Pharmacokinetic Profile of Ganciclovir After its Oral Administration and From its Prodrug, Valganciclovir, in Solid Organ Transplant Recipients
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- Wiltshire, H., Hirankarn, S., Farrell, C. et al. Clin Pharmacokinet (2005) 44: 495. doi:10.2165/00003088-200544050-00003
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Valganciclovir (Valcyte/sR) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+1/recipient negative [R−]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of valganciclovir in 364 D+/R− (intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed.
The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene®, lOOOmg three times daily) and from valganciclovir (900mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed.
Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area under the plasma concentration-time curve values were 46.3 + 15.2 μg · h/mL and 28.0 ± 10.9 μg · h/mL. The relative systemic exposure of ganciclovir was approximately 8-fold higher from valganciclovir than oral ganciclovir. Exposure to ganciclovir from valganciclovir was similar among liver, heart and kidney transplant recipients (46.0 + 16.1, 40.2 + 11.8 and 48.2 + 14.6 μg · h/mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir.
Oral valganciclovir produces exposures of ganciclovir exceeding those attained with oral ganciclovir, but in line with those reported after standard intravenous administration of ganciclovir. This indicates that oral valganciclovir is suitable in circumstances requiring prophylactic use of ganciclovir and allows for more convenient management of patients at risk of CMV disease.
Cytomegalovirus (CMV) is the most common viral infection following solid organ transplantation (SOT) and is a significant cause of morbidity and mortality, especially in high-risk individuals (i.e. CMV seronegative recipients [R−] of an organ from a CMV seropositive donor [D+]).
The efficacy and safety of intravenous[3,4] and oral ganciclovir (Cymevene®1, F. Hoffmann-La Roche Ltd, Basel, Switzerland)[5,6] in the prevention of CMV disease in SOT recipients have been well documented; however, there are a number of limitations with both these formulations. Administration of intravenous ganciclovir is associated with patient inconvenience, high cost and a high incidence of catheter-related infections. On the other hand, oral ganciclovir has low bioavailability, which limits achievable systemic exposure; to deliver plasma ganciclovir exposure 40–50% of that achieved with intravenous ganciclovir 5 mg/kg (generally considered the ‘gold standard’), 3000mg of oral ganciclovir, administered as 12 capsules/day in a three-times-daily regimen must be administered.[8,9]
Valganciclovir (Valcyte®, F. Hoffmann-La Roche Ltd, Basel, Switzerland), a prodrug ester of ganciclovir and L-valine, has recently been developed to overcome these limitations. It is well absorbed from the gastrointestinal tract and rapidly metabolised in the intestinal wall and liver to ganciclovir. Following absorption, the major route for clearance of ganciclovir is renal excretion of the unchanged compound. In liver transplant patients, the systemic exposure of ganciclovir from valganciclovir is approximately 60% relative to intravenous ganciclovir, which is considerably greater than that of orally administered ganciclovir. Similar average systemic exposure values for ganciclovir from valganciclovir have been obtained in healthy and HIV-infected subjects (59%) and AIDS patients (59% with once-daily administration and 64% with twice-daily administration).[11,12] Valganciclovir 900mg provides systemic exposure to ganciclovir similar to that from intravenous ganciclovir 5 mg/kg/day.[13,14]
Patients and Methods
This study was based on a subset of patients taken from a double-blind, double-dummy trial that has recently been published. In brief, patients (n = 364) [intent-to-treat population] were ≥13 years of age and received a first heart, liver, kidney, kidney-pancreas, kidney-heart or kidney-liver allograft, or a second kidney allograft, with a CMV serostatus of D+/R−. Patients were excluded if they had a history of CMV infection or disease, anti-CMV therapy within the previous 30 days, severe, uncontrolled diarrhoea or other evidence of malabsorption.
Patients were randomly assigned in a 2: 1 ratio to receive valganciclovir 900mg once daily or oral ganciclovir 1000mg three times daily. In patients with impaired renal function, the dose was adjusted according to estimated CLCR (table I). Treatment began within 10 days post-transplant (as soon as the patient was able to take oral medication) and continued through to day 100 post-transplant.
Sampling and Assay of Ganciclovir
Plasma levels of ganciclovir were scheduled to be measured on two occasions 6 weeks apart, the first at least 28 days post-transplant. In 61% of patients, the three post-dose samples that covered the absorption (1–3 hours), distribution (5–12 hours) and elimination (22–24 hours) phases were taken on both occasions. Patients were defined as evaluable for pharmacokinetic analysis if they had at least two usable samples on one occasion. No attempts to analyse valganciclovir plasma levels were made as previous studies have shown that post-administration valganciclovir plasma concentrations are very low.[9,11]
Venous blood (5mL) was drawn into ethylene diamine tetraacetic acid (EDTA) Vacutainer® tubes and placed on ice until centrifugation (15 minutes at 2000 rpm) at 4°C within 30 minutes of blood collection. Plasma samples were frozen immediately at −20°C until analysis. Concentrations of ganciclovir were determined using high-performance liquid chromatography with fluorescence detection. This method has a validated range of 0.04–4.00 µg/mL. In this study, the precision of the ganciclovir assay from quality control samples was 4.6–7.8%, and the accuracy was 99–104%.
The pharmacokinetics of ganciclovir after administration of oral ganciclovir or valganciclovir were analysed using the population approach and the nonlinear mixed-effects modelling (NONMEM) software. The first-order conditional estimation method with interaction was used.
An initial structural model of the pharmacokinetics of ganciclovir after administration of valganciclovir was created from rich historical data.[9,11] A two-compartment model was selected, as the pharmacokinetic curves of ganciclovir after intravenous administration are biphasic. CLCR was used as a predictor of renal function and, therefore, clearance of ganciclovir.
The model was parameterised in terms of apparent clearance, apparent central volume of distribution, intercompartment clearance, apparent peripheral volume of distribution and lag-time. Interindividual variability in the rate of absorption, apparent clearance and central volume of distribution was assessed using an exponential error model as illustrated by the following equations:
Rate of absorption (equation 1): where KA is the typical population value of the absorption rate constant; ηKA represents the difference between the jth individual’s KA values and the predicted value; ηKA values are independent, identically distrubuted (i.i.d.) random variables; N(0,ω2) means normally distributed about 0 with variance ω2; and j is the variable for the jth individual.
A combined additive and exponential model was used for the residual random effects. Modelling of interoccasion variability was performed on both apparent clearance and central volume of distribution.
The dataset for valganciclovir was divided into two subsets: (i) the modelling dataset, which comprised data from the first two-thirds of the patients in enrolment order; and (ii) the validation dataset, which comprised data from the last one-third of the patients who were enrolled. Modelling was initiated using draft data while the study was ongoing. Personnel at GloboMax, Marlow, UK, who carried out the modelling were unblinded, while personnel at the sponsor site (Roche, Welwyn, UK) remained blinded.
The modelling dataset from the draft data was used to derive the basic pharmacokinetic model, to select primary covariates (namely bodyweight, CLCR, transplant type) and to model any potential time dependence. Model qualification was performed using the validation dataset from the final data. The final data of all patients in the valganciclovir arm were used to evaluate the influence of secondary covariates (race, sex, time since transplantation, country/continent and concomitant immunosuppressive regimen [ciclosporin, tacrolimus, mycophenolate mofetil and azathioprine]) and to derive the final pharmacokinetic model.
The final model after valganciclovir administration was applied to the pharmacokinetic data from the ganciclovir arm of the study and the predictability of the model was assessed. Subsequently, a combined model was applied to the ganciclovir data from the valganciclovir and ganciclovir arms. A two-compartment model with two different first-order absorption (plus metabolism for valganciclovir) rates and lag-times were used for the valganciclovir and ganciclovir arms of the study. There were twice as many patients in the valganciclovir group than the ganciclovir group, and a simpler administration regimen (once daily rather than three times daily). The model-development and covariate analysis were, therefore, applied to this dataset before any attempts were made to model the data from oral ganciclovir treatment. The absorption rates and lag-times were fixed to results obtained by modelling rich data.[9,11] As there were no data after intravenous administration of ganciclovir, the bioavailability of ganciclovir from valganciclovir was set to unity and apparent volumes and clearances were calculated. The base model included estimated CLCR as a predictor of the clearance of ganciclovir.
Pharmacokinetic Model Assessment
The effect of potential covariates on the pharmacokinetic parameters was modelled separately for each selected pharmacokinetic parameter. Each covariate was modelled as a multiplicative effect of the covariate raised to an estimated power. For all continuous covariates, the covariate effect was centred on the median of the covariate. Categorical covariates with more than two categories were analysed as a multiple of the component binary variables. Binary covariates were normalised to values >0 and a geometric mean of unity.
Selection of Covariates
The significance of including or removing fixed effects into the population model was evaluated by the Likelihood Ratio Test, using forward and backward selection processes with a priori α levels of 0.05 and 0.01, respectively. During forward selection, the effect of each covariate on each basic pharmacokinetic parameter was added to the model. All fixed effects except the coefficient for the power of the covariate were held constant. The effect causing the largest reduction in the OFV was considered to be the most significant and was added to the model if the reduction exceeded 3.841. All the parameters of the new refined model were estimated and the selection process was repeated until no further covariate could be selected. This was the ‘full’ model.
The importance of each covariate was re-evaluated by backward selection, eliminating each covariate from the full model, one at a time and separately for each pharmacokinetic parameter. The covariate with the smallest increase in the OFV was excluded if the increase was <6.635 and no substantial increase occurred in the corresponding random effect parameter. The exclusion of covariates was continued as long as a covariate fulfilled the exclusion criteria. The resulting model was called the ‘final’ population pharmacokinetic model. The OFV from each model was tabulated to document the process of model development.
The clinical relevance of the effect of a selected covariate on the corresponding pharmacokinetic parameter was evaluated according to the following criteria and only covariates with clinically relevant effects were included in the final model. For a binary covariate (e.g. sex), a clinically relevant effect was defined as a change in the typical (population) pharmacokinetic value from the lower to the higher value of at least 25%. A continuous covariate (e.g. CLCR) was considered clinically relevant if its inclusion caused at least 10% of the patients in the dataset to have an individual typical pharmacokinetic value outside the range of 80–125% of the typical value of the pharmacokinetic parameter without the covariate.
Model validation was based on both the observed concentrations and on the derived pharmacokinetic parameters. The pharmacokinetic model and parameter estimates obtained from the modelling dataset were used to predict the ganciclovir concentrations and pharmacokinetic parameters for those patients in the validation set, using their dosing and sampling information and the relevant covariate data. The predicted plasma concentrations were then compared with the observed concentrations. The mean difference between observed and model-predicted concentrations (bias), mean-square error of the difference (MSE) and percentage prediction error (PE) were used as predictive performance criteria.
The pharmacokinetic model from the modelling dataset was fitted to the data from the validation dataset to obtain estimates for the individual pharmacokinetic parameters. These parameters were compared with the predicted pharmacokinetic parameters. Bias, MSE and PE were also calculated to evaluate the deviation.
A total of 240 patients (valganciclovir, n = 160; ganciclovir, n = 80) provided suitable plasma samples. The demographics, baseline characteristics and distributions of transplant organ types between the overall patient population and the pharmacokinetic population were comparable.
Base Model Development
As mentioned earlier the initial pharmacokinetic model was developed using rich historical data.[9,11] A complex model with two first-order parallel processes, conceptually corresponding to the absorption and hydrolysis of valganciclovir in the gut wall and liver, described the data better than the simple first-order appearance of ganciclovir in plasma. The population-mean apparent central volume of distribution of ganciclovir derived from the complex absorption model (30.9L) was approximately 34% higher than that from a simple absorption model (23.1L). Apparent clearance was similar in the two models (15.1 L/h vs 15.7 L/h).
Application of these models to the sparse data from this study was generally more satisfactory when the absorption parameters were fixed to those from the historical studies, rather than being estimated. Although the complex absorption model generated a lower OFV, the difference was relatively small compared with that from the modelling of the rich historical data. In addition, the complex model was unstable in that covariance matrices were not obtained and the 30-fold longer run time required for minimisation meant that the simple model was used for the covariate analysis and definitive parameter estimates.
Pharmacokinetic Model After Oral Administration of Valganciclovir
Prior to the primary covariate analysis, the influence of CLCR on ganciclovir clearance, which was included a priori, was removed from the base model. Using the modelling dataset, the most significant primary covariate was found to be CLCR on ganciclovir clearance. Thus, after deletion of some potential outlying samples, the inclusion of CLCR as a predictor of ganciclovir clearance reduced the OFV from 580.1 to 482.2. The relationship between bodyweight and central volume of distribution was also found to be significant (OFV = 471.2). No significant reduction in OFV followed the introduction of interoccasion variability.
The influence of secondary covariates (race, sex, time since transplantation, country/continent and immunosuppressive regimen [ciclosporin, tacrolimus, mycophenolate mofetil and azathioprine]) was assessed using the final data from all patients in the valganciclovir arm. A total of 810 plasma concentrations were included in the final valganciclovir dataset that followed the deletion of 40 outlying samples, which were excluded as they were considered implausible (weighted residuals generally >6); a further 11 samples were below the limit of quantification. Using this reduced dataset, the next most significant covariate was sex on central volume of distribution (OFV reduced from 552.7 to 541.9). Sex was also clinically significant since the change in the typical central volume of distribution from male to female was 58.8%. In the second selection step, tacrolimus dose was the most significant covariate. However, although covariate analysis indicated that tacrolimus was associated with significantly increased clearance of ganciclovir (OFV decreased by 21), this effect was not considered clinically significant as no individual typical clearance was outside 80–125% of the typical value of the model with the covariate excluded. There were no further significant covariates. The full covariate model, therefore, included CLCR and bodyweight as primary covariates and sex as a secondary covariate.
Pharmacokinetic Model After Oral Administration of Ganciclovir
The same two-compartment model with first-order absorption was applied to the pharmacokinetics of oral ganciclovir, but employed the absorption values previously estimated for oral ganciclovir 1000mg three times daily. However, because of the smaller number of patients receiving oral ganciclovir and the fact that oral ganciclovir was given three times daily rather than once daily, the precision of many of the parameters was poor.
Combined Pharmacokinetic Model After Oral Administration of Ganciclovir or Valganciclovir
In order to improve the modelling of the distribution and elimination phases of ganciclovir, the ganciclovir and valganciclovir datasets were combined and a relative systemic exposure parameter introduced. After the omission of 6/417 (1.5%) clear outliers (weighted residuals >7) from the ganciclovir data, a satisfactory fit was obtained. As with the valganciclovir model, the basic combined model fixed the absorption rates and lag-times to previously observed values (different for the two compounds) and used CLCR as a predictor of apparent clearance, and bodyweight as a predictor of central volume of distribution. In addition, subject variability terms for both apparent clearance and for central volume of distribution were included.
The possible effect of organ transplant type on the primary pharmacokinetic parameters (apparent clearance and central volume of distribution) was investigated by covariate analysis. No statistically significant effect was seen, as the reduction in OFV was <3.841 in every case. As with the valganciclovir model, introduction of sex as a predictor of central volume of distribution was statistically significant, with both the OFV and the intersubject variability being reduced. The population-mean central volume of distribution of ganciclovir was estimated to be 56% lower in females than males. This was in addition to females being lighter.
Observed and Combined Model-Predicted Ganciclovir Plasma Levels
Exposure to Ganciclovir
Intravenous ganciclovir has been the cornerstone of the treatment and prevention of CMV disease in SOT recipients;[20,21] however, more recently, oral ganciclovir has been used. Although oral ganciclovir is effective in the prevention of CMV disease,[5,6,22] its low bioavailability (ranging from 6% to 9%) limits achievable systemic exposure. Levels of ganciclovir in plasma higher than those achieved with oral ganciclovir may be required to prevent CMV infection and disease in a significant proportion of high-risk SOT recipients (i.e. D+/R−).
The introduction of the oral prodrug valganciclovir as a potent anti-CMV drug is a significant advance in antiviral prophylaxis in transplant recipients. Initial studies in HIV- and CMV-seropositive patients described the pharmacokinetic parameters of oral valganciclovir.[10,13] Valganciclovir (aqueous solution 360mg once daily) was shown to be rapidly and extensively hydrolysed to ganciclovir, which resulted in significantly greater relative systemic exposure (69%) than with oral ganciclovir (1000mg once daily; 5.6%).
Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. In this study, a structural model of the pharmacokinetics of ganciclovir after oral administration of valganciclovir in SOT recipients was successfully developed; however, application of this model to the pharmacokinetics of ganciclovir after its oral administration was unsuccessful. There were only half the number of patients in the ganciclovir arm compared with the valganciclovir arm of this study and the three-times-daily dosage regimen needed for ganciclovir was much harder to fit with the sparse data. In order to improve the modelling of the distribution and elimination phases, the ganciclovir and valganciclovir datasets were combined and a suitable model was obtained.
In the current study, valganciclovir 900mg once daily produced steady-state plasma concentrations of ganciclovir that were considerably higher than those observed following administration of oral ganciclovir at a dosage of 3000 mg/day. Average exposure to ganciclovir from valganciclovir was approximately 1.65 times (95% CI 1.58, 1.81) that from oral ganciclovir (46.3 vs 28.0 µg · h/mL). Exposure to ganciclovir from valganciclovir was very similar among liver, heart and kidney transplant recipients.
The pharmacokinetics of ganciclovir from valganciclovir compared with oral and intravenous ganciclovir have previously been described in a small single-dose crossover study of 28 liver transplant recipients. Systemic ganciclovir exposure delivered by valganciclovir 900mg (41.7 µg · h/mL) was comparable to that with intravenous ganciclovir 5 mg/kg (48.2 µg · h/mL) and higher than that with oral ganciclovir 1000mg three times daily (20.7 µg · h/mL). These data suggest that exposure delivered by a valganciclovir 450mg dose would equal that achieved with oral ganciclovir 3000mg. However, there are discrepancies between the figures for oral ganciclovir in this study and that of Pescovitz et al. (28.0 µg · h/mL vs 20.7 µg · h/mL, respectively), which stem from the difference between the estimation of 24 hour AUCs after single-dose and steady-state dosing regimens. With oral ganciclovir being administered three times daily, compared with once daily for valganciclovir and intravenous ganciclovir, accumulation is significantly greater (approximately 25% as opposed to 5%). Thus, extrapolation of the data of Pescovitz et al. to steady-state would have given AUCs of approximately 26.0 µg · h/mL and 44.0 µg · h/mL from oral ganciclovir (1000mg three times daily) and valganciclovir (900mg once daily), respectively, which are figures that strongly agree with the results of this study. These findings highlight the appropriateness of valganciclovir 900mg once daily, adjusted for renal function, for prophylaxis in SOT patients; a dose of valganciclovir 450mg once daily would deliver systemic exposure distinctly lower than that of oral ganciclovir 1000mg three times daily.
We observed relative systemic exposure of ganciclovir from valganciclovir to be approximately 8-fold higher than that achieved with oral ganciclovir. This large difference probably results from enhanced absorption of valganciclovir via a peptide-mediated active transport system (PEPT1 and PEPT2), which is similar to that previously described for valaciclovir.[11,24,25] The exposure of ganciclovir delivered by valganciclovir allows exposures similar to those achieved with intravenous ganciclovir as described earlier.
As with oral and intravenous ganciclovir, a minimum of approximately 80–85% of ganciclovir delivered by valganciclovir is excreted in urine. Consequently, the pharmacokinetics of ganciclovir is markedly altered in patients with renal impairment.[11,26,27] Dosage adjustment is required to ensure adequate drug exposure while avoiding the adverse events (e.g. neutropenia) that are associated with ganciclovir therapy.[5,15,22] The dosage of ganciclovir can be adjusted based on predicted CLCR, in many cases using the Cockroft-Gault equation. An appropriate dosing algorithm facilitates the initial administration of valganciclovir in SOT recipients in clinical practice, as has been demonstrated for ganciclovir in SOT recipients. Suboptimal ganciclovir exposures have been described in patients administered dosage according to an earlier dosing algorithm based on CLCR. In our study, the dosing algorithm (originally developed for valganciclovir in patients who were renally impaired, but otherwise healthy ) was successful in delivering consistent systemic exposure to ganciclovir in patients whose renal function varied by almost an order of magnitude. Analogous dose-AUC relationships would be expected for recipients of other SOTs (e.g. lung), which suggests that valganciclovir is appropriate for CMV prophylaxis in other types of SOT.
In conclusion, the population pharmacokinetic model developed for ganciclovir after administration of valganciclovir and oral ganciclovir to SOT recipients was validated and generated data were consistent with those from other SOT studies. Valganciclovir produces systemic exposure to ganciclovir exceeding that attained with oral ganciclovir. Average exposure to ganciclovir from valganciclovir was similar across liver, heart and kidney transplant recipients. The dosing algorithm employed was successful in delivering comparable exposure to ganciclovir irrespective of large differences in renal function. The results of this study indicate that valganciclovir is appropriate in circumstances requiring ganciclovir, but additionally provides convenient, once-daily oral administration in patients at risk of CMV infection and disease.
The use of trade names is for product identification purposes only and does not imply endorsement.
This study was funded by Hoffman-La Roche Ltd, Basel, Switzerland. Hugh Wiltshire is an employee of the sponsor. Mark Pescovitz has received honoraria for speaking and is a consultant to the sponsor. Atul Humar is a consultant for the sponsor. Barbara Alexander, Emily Blumberg and Richard Freeman have received honoraria for speaking for the sponsor.