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REGULAR ARTICLES |
*
Division of Immunology and Organ Transplantation, Department of Surgery,
University of Texas Houston Health Science Center - Medical School, Houston,
Texas
Biometrics Consulting, Houston, Texas
Covance Health Economics and Outcomes Services, Inc., Washington,
DC
§
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Correspondence to Dr. Barry D. Kahan, Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Houston Health Science Center - Medical School, 6431 Fannin, Suite 6.240, Houston, TX 77030. Phone: 713-500-7400; Fax: 713-500-0785; E-mail bkahan{at}orgtx71.med.uth.tmc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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28.4% for the average concentration (Cav),
i.e., the dosing interval-corrected area under the concentration-time
curves, and 36% for the trough concentration (C0). The
incidence of chronic rejection over a period of 5 yr was 24% among the less
variable (LV) versus 40% among the variable (V) cohort. The economic
analysis revealed that the total mean facility and physician costs per patient
were $48,789 versus $60,998, respectively (P < 0.01). The
degree of variability displayed by any individual could only be predicted by
serial measurements of CsA concentrations, and not by demographic features,
laboratory determinations, clinical characteristics, individual or mean values
of any observed CsA concentration, or other pharmacokinetic parameters
calculated following a single drug exposure. Thus, strategies that reduce
intrapatient variability of CsA exposure over time may lead to reductions in
chronic allograft loss and in treatment costs. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Similar to findings with other critical dose drugs, a pharmacokinetic approach using estimates of the area under the concentration-time curve (AUC) or the corresponding dosing interval-corrected value, Cav (5), offers a more reliable indicator of an individual patient's proclivity toward inadequate immunosuppression (6,7) versus nephrotoxicity (8). Thus, we adopted a concentration-control strategy that individualizes long-term CsA doses to maintain target Cav values (9). Analysis of the utility of this approach to reduce the likelihood of chronic rejection in 204 CsA-prednisone-treated renal transplant recipients revealed a significant impact of the degree of intraindividual variability of drug exposure over time posttransplant (10). Although this analysis identified variability, it did not determine the percent coefficient of variation that reflected the greatest sensitivity with the least probability of a false diagnosis of chronic rejection. Therefore, the purposes of the present analysis were: (1) to extend the original database for an additional 12 mo of clinical and pharmacokinetic followup; (2) to use a receiver operating characteristic (ROC) analysis (11) to establish the inflection point on a plot of intraindividual coefficient of variation (%CV) of CsA exposure, estimated based on either Cav or C0 values, versus occurrence of chronic rejection; and (3) to determine whether the patient cohorts with variable versus less variable behaviors show different health care costs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CsA Concentration Measurements
Whole blood samples for pharmacokinetic profiles were obtained before
(C0; trough) as well as 2, 4, 6, 10, 14, and 24 h after
dosing for patients treated with a once-daily CsA regimen, and before as well
as 2, 4, 6, 8, 10, and 12 h after dosing for patients treated with a
twice-daily CsA regimen. Whole blood CsA concentrations were estimated using a
monoclonal selective antibody in the fluorescence polarization immunoassay
(TDx®; Abbott Laboratories, North Chicago, IL)
(13).
CsA Concentration-Control Regimen
Pretransplant pharmacokinetic studies were used to select starting CsA
doses, as described previously
(14,15).
In the initial posttransplant period, CsA was delivered by continuous
intravenous infusion for 48 to 72 h at a dose calculated to produce a
steady-state concentration (Css) of 400 ± 50 ng/ml
(16). Thereafter, the
continuous intravenous infusion CsA dose was tailored by linear extrapolation
based on the ratio of the observed-to-target Css values.
The infusion was discontinued upon satisfactory absorption of a concomitant,
orally administered CsA dose, i.e., documentation that maximum
concentration (Cmax) minus Css was
greater than 700 ng/ml CsA.
Patients were initially assigned to a once- versus a twice-daily
oral dose regimen according to their CsA clearance rate, i.e., the
ratio of the intravenous dose (mg/kg per d) to the Css
(ng/ml) (17): Values <325
ml/min indicated a once-daily regimen (<325), and those above this rate a
twice-daily regimen (325)
(18). Thereafter, the dosing
interval was selected to maintain C0 250 ± 50
ng/ml, and the actual CsA dose (in mg) was adjusted to maintain
Cav = 550 ± 50 ng/ml for the first posttransplant
month. During the subsequent 2 mo, dosing intervals were selected to maintain
C0 200 ± 50 ng/ml, and twice weekly
pharmacokinetic profiles guided dose adjustments to achieve
Cav = 500 ± 50 ng/ml. From 3 to 6 mo
posttransplant, monthly pharmacokinetic profiles guided dose adjustments to
achieve Cav = 450 ± 50 ng/ml and
C0 175 ± 50 ng/ml. From 6 to 12 mo
posttransplant, alternate month pharmacokinetic profiles guided dose
adjustments to achieve Cav = 400 ± 50 ng/ml and
C0 150 ± 50 ng/ml. Thereafter, pharmacokinetic
profiles were performed every 3 to 6 mo to guide dose adjustments to maintain
Cav = 350 ± 50 ng/ml and C0
100 ± 50 ng/ml. Comparison of the target with the (mean observed)
and [one quartile range] of Cav values at each
posttransplant interval showed reasonable application of the
concentration-control strategy: namely, 550 ng/ml (555.62) [128] during the
first month; 500 ng/ml (504.70) [95] from months 1 to 3; 450 ng/ml (432.14)
[85] for months 4 to 6; 400 ng/ml (393.22) [72] for months 7 to 12; and 350
ng/ml (351.29) [65] for months 13 to 90, respectively
(9). If an adverse event
occurred or if the CsA dose had to be adjusted, a pharmacokinetic profile was
performed after at least three (and usually seven) dosing intervals.
C0 independent of the pharmacokinetic profiles were not
measured in this protocol.
Pharmacokinetic Parameter Calculations
Whole blood steady-state CsA concentration-time data were analyzed by
standard noncompartmental methods
(19). The data set included a
total of 4678 pharmacokinetic profiles from 204 patients—an increase of
793 profiles over our previous report
(10). The highest measured
whole blood CsA concentration and the corresponding sampling time were defined
as Cmax and tmax, respectively. The
drug concentrations at the beginning and at the end of the dosing period were
designated as C0, and C12 or
C24, respectively. The linear trapezoidal rule was used to
calculate the AUC from concentration values within the dosing interval, and
corrected to the Cav by dosing interval adjustment
(AUC/
, in hours). The initial absolute bioavailability (F) was
estimated by the dose-corrected AUC after oral versus intravenous
infusion (14). In addition to
the mean (±SD) and the median, absolute, and dose-corrected values of
the pharmacokinetic parameters, the intrapatient %CV, defined as ([SD/mean]
x 100), was calculated for each pharmacokinetic parameter. The mean
numbers of profiles were similar for patients stratified by the demographic
characteristics of age and race (data not shown).
Clinical Management and Diagnosis of Rejection
After the first 6 mo, patients were examined every 90 to 180 d in the
Transplant Center, depending on the exigency of other medical complications.
Each visit included a physician's assessment by history and physical
examination, as well as a complete blood count and Sequential Multiple
Analysis of 20 chemical constituents laboratory test panel. Alternate visits
also included a 24-h urinary protein determination. Histopathologic evidence
of chronic rejection by renal transplant biopsy was mandated in patients
experiencing deterioration of renal function as evidenced by an elevation of
serum creatinine >30% above baseline, by proteinuria, and/or by
progressive/persistent hypertension refractory to two-agent antihypertensive
therapy.
The diagnosis was always confirmed by the presence of histopathologic features of obliterative vascular disease, including arterial and/or arteriolar endothelial and smooth muscle changes, which were frequently accompanied by glomerulopathy. Tubular atrophy and/or interstitial fibrosis alone were not deemed sufficient conditions to establish the diagnosis of chronic rejection.
Treatment Cost Calculations
Nurse reviewers examined the medical charts for 195 of the 204 patients in
a blinded manner. The reviewers identified medical services provided over the
5-yr periof after the transplant procedure or until the patient reached one of
the following end points: switched to another immunosuppressive regimen,
retransplant, or death. The specific medical services abstracted included all
hospitalizations, inpatient procedures, outpatient visits, and procedures
related to renal transplant care. The average follow-up period for the
economic analysis was 54 mo, and was comparable between groups.
Facility and physician services were assigned costs based on Medicare reimbursement rates in 1997. Inpatient facility costs were based on abstracted Diagnosis Related Group (DRG) codes and corresponding Medicare payment rates. Inpatient physician services were determined based on the abstracted International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure codes. For each ICD-9-CM code, the appropriate procedure-based Current Procedural Terminology (CPT) codes for both surgeons and anesthesiologists were selected (20). If a patient was admitted to the hospital without undergoing major procedures, physician costs were assigned according to the length of hospital stay. Hospital outpatient professional services also were identified by CPT codes. CPT codes were matched to the corresponding relative value unit from the Resource-Based Relative Value Scale (21), which was then used to estimate physician costs based on the 1997 Medicare Fee Schedule for Houston, Texas (20).
Outpatient facility costs were estimated using the Ambulatory Patient Group (APG) payment system and the corresponding Medicare reimbursement levels (22). This system is similar to the Ambulatory Payment Classification (APC) hospital outpatient department payment system to be adopted by Medicare in the near future. The costs of outpatient laboratory tests were estimated using the 1997 Clinical Laboratory Fee Schedule for Texas (23).
Statistical Analyses
To compare the occurrence of chronic rejection to the distribution of
demographic factors and clinical features among the 204 patients, we used
t tests for continuous variables (such as recipient age, donor age,
and dry weight) and Fisher exact tests for categorical variables (such as
race, gender, and donor source). For multiple laboratory determinations,
clinical parameters, and pharmacokinetic values (such as hemoglobin, total
protein, and number of antihypertensive medications), we used t tests
to compare the mean values of the clinical parameters of patients who did not
versus those who did experience chronic rejection during the
observation period. The entire follow-up period was subdivided into total time
before the diagnosis of chronic rejection, as well as subsets of mean values
within the time intervals of 3 to 6, 6 to 12, 12 to 24, and 24 to 36 mo after
transplantation.
Logistic regression models were used to assess whether an individual clinical parameter was associated with the occurrence of chronic rejection, while controlling for the influence of demographic factors or laboratory values that we have already demonstrated to be related to the occurrence of chronic rejection in this patient cohort. Backward elimination was then used to determine which factors/values would remain in the model. After the pharmacokinetic variables that influenced the occurrence of chronic rejection were identified, ROC curves were constructed to depict the ability of individual variables to predict the occurrence of chronic rejection (11,24). Each ROC curve expressed the capacity for a clinical parameter to predict rejection, taking into account both the accurate predictions (sensitivity, or true-positive rate) and inaccurate predictions of chronic rejection (false-positive rate). The time to chronic rejection was compared between cohorts using a Kaplan-Meier analysis. A general linear models procedure was used to estimate the variability of clinical parameters over time using a repeated-measures ANOVA (MANOVA), as well as univariate and multivariate analyses, to test the hypothesis that variability neither decreased nor increased over time (25). All analyses were performed using SAS version 6.12 on a personal computer (26).
Costs were compared between groups using the Mann-Whitney test, a nonparametric alternative to the t test. All statistical tests were two-tailed and performed with P < 0.05 as the upper limit of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.0001), which was defined as an
increase of at least 25% over the baseline value of serum creatinine, without
evidence of rejection upon transplant biopsy but with reversal upon CsA dose
reduction. Although an initial univariate analysis suggested that chronic
rejection was directly associated with dry weight (P = 0.0135) and
inversely with CsA dose per day (P = 0.0113), multivariate logistic
regression models showed that these factors were not significant. Clinical
outcome was not associated with the other demographic factors, including donor
or recipient age or gender, donor source, repeat transplant, mode of previous
dialysis treatment versus preemptive transplant, diagnosis of
diabetes mellitus, HLA mismatch, or incidence of infection (data not
shown).
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Pharmacokinetic Values Associated with an Increased Risk of Chronic
Rejection
This study revealed an inverse association between the fraction of patients
free of the occurrence of chronic rejection and the %CV values for
Cav or C0
(Figure 1). There were strong
associations between the occurrence of chronic rejection and the %CV both of
observed and dose-corrected values for Cav (P =
0.002 and P = 0.001, respectively) to a greater extent than
C0 (P = 0.004 and P = 0.052), but only
for the observed %CV of Cmax (P = 0.033)
(Table 2). There was no
statistically significant difference among the overall mean (or immediately
precedent) values of the observed (or dose-corrected) trough concentrations
(C0 or C12/24),
Cmax, or Cav between subjects free of
versus those afflicted with chronic rejection (data not shown).
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To determine the inflection point at which the %CV provided the most
sensitive prediction of chronic rejection, we performed ROC analyses. For a
given %CV, the ordinate value shows the percentage of patients with the
diagnosis of chronic rejection (true-positive results), and the abscissa value
shows the percentage of patients without evidence of chronic rejection
(false-positive results). Figure
2 shows that the ROC plot of %CV Cav has a
lower inflection point, i.e., 28.4%, and includes a larger area of
predictive significance, i.e., 6301 units, than the %CV
C0, with an inflection point at 36% and an area of 5898
units. (An ROC analysis failed to show a significant predictive effect of
Cmax values [data not shown].) Thus, the analysis defined
the variable (V) cohort as the group of patients with %CV of
Cav 28.4% and C0 36%, and
the less variable (LV) group as those patients with values below the
inflection point (Figure
3).
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The inflection points of %CV Cav 28.4% or %CV
C0 36% yielded similar values of sensitivity (77.5%)
and specificity (39%) (Table
3). Furthermore, both C0 and
Cav parameters showed higher negative predictive values
(76.5 and 76.8%, respectively) than positive predictive values (40.4 and
40.7%, respectively). These findings suggest that a low coefficient of
variation is a better predictor of patients who will not experience chronic
rejection than a high coefficient is of those who will develop this
complication.
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Time-to-Event Analysis
Although patients did not undergo protocol biopsies at stipulated intervals
posttransplant, the LV cohorts showed a longer time than the V cohorts to the
diagnosis of chronic rejection (Figure
4). For variability of both Cav and
C0, the Kaplan-Meier analysis revealed significant
differences between the cohorts, i.e., P = 0.001 and
P = 0.006, respectively.
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Lack of Association between the Degree of Pharmacokinetic Variability
and Demographic Factors, Clinical Characteristics, or Laboratory Values
The demographic, clinical, and laboratory values (data not shown) were
similar between members of the V and LV cohorts, suggesting that it is
unlikely that membership in each cohort reflected comorbid conditions. The
mean follow-up periods in the LV and V cohorts were 3.49 and 3.58 yr,
respectively (P = 0.73, NS). Furthermore, the mean number of
pharmacokinetic profiles per patient was only slightly greater for the V group
(23.86 ± 8.24) than the LV group (21.1 ± 7.64; P =
0.018 by two-sample t test).
In addition, there was no correlation between the mean concentrations or pharmacokinetic parameter values (C0, C12/24, Cmax, or Cav) among patients in the V versus LV cohorts for Cav (Table 4) or C0 (data not shown). Furthermore, there was no relationship between the degree of posttransplant variability for Cav or C0 and the absolute oral bioavailability or initial drug clearance rate, as determined using paired intravenous and oral administration of CsA in the early postoperative period (data not shown).
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Distribution of Variability in the Population
Frequency plots of the fraction of patients with individual %CV values
revealed that the LV cohort, defined as Cav 28.4% and
C0 36%, comprised only 33% of patients. Serial
comparisons revealed that the patients in the LV cohort showed relatively
constant %CV values over time (data not shown). Similarly, examination of the
%CV at various intervals posttransplant confirmed that patients in the V
cohort within the first posttransplant year did not show a decrease in
intrapatient variability over time using repeated-measures ANOVA and
univariate (Greenhouse-Geisser or Huynh-Feldt) and multivariate (Wilks'
statistic) tests.
Health Economics
Table 5 shows the medical
resource utilization over the 5-yr posttransplant period among the V and LV
CsA bio-availability groups. Fewer patients in the LV group were
rehospitalized compared to those in the V group (62% versus 83%,
P < 0.05). The LV group had a mean of 2.5 rehospitalizations per
patient, compared with 4.0 rehospitalizations per patient among the V group
(P < 0.05). Furthermore, the mean length of stay for the
transplant hospitalization was shorter in the LV group compared to the V group
(8.3 versus 10.6 d, respectively; P < 0.05; data not
shown). Compared to the V group, patients in the LV group also received
significantly fewer administrations of Solu-Medrol antirejection therapy (30%
versus 64%, P < 0.05). Eliminating from the analysis all
rehospitalizations for non-renal-related conditions (cardiovascular disorder,
lung disease, fracture, etc.) did not diminish the differences between the
groups. Differences were also observed in outpatient resource utilization. The
LV group had a lower mean number of outpatient renal care visits compared to
the V group (17 versus 21, P < 0.05)
(Table 5). In addition, the
mean number of outpatient renal scan procedures per patient was lower among
members of the LV group compared to the V group: Approximately 33% of the LV
patients underwent at least one renal scan, compared with 52% of the patients
in the V group (P < 0.05)
(Table 5). A total of 25 (36%)
patients in the LV group and 32 (25%) patients in the V group reached an end
point of switching immunosuppressive regimens, retransplant, or death. In
addition, seven (10%) of the LV patients and six (5%) of the V patients were
lost to follow-up.
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The differences observed in medial resource utilization between the V and the LV groups were reflected in renal care costs. Over the entire period, mean per-patient facility costs for all renal-related rehospitalizations for the LV and V groups were $11,788 and $23,391, respectively (P < 0.01; data not shown). Mean per-patient outpatient facility costs also were lower for the LV group ($2,823) than for the V group ($3,541; P < 0.05). Overall, the total inpatient and outpatient health care costs, including both facility and physician costs and including the initial hospitalization, for the LV and V groups were $48,789 (median = $37,322) and $60,998 (median = $49,646), respectively (P < 0.01) (Figure 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Low pharmacokinetic variability may confer relatively constant CsA immunosuppressive exposure. Indeed, the high degrees of intraindividual variability documented with many widely used drugs, such as dihydropyridine calcium channel blockers, have also been associated with adverse impacts, particularly among individuals afflicted with illnesses in which a lack of efficacy has dire clinical consequences, i.e., the chemotherapeutic treatment for human immunodeficiency disease.
In addition to finding a role of variability, the present study detected an association between the diagnosis of nephrotoxicity and the occurrence of chronic rejection. This association, which had been suspected but not shown previously, may be explained in at least two ways. This phenomenon may represent an error in diagnosis, wherein the "nephrotoxic event" in fact indicates a progressive albeit subclinical rejection or a nonimmunologic nephropathic process. In those cases, CsA dose reduction may improve renal function, presumably by ameliorating the drug-induced nephrotoxic component of the overall injury. Alternatively, the drug-induced nephrotoxic injury may lower the intrinsic resistance of the allograft to a subsequent chronic rejection process. Although drug-induced renal dysfunction represents a major indication for CsA dose reduction, it appears likely that this factor alone would predispose to chronic rejection, unless the CsA dose is drastically lowered beyond a certain amount (27). Indeed, during any given time interval, there was no significant difference between the mean observed or dose-corrected Cav values, or between the median CsA doses administered to the groups of putatively nephrotoxic patients afflicted with (381.45 mg/d; n = 71) versus those free of (337.16 mg/d; n = 133) chronic rejection. The only significant association other than intraindividual variability with the diagnosis of nephrotoxicity was the dose-corrected Cmax (P = 0.039; data not shown), a finding that confirms our previous observation (7).
The association between the inflection points reflecting low
intraindividual variability of drug exposure (%CV Cav
28.4% and %CV C0 36%) was more robust for its
negative than for its positive predictive value for the diagnosis of chronic
rejection. The limited capacity of a high level of variability to predict
patients who would experience chronic graft failure may be the result of
preeminent and inconsistent risk factors that overpower the biopharmaceutic
effect of variability, including CsA-resistant induction of B cell antibody
production, preexistent donor kidney injury and/or limited renal mass
(28), or independent
pharmacodynamic variabilities of the efficacy of drug effect. For example,
Batiuk et al. (29)
observed that CsA produces incomplete degrees of and inter-individual
differences in inhibition of calcineurin activity, the putative target of drug
action. We plan to study the association between estimates of kinetic
variability and calcineurin activity in the same manner that Vozeh et
al. (30) documented a
linear relation between theophylline concentrations and lung functions in
asthmatic patients. The planned studies may help clarify the association
between pharmacokinetic parameters and dynamic slopes or maximal effects of
CsA at its calcineurin target.
The finding that %CV C0 offers a more useful (albeit
less sensitive) measure of variability than %CV Cav
extends earlier findings of an association between a high degree of trough
concentration variability in the early posttransplant period and acute
rejection episodes in renal
(31) and heart and lung
(32) transplant recipients.
Furthermore, Savoldi et al.
(33) found that among a cohort
of 157 renal transplant recipients, patients with a %CV of
C0 below the median value of 31% showed a significantly
greater incidence of functioning allografts than did patients with higher
variability (mean period of 7 ± 2.3 yr). The present analysis extends
these findings by identifying 36% as the inflection point for
C0.
It seems more likely that variable oral absorption of CsA, rather than drug clearance rates, explains the present findings, since our previous studies failed to document significant changes in CsA clearance rates over time posttransplant in the absence of concomitant drug therapy altering cytochrome P450 3A4 activity (7). This hypothesis is consistent with the observations of Sanathanan and Peck (34): Variability of absorption of a variety of drugs enhances the effects of pharmacokinetic variation. However, it will be important to combine pharmacokinetic profiling with erythromycin breath tests (35) to exclude the influence of changes in hepatic disposition on drug variability.
All patients were concentration-controlled based on adjustment of CsA doses to achieve similar levels of exposure, i.e., Cav = 350 ± 50 ng/ml, based on pharmacokinetic profiles. It is impossible to ascertain whether a different target Cav value would reduce the risk of patients experiencing chronic rejection versus nephrotoxicity, and indeed whether patients maintained at this Cav would show less impact of variability on outcome. Furthermore, the inflection points of ROC curves may vary, depending on the concentration targets, the patterns of patient care, and the precision of the concentration monitoring programs either to obtain precisely timed C0 samples or to perform pharmacokinetic profiles for Cav values. Therefore, transplant centers should perform their own ROC analyses to examine the impact of %CV; the findings may vary according to not only patient characteristics but also the immunosuppressive regimen.
One might propose several explanations for the occurrence and biologic implications of intraindividual pharmacokinetic variability. First, because it persists over a long time period and is not associated with age, variability is unlikely to reflect maturational effects akin to those observed in pediatric and adolescent populations (36). Second, it seems unlikely that low variability is merely a reflection of better patient compliance to the immunosuppressive regimen. Patients in the V cohort neither admitted nor seemed to display evidence of noncompliance to a greater degree than did their LV counterparts (data not shown). Indeed, patients in the V cohort underwent outpatient follow-up a significantly greater number of times within each time interval than patients in the LV cohort (Table 5). Third, the long-term persistence of the pharmacokinetic variability suggests that it is unrelated to recovery of the impaired gastrointestinal function associated with chronic renal failure. Thus, one can only speculate that variability is due to episodic absorptive variations caused by coadministered over-the-counter medications and/or a variety of foods in the diet. Unfortunately, there are no reliable, quantitative, and clinically relevant surrogate techniques to evaluate intestinal factors that might predispose patients to variable drug absorption.
At least two strategies may be envisioned to overcome the adverse impact of high degrees of CsA variability described herein. On one hand, combination therapy of CsA with additional agents (mycophenolate mofetil [(37)] and/or sirolimus [(38)]) may potentiate the immunosuppressive effects and possibly exert direct actions to mitigate smooth muscle cell proliferation—a pathognomonic feature of chronic rejection. A 3-yr study is under way to compare the effects of addition of sirolimus to reduce the incidence of chronic rejection among CsA-treated patients. On the other hand, an improved biopharmaceutical formulation of CsA might increase the proportion of patients in the LV group. The new microemulsion CsA formulation Neoral® (39) seems to afford more consistent absorption, at least during the first 12 mo, i.e., a mean %CV of 18% compared to 36% for the oil-based formulation (B. Kahan, unpublished data). Indeed, potential cost benefits associated with the microemulsion formulation have been shown in a retrospective medical chart review of patients at Canadian centers participating in a multinational, randomized clinical trial comparing Neoral® to Sandimmune® (40).
The economic evaluation only sought to examine the correlation between pharmacokinetic variability and costs derived from the perspective of the transplant service. If a broader perspective was adopted and costs for other renal-related services, such as dialysis, were incorporated, it is likely that costs for these services would be disproportionately higher in the V group versus the LV group because a higher proportion of patients in the former group experienced chronic rejection (39% versus 22%, respectively) and likely required institution of dialysis. Thus, the differences in costs incurred within the two groups may have been higher if a broader perspective were evaluated. Future studies should use a decision analysis that determines the costs associated with true-positive, false-positive, true-negative, and false-negative results of the estimates of interindividual variability to assess the value of serial pharmacokinetic profiling to effectively predict the occurrence of chronic rejection and to test whether the present values for variability are optimal.
This study provides a longitudinal view of the impact of pharmacokinetic variability on chronic rejection incidence, as well as on inpatient and outpatient medical resource utilization, over the first 5 yr after renal transplantation. Members of the LV cohort displayed a reduced risk of chronic rejection and incurred significantly lower treatment costs. The findings suggest that more consistent drug absorption among the renal transplant recipient population may improve long-term outcomes and result in substantial cost advantages.
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Acknowledgments |
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