The clinical use of cyclosporine (CsA) has historically been complicated by incomplete and unpredictable absorption from the gastrointestinal tract. These factors significantly increase the risks of both acute and of chronic rejection and diminish the predictive value of therapeutic drug monitoring (1–6). The most recent formulation of CsA (Neoral, Novartis Pharma, Basle) uses microemulsion technology to ensure uniform drug dispersion within the absorptive region of the intestinal lumen (7). This results in enhanced bioavailability; relative independence from the effects of food, bile flow, and gastrointestinal dysfunction; and reduced inter- and intraindividual variability of exposure (7–12). Therefore, Neoral may be administered orally from the day of surgery and is consequently the preferred formulation of CsA for patients undergoing solid organ and bone marrow transplantation.
Therapeutic drug monitoring of CsA has traditionally been conducted using a single predose specimen to measure whole blood “trough” concentration (C0). However, it is now evident that drug exposure, estimated by the area under the time-concentration curve (AUC), is more closely related to clinical events than this single measurement (4,5). Because it is generally impractical to perform extensive pharmacokinetic (PK) studies on patients under conditions of normal practice, it has been necessary to develop a simple and alternative sparse-sampling method for PK monitoring (13,14). Studies conducted in Canada show that exposure during the first 4 hr of the dosing interval (AUC[0–4 hr]) bears a close and constant relationship to total drug exposure throughout the dosing interval (AUC[0–12 hr]) (R2=0.995) in stable renal transplant patients (15). Mathematical analysis has demonstrated that even two- or three-point limited sampling strategies using concentrations measured predose (C0), after 2 hr (C2), and after 3–4 hr (C3, C4) correlate closely with values obtained by full PK measurement and have a low prediction error (16).
Data available from the multicenter international study in de novo renal transplantation provide a guide to the absorption characteristics and mean AUC levels during the period from 2 weeks to 3 months posttransplant (17), whereas the Canadian randomized pharmacoepidemiologic study provides comparable information in stable patients from 3 months to 10 years posttransplant (15). To construct a viable target range for optimal immunosuppression, additional information on drug exposure and variability is required for the first 2 weeks after transplantation, a critical period when absorption and exposure may be expected to change most rapidly. These data can be combined with information from existing studies to provide an algorithm for therapeutic drug monitoring in which time posttransplant is a key determinant of predicted exposure.
Therefore, the current study was designed to estimate the rate of change in CsA absorption and the between-patient PK variability during the first 2 weeks after renal transplantation, to establish the most robust mathematical algorithms for predicting drug exposure using a limited sampling PK monitoring protocol within the same time frame, and to compare these algorithms with those derived from existing studies of de novo and stable transplantation in patients receiving Neoral and so establish an initial framework for subsequent studies of AUC-based dosing guidelines for Neoral therapy.
Patients and study design
Six renal transplant centers across Canada participated in a multicenter, nonrandomized open-label prospective study in which new renal transplant recipients of cadaveric or living-related grafts were treated with Neoral. The protocol was approved by the ethics committee at each participating center before recruitment of the first subject. Patients 18 years of age or older, who were recipients of cadaveric or living-related kidney transplants, who received Neoral on a b.i.d. regimen, and who were able to give informed consent were qualified for inclusion into the study. Patients who had a current malignancy (apart from localized cutaneous basal and squamous cell carcinoma); known liver disease, gastrointestinal disease, or other disorders that may have altered the absorption or metabolism of CsA; those who were currently receiving another investigational drug or a drug known to influence the absorption or metabolism of CsA, or had received such drugs within a 3-month period preceding transplantation; those who were multiorgan recipients or were previously transplanted with any organ other than a kidney; those known or strongly suspected to be noncompliant with medical therapy or follow-up; and those who were HIV positive, pregnant, or lactating were excluded from the study.
Patients were evaluated for entry into the study by the transplant team at the time of admission for transplantation. During this evaluation, demographic data and clinical history were recorded, along with past medication history. Patients were followed in hospital for the first 7 days posttransplant, during which time the first two PK studies were performed on days 3 and 7. Patients were then seen in the transplant clinic on day 14 for the third PK study, and on day 28 for the final visit to monitor all relevant clinical and therapeutic outcomes. The occurrence and severity of acute rejection, infection or other adverse effects, routine laboratory parameters, and vital signs were assessed at the initial visit and on days 3, 7, 14, and 28.
All patients received treatment with double or triple drug immunosuppression consisting of Neoral, azathioprine or mycophenolate mofetil (MMF), and prednisone. Treatment with Neoral was commenced at a dose of 4 to 6 mg/kg given orally twice daily, starting within the first 12 hr after transplantation. CsA levels were measured at each site by a monoclonal antibody assay specific for the parent molecule, and the dose was adjusted to maintain trough whole blood levels within the range of 250–450 μg/L during the first 2 weeks posttransplant. Azathioprine 1–1.5 mg/kg per day or MMF 1 g p.o. twice daily, were commenced within the first 12 hr after transplantation and were adjusted according to the white blood count or other relevant parameters. Oral prednisone or i.v. methylprednisone were commenced at a dose of 50 to 100 mg per day within the first 12 hr and reduced at a rate of approximately 2.5–5 mg per day.
A PK profile was performed on each of days 3, 7, and 14 after transplantation. A 3-ml whole blood sample was taken immediately before the morning dose of Neoral and at 1, 2, 2.5, 3, 4, 6, 8, and 12 hr postdose. Samples were stored at [minus]20°C, batched and shipped for central CsA analysis to Isotechnika, University of Alberta Hospitals, Edmonton, Alberta. CsA concentrations in whole blood samples were measured by fluorescence polarization immunoassay (Abbott, TDx) using the monoclonal antibody (Novartis Pharma) specific for the parent CsA compound. PK characteristics (mean±1 SD) determined from the 0- to 12-hr CsA concentration data included predose trough level (C0), the postdose trough level (C12), the maximum concentration (Cmax) during the assessed time interval and the time at which it was observed (Tmax), and the CsA exposure (AUC[0–4 hr] and AUC[0–12 hr]) as estimated by the trapezoidal rule. To incorporate the influence of any change in CsA dose, PK parameters were analyzed both with and without adjustment for the dose administered (on a mg/kg basis). All patients who entered the study, who received at least one dose of study medication, and for whom at least one postdose measurement was recorded were included in the formal analysis of this study.
Day-to-day changes in the mean and standard deviation of the PK parameters were examined by means of mixed linear models appropriate for repeated measures studies using PROC MIXED of SAS 6.12. An unstructured variance model was used to allow for day-to-day differences in the between- and within-patient variation. The significance of the differences in variation was determined using a paired-bootstrap procedure in S-PLUS 4.5. For each comparison of time points (e.g., day 3 vs. day 7), a 95% confidence interval for the differences in standard deviations (SD) and coefficients of variation (CV=SD/mean) were evaluated based on 1000 bootstrap samples of patients (18). The differences were declared significant if the confidence interval for the mean difference did not include zero.
Multiple linear regression analysis was used to evaluate the predictive ability of various limited sampling strategies. Models were constructed using one or more of the point concentrations taken during the first 4 hr of sampling (C0, C1, C2, C2.5, C3, C4). A coefficient of determination (R2 value) approaching or exceeding 0.9000 was established a priori as a desirable criterion for a clinically viable predictor.
Factors affecting the risk of rejection were examined using longitudinal logistic regression analysis to predict rejection during all three periods day 3 to day 6, day 7 to day 13, and day 14 to day 28, and traditional logistic regression analysis to predict rejection at each individual period during the study. Factors considered in the models were sex, race, diabetes mellitus, age, AUC, and concomitant medications. All data are reported as mean±SD unless otherwise indicated.
A total of 38 patients were enrolled at six study centers. Two patients did not receive treatment with Neoral. The remaining 36 patients are included in this analysis. Their mean age was 46±12 years; 31 (86.1%) of the subjects were male, 5 (13.8%) were female, 26 (72.2%) were Caucasian, and 8 (22.2%) were Asian. Cardiovascular disease (86.1%) and hypertension (86.1%) were the most prevalent comorbid factors.
Thirty-one patients completed the study to day 3, 25 to day 7, 23 to day 14, and 22 to day 28. Of the 14 patients withdrawn before completion, 9 (25%) were prematurely discontinued due to an adverse event that disrupted the planned dosing schedule for Neoral or necessitated discontinuation of the medication. These included delayed graft function (n=6), renal vein thrombosis (n=1), steroid-resistant rejection (n=1), and nephrectomy (n=1). Four patients withdrew consent for blood sampling, and one patient was discontinued due to an unsatisfactory therapeutic effect caused by inadequate CsA absorption.
By day 14 posttransplant, almost all patients (95.7%) were receiving steroids; more than half were receiving mycophenolate mofetil (56.5%), and less than a quarter (17.4%) were receiving azathioprine. The mean daily dose of CsA adjusted by body weight (mg/kg b.i.d.) at each study visit is shown in Table 1. The mean dose of CsA rose from 3.42±1.05 mg/kg b.i.d. on day 0 to 4.84±0.90 mg/kg b.i.d. on day 3, and 4.92±1.25 mg/kg b.i.d. on day 7, then declined to 4.21±1.32 mg/kg b.i.d. on day 14. Average trough concentrations (±1 SD) in the patients who fulfilled all sampling requirements on days 3, 7, and 14 (n=16) were 367±162 ng/ml, 380±108 ng/ml, and 420±124 ng/ml respectively. There was no significant difference in mean values between the three study days, but the variability in trough level measured by the coefficient of variation was significantly lower on day 14 than that on day 3 (P <0.05). Within this group, the percentage of patients who exhibited trough levels within the target range was 56.2% on day 3, 68.8% on day 7, and 50.0% on day 14.
Mean pharmacokinetic parameters
A nested subset of 16 patients had complete PK data on all 3 sampling days, with no protocol violations or concomitant medications that would impact the analysis. Data from these patients were used for longitudinal pharmacokinetic analysis of drug absorption and predictive modeling of drug exposure. CsA absorption parameters were compared between treatment days 3, 7, and 14 posttransplant (Fig. 1 and Table 2). Predose (C0) and postdose (C12) values both showed a slight and nonsignificant trend to higher levels by day 14, similar to that seen with trough CsA levels. Tmax shortened progressively from day 3 to day 14, so that by day 14, the average value was significantly less than the day 3 value (P =0.0028). Absolute values for Cmax on day 7 (P =0.013) and dose-adjusted values for Cmax on day 7 (P =0.008) and day 14 (P =0.005) were significantly increased by comparison with those on day 3. There were no significant differences in mean values for the absolute AUC[0–12] throughout the period of the study. However, the dose-corrected AUC[0–12] seemed to increase progressively from day 3 to day 14, and by day 14 the average AUC/dose was approximately 20% greater than that on day 3 (P =0.067). AUC[0–4], on average, accounted for 52% of the AUC[0–12] values across the three study days. The correlation between AUC[0–4] and AUC[0–12] increased from 0.803 on day 3 to 0.952 on day 7 and 0.972 on day 14 (all P <0.001). There was no significant change in AUC[0–4] between the study days. However, dose-adjusted AUC[0–4] differed significantly by day (P =0.025), showing a significant increase from day 3 to day 7 (P =0.036), and rising further to day 14 at which it was approximately 31% greater than on day 3 (P =0.009).
CsA concentration profiles seemed to become more uniform over the 14 days of the study. Seven of the 48 PK analyses (14.6%) in the 16 nested subjects showed double concentration peaks: 3 of these occurred on day 3, 3 on day 7, and only 1 on day 14. Consistent with this, there was a significant decrease (P <0.05) in the standard deviations of the absolute AUC[0–12] between days 3 and 14 (SD=3236 vs. 2094 μg·hr/L, 95% confidence interval [CI] for change from 187 to 2386), and of Tmax between day 7 and day 14 (SD=0.93 vs. 0.49 μg.h/L, 95% CI for change from 0.218 to 0.852) (Fig. 2). Relative variability behaved similarly, with significant decreases (P <0.05) in CV from days 3 and 7 (35.0%, 30.6%) to day 14 (21.5%) for AUC[0-12] and from day 7 (47.7%) to 14 for Tmax (33.1%).
Limited sampling analysis
The principal limited sampling models and the corresponding R2 values resulting from the linear regression analyses are shown in Table 3. C0 seemed to be a poor predictor of drug exposure, with R2 values less than 0.5 for AUC[0–4] and 0.7 for AUC[0–12] at all time points.
For AUC[0–12], all 5- and 6-point strategies, three 4-point strategies (C0+C1+C2+C4, C0+C1+C3+C4, C0+C2+C3+C4), and two 3-point strategies (C0+C2+C3, C0+C2+C4) had R2 value approaching or exceeding 0.9 on all three study days. One other 3-point model (C1+C2+C3) had R2 values that met the desired threshold on days 7 and 14 but not on day 3. Of the 2-point predictors, C0+C2, C1+C3, and C2+C4 were the most strongly correlated with AUC[0–12] and C3 seemed to be the most important single predictor with R2 values>0.80 on days 7 and 14.
For AUC[0–4], the models selected correlated even more closely, as expected. All 5- and 6-point models, most 4-point models, and several 3-point models had R2 values approaching or exceeding 0.90 on all 3 study days. Among the 3-point models, C0+C2+C3, C0+C2+C4, and C1+C2+C3 were the most highly predictive, with C1+C2+C3 seeming to be marginally superior. Among the 2-point models, C0+C2, C1+C3, and C2+C4 approached or exceeded an R2 value of 0.90 at the three time points. No single point model exceeded R2 0.9, although C2 and C3 seemed to be the most valuable single point predictors, with R2 values approaching or exceeding 0.80 at most of the three time points.
Ten of the 36 treated patients (27.8%) experienced an episode of acute rejection during the first 28 days posttransplant. Six experienced a single rejection episode, whereas 4 experienced 2 rejection episodes during the time of follow-up. Thirteen of the 14 episodes of acute rejection diagnosed were confirmed by biopsy. One patient experienced graft loss due to acute rejection and was nephrectomized on the 5th day. No deaths occurred in this study.
A longitudinal logistic regression model including AUC[0–12] and clinical and pharmacokinetic variables (race, presence of diabetes mellitus, use of concomitant medications known to influence CsA absorption) showed no correlation between C0 and the risk of acute rejection (P =0.125). In a similar model, lower AUC[0–12] values were marginally associated with increased risk of rejection (P =0.099), whereas lower AUC[0–4] values were significantly associated with increased risk of rejection (P =0.046). None of the other clinical variables examined had a significant influence on rejection risk, and were eliminated from subsequent models to reduce the risk of overfitting. Sex was not considered in the models because all acute rejection episodes in the study occurred in males. The parsimonious models demonstrated a slightly more powerful relationship between both AUC[0–12] (P =0.057) and AUC[0–4] (P =0.031) and rejection risk; subsequent analysis identified single-point indicators of drug absorption, including C2 (P =0.012) and Cmax (P =0.061) as important predictors of clinical risk.
Logistic regression models examining the relationship between CsA exposure and the occurrence of at least one episode of acute rejection within each time period showed a trend toward lower CsA exposure and increased rejection risk as early as the first week, which became statistically highly significant by week 2. Exploratory analyses shown in Figure 3 indicate that mean CsA exposure on day 7 was significantly lower in patients who experienced acute rejection in the second week than in those who were rejection free whether measured by AUC[0–12] (7976±1476 vs. 10,239±2759 μg·hr/L;P =0.048), AUC[0–4] (4027±412 vs. 5623±1389 μg·hr/L;P <0.0001), C2 (1116±183 vs. 1852±522 μg/L;P <0.0001), or Cmax (1415±323 vs. 2084±450 μg/L;P =0.005). The current study population was not sufficiently large to perform a conventional receiver operating curve (ROC) analysis. Therefore, patients were separated into dichotomous groups according to exposure on day 7. Patients who achieved an AUC[0–4] 4,500 μg·hr/L had a markedly reduced risk of subsequent acute rejection compared with those below this threshold (7% vs. 40%;P =0.041; sensitivity, 80%; specificity, 70%; positive predictive value, 40%; negative predictive value, 93%). Measurement of C2 seemed to have even greater discriminant value, and patients who achieved a C2 level greater than 1500 μg/L had a particularly low risk of rejection (0% vs. 58%;P <0.001; sensitivity, 100%; specificity, 75%; positive predictive value, 58%; negative predictive value, 100%) (Fig. 4).
All 36 treated patients experienced at least 1 adverse event (AE). Of the 392 AEs reported (e.g., pain, peripheral edema, nausea, vomiting, constipation), 5% were assessed as severe, 45% as moderate, and 50% as mild. Approximately 10% of AEs were thought to be related to the study medication, and of these, 7 patients required an interruption or reduction in Neoral dose. Only 1 patient in the total study population experienced an opportunistic infection. The mean serum creatinine in patients without graft rejection was 192, 144, and 129 μmol/L, respectively, on days 3, 7, and 14, compared with 398, 350, and 371 μmol/L in those with acute rejection. No association between graft function and CsA exposure measured by AUC[0–12] or AUC[0–4] was observed in either group.
Acute rejection occurs predominantly within the first 3 months after transplantation and is an important barrier to successful engraftment and rehabilitation (19). Inadequate or variable CsA exposure is now believed to be a key determinant of acute rejection, which in turn is closely linked to the development of chronic rejection, the principal cause of late graft loss; early and long-term graft survival may, therefore, both be critically dependent upon achieving and maintaining adequate CsA exposure in the early posttransplant period (4,13,20–24).
This pharmacoepidemologic study was conducted in the first 2 weeks posttransplant in renal transplant patients receiving Neoral to determine the relationship between cyclosporine dose, pharmacokinetics, and clinical events under conditions of routine clinical practice. All patients received Neoral at doses consistent with normal Canadian practice. Mean trough CsA levels were within the target range of 250–450 μg/L on each of the 3 study days, and there was no significant difference between these values, although trough level variability decreased progressively from day 3 to day 14. The proportion of patients who exhibited trough levels within the target range did not change substantially over the study period, remaining between 40% and 60% on days 3, 7, and 14. However, the change in distribution of patients who fell outside the target range was striking; whereas 20%–35% of patients were below the lower limit of 250 μg/L on day 3, this percentage had fallen to 12%–20% by day 7 and 0% by day 14. In contrast, the proportion above the upper threshold of 450 μg/L increased from 23% to 25% on day 3 to 50–52% by day 14, indicating perhaps that the clinical ability to target therapy using trough level monitoring did not improve during this critical time after transplant surgery.
CsA pharmacokinetics altered substantially during the first 2 weeks posttransplant. Tmax shortened progressively to 1.5 hr by day 14, and absolute and dose-adjusted values for Cmax were significantly higher on day 7 and 14 than on day 3. There were no significant differences in the absolute AUC throughout the period of the study, but the dose-adjusted AUC increased progressively and significantly from day 3 to day 14. In general, variability decreased over time; however, only the AUC showed a significant decrease in absolute and relative variability from day 3 to 14, and only Tmax showed a significant decrease in absolute and relative variability from day 7 to day 14. Overall, by day 14, mean values for all PK parameters approximated those of stable renal transplant patients (15).
Conventional AUC measurements involve large numbers of blood samples throughout the dosage interval, and are impracticable for use as a monitoring tool in a clinical setting. Although substantially easier, use of an AUC[0–4 hr] sampling approach is still costly, time-consuming and cumbersome. For this reason, we have attempted to determine an appropriate limited sampling strategy for use in transplantation, which will combine precise and accurate estimations of CsA exposure with clinical convenience and utility. Pharmacokinetic studies have demonstrated that sparse sampling methods may be used to predict exposure using fewer blood samples at key time intervals throughout the dosing interval. In stable renal transplant patients with very uniform CsA concentration profiles, the sparse-sampling methods could be simplified to the point of using two CsA sample concentrations (C0+C2), while retaining a high degree of correlation with drug exposure (16). However, as demonstrated in this study, CsA concentration profiles are not uniform either between or within patients during this early period posttransplant. As a result of this variability, 1-point or 2-point sampling strategies did not precisely predict AUC[0–12] exposure, although several provide a good approximation and almost all were substantially better than C0. Three-point protocols with blood samples between 0 and 4 hr postdose (i.e., C0+C1+C3, C0+C2+C3, or C0+C2+C4) provided very close correlation with CsA exposure (R2 0.88–0.96), especially when compared with the low predictive value for conventional trough levels (R2 0.22–0.69). Several 3-point (particularly C1+C2+C3) or 2-point (C0+C2, C1+C3, C2+C4) algorithms accurately predicted AUC[0–4] with an R2 approaching or exceeding 0.9 and, although slightly less predictive, a single-point sample at C2 has the important value of being simple, rapid, and accurate for prediction of AUC[0–4] in the routine clinical setting.
The data from this study support the concept that rejection risk under conditions of normal practice is related to CsA exposure, but there is no statistical relationship between rejection and trough CsA levels. Longitudinal logistic regression indicated that lower AUC[0–12] values at each of days 3, 7, and day 14 were marginally correlated with an increased risk of rejection, although AUC[0–4] seemed to a more reliable and significant predictor of rejection, consistent with the observation that the greatest interindividual variation in drug exposure occurs during this interval. AUC[0–4] values lower than approximately 4,500 μg·hr/L on day 7 were associated with a significantly increased risk of acute rejection; patients experiencing acute rejection had a mean AUC[0–4] of 3986 μg·hr/L, whereas patients who remained rejection-free had a mean of 5623 μg·hr/L (P =0.0001). These data are consistent with those of Mahalati et al. (25) in adult renal transplant patients (25,26). These investigators showed that AUC[0–4] is closely correlated with outcome (P =0.03), whereas trough levels are not (P =0.42), and proposed a therapeutic range of 4400–5500 μg·hr/L for AUC[0–4 hr] and of 9500–11,500 μg·hr/L for AUC[0–12 hr] for optimal immunosuppression with Neoral. The current study also identified a significant, and perhaps more important, relationship between C2 concentrations and rejection risk. The mean C2 concentration on day 7 in patients with acute rejection was 1063 μg/L compared with 1852 μg/L in those who were rejection free (P <0.0001), and no patients with a C2 level>1500 μg/L experience acute rejection in the following time interval. A similar trend was observed with Cmax (1381 vs. 2084 μg/L;P =0.0011), although the exact time of Cmax is impossible to define without multiple sampling. In contradistinction to Mahalati et al. (25), the current study did not define a relationship between CsA exposure and graft function in patients without acute rejection, perhaps related to the small number of patients involved.
Effective immunosuppression requires that therapeutic levels of CsA exposure be obtained quickly after transplantation, and maintained throughout the transplant course. Accurate and individualized dosing has been limited by several important factors, however. These factors include the narrow therapeutic index of CsA; the pronounced inter- and intraindividual pharmacokinetic variability; the low or erratic bioavailability, and a lack of linear relationship between dose and exposure or trough levels and exposure of its early oral dosage form (Sandimmune) (6); and that trough blood levels do not reliably indicate changes in AUC (6,15,16) due to the relative brevity of the dosage interval compared with the elimination half-life of the drug (6). Trough level monitoring does not accurately predict exposure; it is, therefore, suboptimal for preventing toxicity or graft rejection and should probably now be abandoned (3,4,14,27–29). The greatest precision in predicting drug exposure is obtained using an abbreviated AUC-sampling approach to predict AUC[0–4] or AUC[0–12](15,30). This study shows that, under routine clinical conditions, algorithms using 2 or 3 points sampled within the first 4 hr of the dosing interval provide a simple, inexpensive and precise method for monitoring CsA exposure during the first 2 weeks after renal transplantation. However, the data reported here suggest that use of a single-point surrogate such as C2, which has an R2 value approximating 0.8 throughout this early period, may prove a more simple, practical, and clinically relevant method for determining adequacy of clinical immunosuppression, thereby minimizing costs and complexity of therapeutic monitoring while permitting maximum therapeutic efficacy. This measure has a high specificity and negative predictive value, indicating that rejection is very uncommon above the threshold selected.
In conclusion, this study indicates that CsA absorption changes rapidly during the first 2 weeks posttransplant and that approximately 50% of patients do not reach an AUC[0–4] or C2 value consistent with optimal immunosuppression within the first week at current doses of Neoral. Three approaches may be used to overcome this. First, a starting dose of Neoral higher than 10 mg/kg per day p.o. may be used in all patients and titrated according to absorption profile (AUC[0–4]) from day 3 to achieve CsA concentrations consistent with freedom from rejection. However, the sample variability observed suggests that patients with low absorption may still not achieve these levels within the critical first 3–5 days of therapy, whereas others with high absorption may be exposed to elevated levels and risk toxicity. Alternatively, it may be simpler and more effective to use intravenous CsA with infusion modeled to reproduce the same pharmacokinetic profile and C2 target described here, switching to tailored oral therapy after absorption profiling on day 3. Finally, it may prove beneficial to use an additional nontoxic agent such as an anti-IL-2R antibody to maintain adequate immunosuppression until optimal CsA exposure is achieved with oral therapy.
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