A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients.

PURPOSE: Chronic hepatitis C virus (HCV) is a major problem affecting up to 170 million people worldwide. Two protease inhibitors have recently been approved that will revolutionize treatment. Our objective was to summarize and evaluate the literature pertaining to the pharmacokinetics of boceprevir and telaprevir, in order to provide clinicians with insight into the management of actual and potential drug interactions. SUMMARY: A standardized search using MEDLINE (1948-November 2011), EMBASE (1980-November 2011), IPA (1970-November 2011), Google, and Google Scholar that combined the search terms boceprevir, telaprevir, pharmacokinetics, drug interaction, and drug metabolism was performed. Manual reference searches of chosen articles were completed. Monographs and articles, conference proceedings, and abstracts were evaluated. Boceprevir and telaprevir are both substrates and inhibitors of cytochrome P450 3A4 and telaprevir is a substrate of p-glycoprotein. Levels of boceprevir are decreased in patients taking efavirenz but effects with other antiretrovirals are minimal or unknown. Coadministration with efavirenz may compromise telaprevir levels and should be avoided. Telaprevir may increase levels of cyclosporine, tacrolimus, atorvastatin, and amlodipine, which may expose patients to increased adverse effects. Conclusions. Significant drug-drug interactions occur with both boceprevir and telaprevir. Until studies are reported and experience is gained with these agents, clinicians will need to be careful when administering in high-risk populations and those receiving chronic therapy with interacting agents. Studies are urgently needed in HIV patients taking antiretrovirals and patients taking chronic immunosuppression as these populations are at increased risk of experiencing clinically significant interactions.

Transplanted functional islet mass: donor, islet preparation, and recipient factors influence early graft function in islet-after-kidney patients.

BACKGROUND: The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal. METHODS: Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr). RESULTS: Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to ΔCP/GCr. A negative association to ΔCP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set. CONCLUSION: The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.

Xenotropic murine leukemia virus-related virus does not pose a risk to blood recipient safety.

BACKGROUND: When xenotropic murine leukemia virus-related virus (XMRV) was first reported in association with chronic fatigue syndrome, it was suggested that it might offer a risk to blood safety. Thus, the prevalence of the virus among blood donors and, if present, its transmissibility by transfusion need to be defined. STUDY DESIGN AND METHODS: Two populations of routine blood donor samples (1435 and 13,399) were obtained for prevalence evaluations; samples from a linked donor-recipient repository were also evaluated. Samples were tested for the presence of antibodies to XMRV-related recombinant antigens and/or for XMRV RNA, using validated, high-throughput systems. RESULTS: The presence of antibodies to XMRV could not be confirmed among a total of 17,249 blood donors or recipients (0%; 95% confidence interval [CI], 0%-0.017%); 1763 tested samples were nonreactive for XMRV RNA (0%; 95% CI, 0%-0.17%). Evidence of infection was absent from 109 recipients and 830 evaluable blood samples tested after transfusion of a total of 3741 blood components. CONCLUSIONS: XMRV and related murine leukemia virus (MLV) markers are not present among a large population of blood donors and evidence of transfusion transmission could not be detected. Thus, these viruses do not currently pose a threat to blood recipient safety and further actions relating to XMRV and MLV are not justified.

Accelerometry-based physical activity and exercise capacity in pediatric kidney transplant patients.

BACKGROUND: Low physical activity (PA) is increasingly recognized as a risk factor for children with chronic conditions. A few published studies have measured the exercise capacity of solid organ transplant patients; however, no studies have examined the PA intensity of pediatric kidney transplant patients (PTx) using accelerometry. Therefore, our objective was to complement a gold standard exercise capacity protocol with an objective measure to quantify PA intensity levels of PTx. METHODS: Sixteen PTx (nine girls), 4.9 ± 2.9 years posttransplant, mean age 13.1 ± 4.0 years, participated. Mean diethylenetriamine pentaacetic acid glomerular filtration rate (DTPA GFR) = 76.7 ± 18.0 ml/min/1.73 m(2). Laboratory data included assessment of cardiopulmonary functioning [peak oxygen uptake (VO(2peak))] from cycle ergometry and body composition [dual-energy X-ray absorptiometry (DEXA)]. PA was quantified by triaxial accelerometry (3 days). Field testing (FITNESSGRAM) included progressive aerobic cardiovascular endurance run (PACER), curlups, and sit/reach tests. Sex- and age-based criterion standards were used as reference. RESULTS: Below normative values for VO(2peak) was found in eight children (mean = 27.4 ± 3.3). Accelerometry data identified only three children who fulfilled daily recommended moderate-vigorous PA level; 58.5% of their time was spent in sedentary activity. CONCLUSION: Accelerometry data highlights that not only are PTx patients inactive, the activity they do perform is overall of low intensity. PTx also show compromised exercise capacity and physical fitness. Our results suggest the need to assess PA barriers among PTx. Further research is needed to determine appropriate PA recommendations for children posttransplant.

Association between age and graft failure rates in young kidney transplant recipients.

BACKGROUND: Age at transplant and graft failure risk are associated in young kidney transplant recipients. The risk of graft failure may also vary by current age, irrespective of age at transplant. We sought to estimate age-specific graft failure rates in young kidney transplant recipients and to estimate the relative hazards of graft failure at different ages, compared with at the age of 25 to 29 years. METHODS: We evaluated 90,689 patients recorded in the United States Renal Data System database who received a first transplant when younger than 40 years (1988-2009); 18,310 were younger than 21 years at transplant. Time-dependent Cox models with time-varying covariates were used to estimate the association between age (time-dependent) and death-censored graft failure risk, adjusted for time since transplant and other potential confounders. RESULTS: There were 31,857 graft failures over a median follow-up of 5.9 years (interquartile range, 2.5-10.5 years; maximum, 21.8 years). Crude age-specific graft failure rates were highest in 19 year olds (6.6 per 100 person-years). Compared with individuals with the same time since transplant observed at 25 to 29 years of age, death-censored graft failure rates were highest in 17 to 24 year olds (hazard ratio, 1.20; [95% confidence interval 1.13, 1.27] for 17-20 year olds and 1.20 [1.13, 1.26] for 21-24 year olds; both P<0.0001) and lowest in 5 to 12 year olds (hazard ratio, 0.60; [0.53, 0.68] for 5-9 year olds and 0.56 [0.49, 0.64] for 10-12 year olds; both P<0.0001). CONCLUSION: Among first kidney transplant recipients younger than 40 years, older adolescents and young adults (17-24 years) have the highest risk of graft failure, irrespective of age at transplant.

Pharmacokinetics in stable heart transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations.

BACKGROUND: A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD. METHODS: Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID-based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated. RESULTS: Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC(0-24)) and minimum concentration (C(min)) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%-94.6%) and 87.4% (95% CI, 82.9%-92.0%), respectively (acceptance interval, 80%-125%). There was good correlation between AUC(0-24) and C(min) for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar. CONCLUSIONS: This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD.

Benefits of home-based endurance training in lung transplant recipients.

BACKGROUND: To investigate the effect of home-based exercise training on exercise tolerance, muscle function and quality of life in lung transplant recipients (LTR). METHODS: Twelve LTR and 7 age-matched healthy subjects underwent exercise training (ET, 12-wk, 3×/wk, 40 min). Peak aerobic capacity VO2peak, endurance time (T(end)), minute ventilation (VE) quadriceps strength, percentage of type I fiber (%Ifb), fiber diameters and chronic respiratory questionnaire were assessed before and after ET. A positive response to ET was defined as an improvement in T(end) at least comparable to the mean change observed in healthy subjects. RESULTS: Training significantly improved T(end) (+12 ± 11 min), isowatt during exercise (-5.5 ± 2.6L/min), muscle strength (+4.6 ± 2.6 kg) and dyspnea score (+0.6 ± 0.9) in LTR (p < 0.05), leading to recovery of T(end) and muscle strength up to healthy subjects' values. In responders (n = 6), VO2peak, %Ifb and fatigue score were improved after training (p < 0.05). Non-responders had lower %Ifb and greater delay between surgery and the beginning of the study than responders (56 [21-106] vs. 8 [2-59] months respectively, p = 0.03). CONCLUSIONS: Home-based ET was effective to improve exercise tolerance, muscle strength and quality of life in LTR but more successful in patients with moderate muscle dysfunction and in the first years after transplantation. Multicenter and controlled-studies are needed to confirm the benefits and optimal modalities of home training in LTR.

Influence of exhaustive exercise on the immune system in solid organ transplant recipients.

Prolonged exhaustive exercise has a great impact on the immune system of athletes and leads to a transient weakening of the immune system. A host of studies has documented changes of immune parameters in peripheral blood following exercise. Concerning the effect of exhaustive exercise in transplant recipients there is little knowledge at present. We analysed peripheral blood in healthy athletes and transplant recipients who participated in the "Euregio cycling tour 2009" before and immediately after they performed 81 km of cycling that included ascending more than 1800 m in altitude. A full blood count and an automated differential count as well as microarray analysis were performed before, immediately after and one day after exercise in 10 male patients carrying a kidney transplant and in 10 controls matched in age and gender. Comparing the absolute increase in neutrophils in these two groups, we detected that the relative increase in neutrophils was significantly smaller in transplant recipients compared to their corresponding controls after exhaustive exercise. While both groups were comparable in performance, microarray analysis revealed a markedly different pattern of gene expression in transplant recipients compared to their controls. From the 130 genes that were significantly upregulated in controls immediately after exercise, only 12 genes were also upregulated in transplant recipients. 64 different genes were upregulated in transplant recipients only. Our findings may be related to the immunosuppressive medication that the transplant recipients took and therefore it should also be discussed that regular exercise might reduce the need for immunosuppressive medication in transplant recipients.

Development of the Organ Donation and Transplantation Knowledge Survey for use in Asian American adolescents.

The need for kidney transplantation among Asian Americans is increasing owing to hypertension, diabetes mellitus, and the shortage of available organs. This need is likely to increase as the relatively young Asian population ages. However, knowledge about organ donation and transplantation in this population has been little investigated. The objectives of this study was to develop an Organ Donation and Transplantation Knowledge Survey for use in Asian Americans and to examine its psychometric properties. Internal consistency (Cronbach alpha) and factor analyses were used to determine the reliability and validity of the survey in 121 Asian American adolescents residing on the Big Island of Hawaii. Our results indicate that the survey had adequate reliability and was psychometrically valid for evaluating knowledge about organ donation and transplantation. More studies are needed to validate the usefulness and psychometric properties of the Organ Donation and Transplantation Knowledge Survey in other groups.

Kidney and recipient weight incompatibility reduces long-term graft survival.

Long-term function of kidney allografts depends on multiple variables, one of which may be the compatibility in size between the graft and the recipient. Here, we assessed the long-term consequences of the ratio of the weight of the kidney to the weight of the recipient (KwRw ratio) in a multicenter cohort of 1189 patients who received a transplant between 1995 and 2006. The graft filtration rate increased by a mean of 5.74 ml/min between the third and sixth posttransplantation months among patients with a low KwRw ratio (<2.3 g/kg; P<0.0001). In this low KwRw ratio group, the graft filtration rate remained stable between 6 months and 7 years but then decreased at a mean rate of 3.17 ml/min per yr (P<0.0001). In addition, low KwRw ratios conferred greater risk for proteinuria, more antihypertensive drugs, and segmental or global glomerulosclerosis. Moreover, a KwRw ratio<2.3 g/kg associated with a 55% increased risk for transplant failure by 2 years of follow-up. In conclusion, incompatibility between graft and recipient weight is an independent predictor of long-term graft survival, suggesting that avoiding kidney and recipient weight incompatibility may improve late clinical outcome after kidney transplantation.

UK Renal Registry 12th Annual Report (December 2009): chapter 5: demographic and biochemistry profile of kidney transplant recipients in the UK in 2008: national and centre-specific analyses.

INTRODUCTION: National renal transplant registries routinely report on centre-specific patient and graft survival following renal transplantation. However, other outcomes such as graft function (as measured by eGFR), haemoglobin and blood pressure are also important indicators of quality of care. METHODS: Transplant activity and incident graft survival data were obtained from NHS Blood and Trans-plant, laboratory and clinical variables and prevalent survival data were obtained from the UK Renal Registry. Data were analysed separately for prevalent and one year post-transplant patients. RESULTS: Increasing live and nonheartbeating donors were responsible for the increasing transplant activity. Graft failure occurred in 2.9% of prevalent transplant patients and death rates remained stable at 2.4/100 patient years. In transplant recipients with a specified cause of death, 21% died due to malignancy and 21% as a consequence of cardiac disease. There was centre variation in outcomes including eGFR and haemoglobin in prevalent and 1 year post-transplant recipients. Analysis of prevalent transplants by chronic kidney disease stage showed 14.7% with an eGFR <30 ml/min/1.73 m(2) and 2.1% <15 ml/min/1.73 m(2). Of those with CKD stage 5T, 40.4% had Hb concentrations <10.5 g/dl, 25.9% phosphate concentrations >or=1.8 mmol/L, 9.0% adjusted calcium concentrations >or=2.6 mmol/L and 40.8% PTH concentrations >or=32 pmol/L. With the exception of PTH, transplant recipients with CKD stage 5T were less likely to achieve the UK standards compared to prevalent dialysis patients. CONCLUSION: Wide variations in clinical and biochemical outcomes amongst transplant recipients continue to exist and may reflect differences in healthcare delivery across the UK.

Period analysis for more up-to-date graft and patient survival estimates in transplantation: an evaluation using united network for organ sharing data.

BACKGROUND: Traditional, cohort-based survival analysis approaches may provide outdated graft and patient survival estimates in times when clinical progress is rapid. Period analysis, a survival analysis method that uses left truncation and was shown to provide more up-to-date survival estimates than traditional, cohort-based methods in other medical fields, may improve the timeliness of survival monitoring in transplantation. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we evaluated, through a series of comparisons, how well most up-to-date 5-year survival estimates potentially derivable by two commonly used cohort-based methods and the period method would have been able to predict the later observed survival of corresponding most recent transplants in the dataset between 1992 to 1994 and 2001 to 2003. RESULTS: In the analysis of overall survival, period analysis provided a best prediction for 93 of the 100 evaluated point estimates, whereas among 350 evaluated point estimates of age-specific survival, period analysis provided a best estimate on 254 occasions (72.6%), compared with 49 (14.0%) and 82 (23.4%) occasions for the cohort-based approaches. Mean average absolute differences between period estimates and the later observed survival were meaningfully lower than those obtained by traditional methods, indicating that period estimates may provide much better survival predictions for recently transplanted grafts and patients than estimates derivable at the same time by traditional survival analysis approaches. CONCLUSION: The timeliness of survival monitoring can be meaningfully improved by the application of period analysis. The use of period analysis for providing more up-to-date survival estimates in transplantation may be encouraged.

The relationship between heart rate and oxygen consumption in heart transplant recipients during a cardiopulmonary exercise test: heart rate dynamic during exercise test.

BACKGROUND: In healthy subjects, the percentage of heart rate reserve (%HRR) versus the percentage of oxygen consumption reserve (%VO(2)R) is the closest relationship between heart rate and VO(2) and it seems also to be true to heart failure patients only if they are under optimized beta-blocker therapy. AIM: To evaluate the closest relationship between heart rate and VO(2) (%peak heart rate versus %peak VO(2); %HRR versus %VO(2)R or absolute heart rate versus absolute VO(2)) in heart transplant recipients during a treadmill cardiopulmonary exercise test. METHODS: A total of 19 sedentary heart transplant recipients (5.4 ± 3.3 years after transplant) in a stable condition (for, at least, 3 months), were recruited to perform a cardiopulmonary exercise test. The relationship between %HRR-%VO(2)R, %peak heart rate versus %peak VO(2) and absolute heart rate versus absolute VO(2) were tested. RESULTS: The strongest relationship was found between %HRR-%VO(2)R (r = 0.95, p<0.0001), followed by %peak heart rate versus %peak VO(2) (r = 0.91, p<0.0001) and absolute heart rate versus absolute VO(2) (r = 0.67, p<0.0001). The mean regression line did not coincide with the line of identity in any group (p<0.0001 for all groups). CONCLUSION: The %HRR versus %VO(2)R showed the closest relationship followed by %peak heart rate versus %peak VO(2) and absolute heart rate versus absolute VO(2). Despite this, the perfect reliability of the heart rate versus VO(2) was not found.

Does heart rate predict allograft vasculopathy in heart transplant recipients?

Experimental data suggest that heart rate is directly associated with the progression of atherosclerosis. We evaluated the prognostic importance of heart rate measured at rest 3 months after transplantation in 143 heart transplant recipients. During the follow-up (mean 9.5 years, range 2-23 years) 56 patients had coronary lesions. Survival without coronary lesion at angiography did not significantly differ between patients with a basal heart rate > or ≤97/min (median, p=0.44). This series does not support a prognostic influence of heart rate for cardiac allograft vasculopathy.

Successful transfer of day 10 horse embryos: influence of donor-recipient asynchrony on embryo development.

A total of 78 day 10 horse embryos were transferred non-surgically to recipient mares that had ovulated 9, 7, 6, 5, 4, 3, 2 or 1 day after (negative asynchrony), on the same day (synchronous), or 2 or 4 days before (positive asynchrony) the donor (n=6 or 8 mares per group). Pregnancy rates between 100% (6/6) and 63% (5/8) were seen in recipient mares that were between +2 and -6 days asynchronous. Embryo survival to the heartbeat stage declined in recipients that were -7 days asynchronous and no embryos survived in recipients that were -9 days asynchronous. Irrespective of uterine asynchrony, cessation of embryo mobility and fixation at the base of a uterine horn occurred when the conceptus was approximately 17 days old. Conceptus growth and development was slowed when embryos were placed in negatively asynchronous uteri. At the greatest degree of negative asynchrony at which embryos survived to the heartbeat stage, i.e. -7 and -6 days, development of the embryo proper and allantois was retarded. Luteostasis was achieved in recipient mares when day 10 embryos were transferred to recipient mares at any stage of asynchrony between -9 and +2 days with respect to the donor. These results indicate that in the horse, there is a wide window for establishment of pregnancy following embryo transfer to asynchronous recipients. Although progesterone priming of the uterus to a stage equivalent to that of the transferred embryo does not appear to be a prerequisite for embryo survival, it does nonetheless influence embryonic development.

Transplanted neural precursors enhance host brain-derived myelin regeneration.

In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural precursor cell (NPC) transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice. Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC-OPC coculture system. These experiments indicated that NPCs induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances host-derived myelin regeneration following chronic demyelination. This trophic effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.

Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements.

Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients' morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring. Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66 +/- 10% (mean +/- SD), a maximum plasma concentration of 3.1 +/- 0.8 mg/L after a dose of 450 mg and of 6.6 +/- 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0 +/- 1.0 hours, area under the plasma concentration-time curve values of 29.1 +/- 5.3 mg.h/L and 51.9 +/- 18.3 mg.h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 +/- 3.8 L/h, an elimination half-life of 5.3 +/- 1.5 hours and an apparent terminal volume of distribution of 101 +/- 36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption. The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC(50)) among CMV clinical strains of 0.7 mg/L (range 0.2-1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated. The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.