg/liter, respectively; p = 0.02) and similar to 900 mg valganciclovir (7.93 ± 3.97 mg/liter; p = 0.78). A higher area under the curve at 0-24 hours (AUC(0-24)) was found with 900 mg valganciclovir compared with intravenous 5 mg/kg/day ganciclovir (47.8 ± 19.7 vs 32.9 ± 10.8 mg · hour/liter, respectively; p = 0.049). The AUC(0-24) for 450 mg valganciclovir twice daily was 45.5 ± 22.9 mg · hour/liter. Valganciclovir at 900 mg/day resulted in the equivalent of a mean daily dose of 7.7 mg/kg intravenous ganciclovir. Higher systemic ganciclovir exposures occurred after 900 mg/day valganciclovir compared with intravenous 5 mg/kg/day ganciclovir. Valganciclovir therapeutic drug monitoring may be warranted in select lung transplant patients to avoid increased toxicity.

Use of Valganciclovir for Prevention and Treatment of Cytomegalovirus Disease

The development of a valine ester for ganciclovir has allowed much-improved absorption and bioavailability of oral ganciclovir and has had a significant impact on the prevention and management of cytomegalovirus infection in the immunocompromised host. Valganciclovir offers ~60% bioavailability after oral ingestion. The administration of 900 mg of valganciclovir orally is comparable to a dose of intravenous ganciclovir of 5 mg/kg, although the peak level of ganciclovir is higher than that of oral valganciclovir [ 1 ] . Given this comparability, the use of valganciclovir for preemptive therapy and even for treatment of cytomegalovirus is becoming quite common, even with limited comparative trial data [2]. The article by Len et al [3] from the Spanish Network for Research on Infection in Transplantation (RESITRA) in this issue of Clinical Infectious Diseases reports an observational study that offers some insight into the efficacy of valganciclovir for the prevention and treatment of cytomegalovirus disease. Although this study d sign is not as rigorous as a randomized trial, and although it was subject to some investigator and clinician bias in patient selection, the data are nevertheless compelli g and demonstrate that valganciclovir can be used for preemptive therapy for cy omegalovirus infection in organ transplant recipients [3]. The definitions of success and failure in this study are rigorous, and the number of patients studied was large. Once viral replication was established, it is quite clear that valganciclovir is effective for viral suppression, to prevent progression to cytomegalovirus syndrome or organ disease. The vast majority of the data in this study derive from kidney and liver transplant recipients (and, to a lesser extent, from heart transplant patients); therefore, generalizability of the results to lung or kidney-pancreas transplant recipients is probably not justified. Furthermore, the data provide a limited experience regarding the cytomegalovirus antibody-negative recipients of transplants from antibody-positive donors, who represent the highestrisk group for late-onset and relapse. Thus, additional studies are required for these groups to provide information for such use. However, I think transplant programs can feel confident that the use of valganciclovir for preemptive therapy has merit for the vast majority of organ transplant recipients. In many programs, it is already the standard of care for either prophylaxis or preemptive therapy. Although the US Food and Drug Administration has cautioned against the use of valganciclovir for prevention of cytomegalovirus infection in liver transplant recipients [4], the data here support its use and also are consistent with what many liver transplantation programs are actually using as their protocol. The data from this Spanish group are not as compelling regarding the use of valganciclovir for treatment of invasive cytomegalovirus disease, which they label disease in tables 2 and 3 of their article [3]. The success rate of 75% is less than the success rate for intravenous ganciclovir (87.5%) or intravenous ganciclovir followed by valganciclovir (96.2%). Although the difference was not statistically significant, only 8 patients with focal were treated exclusively with valganciclovir. Although there were only 2 treatment failures, I believe that more experience will be necessary to conclude that valganciclovir therapy is appropriate initial management of tissue invasive disease. The authors do not indicate the lo-

Modulation of Ganciclovir Intestinal Absorption in Presence of Absorption Enhancers

The purpose of this investigation was to study the influences of absorption enhancers in increasing oral bioavailability of Ganciclovir (GAN) by assessing the transepithelial permeation across cell monolayers in vitro and bioavailability in rats in vivo. The permeation of GAN across Caco-2 and MDCK cell monolayers in the absence/presence of dimethyl-beta-cyclodextrin (DMbetaCD), chitosan hydrochloride (CH), sodium lauryl sulphate (SLS), and their combinations was studied for a 2-h period. GAN was administered to rats in absence/presence of absorption enhancers and drug contents in plasma were estimated. We found that the apparent permeability coefficient (Papp) of GAN in absence of absorption enhancers (control) were 0.261 +/- 0.072 x 10(-6) and 0.486 +/- 0.063 x 10(-6) cm/s in Caco-2 and MDCK cell monolayers, respectively, whereas in the presence of DMbetaCD, CH, SLS, and their combinations, Papp of GAN increased by 5- to 25-fold and 7- to 33-fold as compared to control in Caco-2 and MDCK cell monolayers, respectively. However, in rats, the maximum enhancement in bioavailability of GAN during coadministration of these absorption enhancers was only fivefold compared to GAN control. To conclude, the absorption enhancers-DMbetaCD, CH, SLS, and their combinations demonstrated significant improvement in transepithelial permeation and bioavailability of GAN.

New prophylactic treatment strategy for cytomegalovirus disease.

The pharmacology, pharmacokinetics, safety, and efficacy of valganciclovir, an oral prodrug for ganciclovir, used to prevent cytomegalovirus (CMV) disease in solid organ transplant recipients are described. Valganciclovir was developed to overcome the disadvantages associated with ganciclovir, which include low oral bioavailability, limited efficacy because of the development of viral resistance, and the need for frequent administration, which can adversely affect patient adherence. Valganciclovir is rapidly converted to ganciclovir; systemic exposure to the parent drug is low and short in duration. The oral bioavailability of ganciclovir from valganciclovir is 10 times higher than that from the original ganciclovir formulation. Food increases the oral bioavailability of valganciclovir. In a four-way, randomized, crossover pharmacokinetic study of 28 liver transplant recipients, single doses of valganciclovir 900 mg and intravenous ganciclovir 5 mg/kg resulted in a similar ganciclovir systemic exposure. The systemic exposure was proportionately lower with a single 450-mg dose of valganciclovir but similar to that of oral ganciclovir 3 g administered in three divided doses. In the recent multicenter, randomized, double-blind, double-dummy PV16000 trial in 364 solid organ transplant recipients at high risk for CMV disease (i.e., CMV-negative recipients of CMV-positive donor organs), valganciclovir 900 mg once daily was as effective in preventing CMV-disease as oral ganciclovir 1 g three times daily. Resistance was reported with ganciclovir but not with valganciclovir. Both drugs were well tolerated.

Valganciclovir.

Valganciclovir is a prodrug of ganciclovir which has been developed for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Oral valganciclovir is rapidly absorbed and hydrolysed to ganciclovir. The oral bioavailability of ganciclovir after oral valganciclovir administration is high. Oral valganciclovir 900 mg provides a daily exposure of ganciclovir comparable to that of intravenous ganciclovir 5 mg/kg. A single, randomised, nonblind study indicated that oral valganciclovir (900mg twice daily for 3 weeks then 900 mg once daily) and intravenous ganciclovir (5 mg/kg twice daily for 3 weeks then 5 mg/kg once daily) were equally effective in the treatment of newly diagnosed CMV retinitis in 160 patients with AIDS. Valganciclovir appears to have a similar tolerability profile to intravenous ganciclovir during induction therapy in patients with AIDS and newly diagnosed CMV retinitis. During maintenance therapy with valganciclovir, the most commonly reported adverse events included neutropenia, anaemia, thrombocytopenia, gastrointestinal (including diarrhoea, nausea, vomiting and abdominal pain), fever, headache, insomnia, peripheral neuropathy, paraesthesia and retinal detachment.

Development of predictive pharmacokinetic simulation models for drug discovery

As discovery chemistry produces increased numbers of potential drug compounds, the use of ADME (absorption, distribution, metabolism, and excretion) properties is becoming increasingly important in the drug selection and promotion process. A computer simulation model has been developed and validated to predict ADME outcomes, such as rate of absorption, extent of absorption, etc. using a limited number of in vitro data inputs. The oral bioavailability of ganciclovir in dogs and humans was simulated using a physiologically based model that utilized many biopharmaceutically relevant parameters, such as the concentration of ganciclovir in the duodenum, jejunum, ileum, and colon at various dose levels and solubility values. The simulations were run and compared to dog and human in vivo data. The simulation results demonstrated that the low bioavailability of ganciclovir is limited by compound solubility rather than permeability due to partitioning as previously speculated. This technology provides a breakthrough in in silico prediction of absorption and with its continued development and improvement, will aid drug discovery and development scientists to produce better pharmaceutical products.