Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3 mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than in adults, with an AUC of 861 ± 805 vs2629 ± 1487 μmg × h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59 ± 0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077 ± 1551 μg × h/l compared to 1795 ± 973 μg × h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These data suggest that 12 h post-dose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT. Bone Marrow Transplantation (2000) 26, 545–551.
The use of cyclosporin A (CsA) has been complicated by its high inter- and intra-patient pharmacokinetic variability,123456 which is largely due to variability in intestinal absorption.67 Patients with impaired intestinal integrity may have additional problems with absorption of CsA, further complicating selection of a therapeutic dose. The pharmacokinetic variability observed with earlier CsA formulations such as standard emulsion CsA has prompted monitoring of CsA in blood to ensure appropriate concentrations are attained.4 Neoral (Novartis Pharma, Basel, Switzerland), a new microemulsion preparation of CsA, is absorbed independent of bile secretion in the gut8 and has increased absorption and less variable pharmacokinetic parameters compared to the standard emulsion CsA (Sandimmune, Novartis Pharma) in solid organ transplant recipients.89
CsA is used extensively in bone marrow transplantation (BMT) both in children and adults. These patients have important differences in intestinal integrity compared to solid organ transplant recipients that may affect the absorption of standard emulsion CsA.10 These differences include mucositis secondary to the preparative regimen used in BMT,10 graft-versus-host disease (GVHD) and viral infections secondary to cytomegalovirus (CMV) or adenovirus, resulting in diffuse inflammation of the intestinal tract.11 Microemulsion CsA may therefore provide improved absorption and increased blood concentrations in the BMT population, as well as better control of CsA pharma- cokinetic variability, as compared to standard emulsion CsA, potentially improving the therapeutic efficacy of oral CsA in BMT patients.
This is the first study to evaluate the pharmacokinetics of microemulsion CsA in BMT patients during the second 2 weeks post transplant, when they are normally changed from the intravenous to the oral formulation. The study examined the effects of recipient age, GI inflammation, microemulsion CsA formulation (capsule vs solution), administration with either liquid or solid food, and concomitant drugs on CsA pharmacokinetics. In addition, intra- and inter-patient variability of CsA absorption was evaluated in the adult population.
Materials and methods
All patients at Vancouver Hospital and Health Sciences Center and British Columbia's Children's Hospital who received an allogeneic (related matched or mismatched, or unrelated) BMT and were treated with CsA for GVHD prophylaxis were eligible for study entry. Patients were excluded if they were not capable of taking oral medications, had severe renal disease (estimated creatinine clearance of <60 ml/min in adults or <50% of expected for age in those less than 18 years), or had severe hepatic disease (serum bilirubin >60 μmol/l, and/or ALT or AST >3 times normal for age). Estimated creatinine clearance was calculated according to the Gault formula. Informed consent was obtained from all patients or their legal guardians by the attending physician or study nurse, using forms approved by the University of British Columbia Clinical Research Ethics Board and following the guidelines for use of human subjects in research.
Patients received a continuous intravenous infusion (CI) of CsA starting at 3 mg/kg/day for at least 5 days before initiation of the study and were maintained on this therapy until the end of the study. CsA dosing was modified according to a standard protocol to maintain a whole blood concentration of approximately 150 ng/ml. No alteration in dosage was allowed during the 72 h before the first oral dose of the study. CsA blood concentrations were obtained 72, 48, and 24 h before the first oral dose of microemulsion CsA was administered to ensure that steady-state CsA concentrations had been reached. Patients in whom any of the three CsA concentrations varied by more than 25% from the mean of the three CsA concentrations were excluded. All patients received a first oral dose of 3 mg/kg of microemulsion CsA on day 21 ± 7 after BMT in addition to the CI of CsA. Blood samples for pharmacokinetic evaluation were collected pre-dose and at 0.5, 1.0, 1.5, 2.5, 5, 7 and 12 h post dose. After a period of 48 h to permit washout of the oral CsA, the adult patients received a second dose of microemulsion CsA at 3 mg/kg and a second pharmacokinetic study was performed. The total study period involved 3 contiguous days with pharmacokinetic evaluations on days 1 and 3. In order to improve patient compliance on the study, the oral dose formulation of capsule or liquid was at the patients discretion due to the fact that patients with mucositis, GVHD or nausea prefer one formulation over the other. The type of formulation was recorded and analyzed as a variable as described below.
CsA concentrations were measured using the TDX monoclonal fluorescence polarization immunoassay (Abbott Diagnostics, Abbott Park, IL, USA).4 The assay had an inter-assay c.v. of <5% over a concentration range of 100 to 1000 μg/l and was linear over the therapeutic range with a sensitivity of 25 μg/l. The maximum whole blood concentration (Cmax) and its time of occurrence (tmax) following each oral dose were determined from a plot of CsA concentration vs time. The area under the concentration-time curve throughout the first 12 h of the dosing interval (AUC0–12) was calculated using the linear trapezoidal rule with the concentration of CsA at C0 subtracted from each time point. Intra-patient variability was calculated as shown below:
Demographic and clinical evaluation
Baseline variables included recipient age, diagnosis and preparative regimen. Patients were evaluated on each of the 3 study days to determine the presence of infection, mucositis, diarrhea, intestinal GVHD, neutropenic enterocolitis, liver or renal toxicity, and use of parenteral nutrition. Mucositis was defined as a complaint of pain in the mouth, throat or difficulty swallowing that had been present from within 7 days post BMT. Mucositis was graded as per criteria from Miller et al12 and patients with greater than stage II mucositis were classified as having mucositis. The oral mucositis criteria were as follows: grade I = soreness/ erythema; grade II = erythema, ulcers, can eat solids; grade III = ulcers, requires liquid diet only; grade IV = alimentation not possible. Intestinal GVHD was defined as diarrhea or nausea that had presented more than 7 days after BMT. Additional symptoms of GVHD were cramping abdominal pain followed by diarrhea, ileus, melena, a diagnostic intestinal biopsy for GVHD and concurrent skin or liver GVHD. Patients were classified as having clinically significant GVHD if they were equal to or greater than stage II intestinal clinical symptoms (⩾1000 ml/day in patients >16 years or ⩾15 ml/kg/24 h in children ⩽16 years and ⩽50 kg). Infection was excluded in all patients with diarrhea by routine bacterial, viral, fungal cultures, evaluation for C. diff. toxin, and examination for ova and parasites. None of the patients evaluated had evidence of infection.
The dose, frequency and duration of administration of all drugs known to affect CsA pharmacokinetics were recorded. Data were collected regarding the ingestion of concurrent liquids (water, juice or other beverages) or solid foods or oral supplement such as peptamin within 30 min of the drug administration. Patients were not allowed to take grapefruit juice as a concurrent oral agent.
Analysis of AUC0–12 and Cmax was performed using ANOVA with the patient as a between subject factor, days of the assay (days 1, 2, and 3), treatment, and carry over (from previous treatment) as within subject factors. Adults and children were analyzed separately. Analysis of the tmax included a modified categorical modeling instead of a straight ANOVA since the distribution of tmax was unlikely to approximate a normal distribution. Analyses of the within-patient dose effect were performed using paired t-tests of the transformed response variables. Analyses of the between patients effects (eg age, concomitant medications, GI inflammation) were performed using two sample t-tests of the transformed response variables, analyzing each dose separately.
Sparse sampling modeling of AUC was performed as a stepwise regression analysis using the incremental AUC0–12 values and the untransformed, incremental point concentrations C0 to C12. Predictors were chosen using a forward selection strategy. Analysis of Cmax, AUC0–12, and C12 were conducted on square root transformed data and tmax values were log transformed prior to analyses. The transformations were chosen on the basis of normal probability plots of residuals from all analyses. For ease of interpretation, all summary statistics were reported for the untransformed response variables. Analyses were conducted using S-PLUS and SAS. Statistical significance was determined as an observed P value of less than 0.05.
Patient demography and clinical course
Twenty adults (mean age 42.6 years, range: 24–54 years) and seven children (mean age 7.0 years, range: 0.8–14.2 years) were enrolled and evaluated. The diagnoses in adults were ALL (n = 2), AML (n = 5), CML (n = 3), multiple myeloma (n = 2), severe aplastic anemia (n = 1), non-Hodgkin's lymphoma (n = 2), CLL (n = 2), and MDS (n= 3). In the children the diagnoses were ALL (n = 2), AML (n = 1), CML (n = 2), Wiskott–Aldrich syndrome (n = 1) and severe aplastic anemia (n = 1). The preparative regimens used in adults were cyclophosphamide, total body irradiation (TBI) ± another drug (n = 11), busulfan + cyclophosphamide (n = 8), and cyclophosphamide + antithymocyte globulin (n = 1). In the children, three received cyclophosphamide, TBI ± another drug and four received busulfan + cyclophosphamide. Acute intestinal GVHD developed in two adults and mucositis in 11 adults for a total of 13. In the children, four developed either clinical intestinal GVHD or mucositis.
Cyclosporine pharmacokinetics and variability
A total of 43 pharmacokinetic studies were conducted in the 27 subjects: 36 in adults and seven in children. All adult patients had at least one pharmacokinetic study that was suitable for evaluation. Cyclosporine exposure was significantly diminished in children when compared with the first evaluable pharmacokinetic course from each of the 20 adult patients (Table 1). Cmax was reduced by over half (P = 0.037), and AUC by two thirds (P = 0.001), while C12 was equal to or lower than C0 in all the children (P = 0.004). By contrast, tmax was not significantly different between the two groups.
Six adult patients did not complete both pharmacokinetic studies, either because they vomited within 1 h of the oral dose or because pharmacokinetic samples were not collected at all prescribed time points, and were excluded from analysis of intra-patient variability. The results for the remaining 14 adult patients are shown in Figure 1 and Table 2. There was no significant difference in any of the principal pharmacokinetic parameters Cmax, tmax, AUC or C12 following dose 1 or dose 2. Inter-patient variability in adults for Cmax was 83% for dose 1 and 45% for dose 2, and for AUC was 87% for dose 1 and 54% for dose 2. These results did not differ from those in children. Intra-patient variability for Cmax was 0.58 ± 0.40 and for AUC was 0.59 ± 0.34.
Effect of GI mucositis and GVHD on CsA absorption
Of the 36 pharmacokinetic studies performed in adults, 21 were conducted in patients with GI inflammation due to either GVHD (n = 4) or mucositis (n = 17), while in the remaining 15 no GI inflammation was recorded (Table 3). For patients receiving the first dose of CsA, Cmax was 65% (P = 0.19) and AUC 71% (P = 0.02) higher in those who had GI inflammation (Figure 2). There was no statistically significant difference in either of these parameters for patients with mucositis compared to those with GVHD of the gut although numbers were small (Table 3). Evaluation of the second dose in adults and the single curve in children revealed a similar trend with a higher Cmax and AUC in children who had GI GVHD or mucositis, but the differences were not statistically different. The presence of GI inflammation did not have a significant effect on inter- or intra-patient variability.
Effect of concomitant factors on CsA absorption
The preparative regimen, concurrent medications, supportive care measures, use of parenteral nutrition, infection or mild liver or kidney dysfunction did not have a demonstrable effect on the pharmacokinetics of microemulsion CsA in adult recipients. The mean AUC for 11 adults who received cyclophosphamide/total body irradiation (CY/TBI) ± other was 3063 ± 1490 μg × h/l compared to 1949 ± 1394 μg × h/l in those who received busulfan/ cyclophosphamide (Bu/CY) ± other (P = 0.16), although one adult patient who received cyclophosphamide/ antithymocyte globulin (CY/ATG) had an AUC higher than for either of the other preparative regimens. None of the patients received erythromycin, diltiazem, verapamil, or other possible medications known to affect CsA blood concentrations, and there was no statistically significant effect of any other co-medication examined on AUC, including fluconazole, nifedipine, steroids, anticonvulsants and digoxin. The AUC, was not significantly different for patients who received CsA as a capsule (2122 ± 1025 μg × h/l; n = 8) or a liquid (2966 ± 1685 μg × h/l; n = 12; P = 0.22) formulation, nor was there a difference between patients who received CsA with liquid (2475 ± 1536 μg × h/l; n = 13) or with food (2981 ± 1663 μg × h/l; n = 7; P = 0.72). There was no correlation between the AUC, the creatinine, total bilirubin or direct bilirubin levels.
Sparse sample modeling of AUC
Identification of the optimum sparse sample models for prediction of AUC was performed using a forward selection stepwise regression analysis. Because the values employed represent incremental blood concentrations, C0 was equal to zero μg/l for all subjects. Analysis was conducted independently for adults and children, and the principal results derived from the first pharmacokinetic profile are reported in Table 4. In adults, the model incorporating all seven time points (0.5, 1, 1.5, 2.5, 4, 7 and 12 h) correlated most closely with measured AUC (r2: 0.988). All six-point models showed excellent correlation with r2 values of 0.929–0.987, with the exception of that excluding C7 in which the r2 value fell to 0.679. Five-point and four-point models including times 0.5 or 1 h, 2.5, 5, and 7 h also performed well (r2 > 0.94), and all three-point models including 2.5, and 7 h also demonstrated r2 values above 0.95. Only two two-point predictors exceeded an r2 value of 0.90 (C1.5 and C5, and C2.5 and C5) and all one-point sparse sample predictors fell below the r2 value of 0.9. No single-point predictor exceeded an r2 of 0.688 (C2.5 h) and C12 had an r2 of 0.012. In children, the strength of the association also declined with the gradual reduction in the number of explanatory time points, but remained slightly superior to that in adults for all models evaluated. The combination of C1.5 and C5 appeared to be the most appropriate two-point predictor (r2: 0.976); no other two-point predictor models exceeded the target value of 0.9. Also, no single point predictors exceeded the target value of 0.9, although C0.5 and C1.5 both exceeded an r2 value of 0.8.
We present the first study to evaluate the pharmacokinetics of the microemulsion formulation of oral CsA, Neoral, in BMT patients. Pharmacokinetic analyses were performed at 14–28 days after BMT, a time when many patients are changed from the i.v. to the oral formulation. The study design employed paired identical oral doses given 48 h apart in order to study drug exposure and inter- and intra-patient variability, and to assess the influence of age, concurrent conditions, comedications and GI inflammation secondary to either mucositis or intestinal GVHD on CsA absorption. The major factors that affected whole blood concentration of CsA were recipient age and the presence of GI inflammation. The former has been previously described,13 but the effect of GI inflammation appears to be a novel observation.
The data reported here show that absorption of CsA is delayed and reduced in both adults and children by comparison with patients receiving solid organ transplantation. Tmax occurred after 2–4 h, compared with 1–2 following kidney or liver transplantation.1415 The dose normalized AUC0–12 ranged from 287 μg × h/l/mg/kg in children to 876 μg × h/l/mg/kg in adults, approximately half the values reported in the 2–4th week after renal transplantation. We observed substantial inter-patient variability in CsA blood concentrations after microemulsion CsA administration, in contrast to the relatively low inter-patient variability (c.v. 0.13) previously noted in young stable renal transplant patients.14 We also observed a high intra-patient variability in adult patients. Cmax was 7% higher and mean AUC 21% higher on the second dose in these subjects, in contrast to a previous study16 which showed a significantly lower Cmax (decreased by 9%) and AUC (6% decrease) for the second dose. It is, however, consistent with other studies of microemulsion CsA in renal transplantation patients that demonstrated a high level of variability early after transplantation.17
CsA exposure was increased in patients with GI inflammation secondary to mucositis or intestinal GVHD, producing a significant increase in AUC and a similar, although nonsignificant, trend with Cmax. The effect on the AUC was more pronounced in patients with GVHD compared to mucositis. The increase in exposure may be explained by four factors. First, a general increase in capillary permeability due to intestinal inflammation. Second, inflammation may decrease the multidrug resistance function in the intestinal wall epithelium, resulting in decreased pumping of CsA from the enterocyte into the intestinal lumen.181920 Transport of CsA across intestinal cells appears to be modulated by directional efflux, mediated by a P-glycoprotein-like pump.2122 In vitro studies with the Caco-2 cell line have shown that the P-glycoprotein efflux pump causes an increase in the metabolism of CsA during the course of its transport by slowing down the transport of CsA molecules across Caco-2 cells.23 Third, decreased cytochrome CYP3A4 function may result in reduced intracellular metabolism of CsA within the enterocyte, allowing increased drug absorption.2425 The quantitative importance of this effect is uncertain, since studies have suggested that CYP3A4 function is more important in hepatocyte metabolism of CsA than in intestinal mucosal cells,23 while the increased CsA blood concentration induced by concomitant administration of grapefruit juice appears to be primarily due to inhibition of this enzyme in the intestinal mucosa.25 Fourth, inflammation may decrease gut motility and result in prolonged transit of CsA through the small intestine leading to increased absorption.19 This may be particularly important with microemulsion CsA since absorption from this formulation is relatively bile-independent, whereas reduced bile production or release due to intestinal GVHD or mucositis may decrease the absorption of other formulations thus masking the effects of intestinal inflammation.
Sparse sampling analysis revealed that two-point predictors could be employed to closely approximate the AUC in both adults and children. This is in marked contrast to the low predictive power observed for the trough (C12) level in both patient groups, a measurement that is usually employed to adjust CsA dosages in BMT patients. Both of these observations are consistent with findings from studies in solid organ transplant recipients. There is controversy regarding the correlation of C12 levels with reduction of GVHD in BMT patients.2627 This is readily explained by the poor correlation observed between C12 and AUC, which more accurately reflects the pharmacological exposure of CsA. This study suggests that measurement of whole blood concentrations at time points throughout the dosing interval may be more appropriate for adjustment of CsA dosing, although the individual points chosen depend upon the clinical approach adopted. The use of incremental concentrations in patients simultaneously receiving intravenous CsA precludes the use of a C0 concentration, as in this case. Under these conditions, AUC may be predicted most accurately by limited sampling models using an early time point (1.5–2.5 h), approximating peak concentrations, and a later point in the elimination phase (4–6 h). Increased metabolism of CsA in children resulting in decreased whole blood levels has been described previously in BMT patients receiving standard emulsion CsA,28 and our study confirmed that this is also true for the microemulsion CsA preparation, Neoral. It has been suggested dosing every 8 h may be more appropriate in children receiving solid organ transplants, and the data reported here indicate that this may also pertain to children receiving BMTs. Children receiving microemulsion CsA should be closely monitored and require higher initial oral doses compared to adults.
The findings reported here show that bioavailability of CsA is low and heterogeneous in the early weeks after BMT, and suggest that direct extrapolation of CsA pharmacokinetics from solid organ transplantation to the early post-BMT period may be inappropriate. This is particularly true when subjects are receiving therapy by both oral and intravenous routes, since under these conditions the observed variability represents the combined variability of both the continuous intravenous infusion and the incremental oral dose. The most important factors influencing drug exposure were recipient age and the presence of GI inflammation. This study revealed no significant effect of concomitant drugs on CsA absorption, consistent with the exclusion of drugs known to affect CsA blood levels.29 Patient discretion in selection of the oral CsA formulation may also have introduced variability, although we could not identify differences in absorption between capsule and liquid formulations. Finally, we have demonstrated that limited sampling models are more highly predictive of the AUC than use of the C12 trough alone. Whether the use of these different sampling time points correlates more closely with therapeutic efficacy in BMT patients remains to be determined. We have not yet studied BMT patients at later time points post transplant, when GI inflammation is less frequent, and when it is possible that the bioavailability and pharmacokinetics of CsA may correspond more closely to those in solid organ patients.
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We wish to thank the BMT nurses and physicians in the BMT programs and Julia Schultz for editorial assistance in preparation of this manuscript. In particular, we would like to thank Drs Ron Anderson, Jeff Davis, Chris Fryer, Sheila Pritchard, John Sheperd, Stephen Nantel, Hans-G Klingemann, Michael Barnett, Donna Hogge, Heather Sutherland, and John Wu. This study was fully funded by an unrestricted grant from Novartis Pharma Canada Inc (Dorval, Canada). Part of the data presented in this manuscript has been published in Transplant Proc 1998; 30: 1668–1670.
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Schultz, K., Nevill, T., Balshaw, R. et al. Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation. Bone Marrow Transplant 26, 545–551 (2000). https://doi.org/10.1038/sj.bmt.1702545
- cyclosporin A
- bone marrow transplantation
- graft-versus-host disease
- age-related effects
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