[Innovation instead of imitation -- news in drug therapy].
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Antibodies, Monoclonal↗
Biomedical subjects
E A Mueller
Publications and source records attributed to E A Mueller.
Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
OBJECTIVES: To investigate the clinical efficacy and safety of a newly developed diclofenac patch in the topical treatment of blunt impact injuries. METHODS: This was a randomised, placebo controlled, double blind, multicentre study in 120 patients with traumatic blunt soft tissue injury. Within 3 h of the injury participants of sport competitions and training camps were enrolled and treated twice daily with the diclofenac or a placebo patch over a period of 7 days. Patients were randomised (1:1) to two parallel groups. Tenderness produced by pressure was measured twice daily during the first 3 days after enrollment as well as at day 7. Tenderness was defined as the amount of pressure (measured by a calibrated caliper at the centre of the injury) that first produced a pain reaction as reported by the patient. RESULTS: The primary efficacy variable was the area under the curve for tenderness over the first 3 days. The diclofenac patch was significantly more effective than placebo (p<0.0001). The treatment effect was 64.7 kp h/cm2 (95% confidence interval 48.7 to 80.9) between diclofenac and placebo patches. These results were supported by all secondary efficacy variables. The diclofenac patch produced rapid pain relief as reflected by the time to reach resolution of pain at the injured site which was significantly shorter compared to placebo (p<0.0001). The diclofenac patch was well tolerated. The most frequently observed adverse events were local cutaneous adverse reactions (pruritus, rash) of minor severity occurring with the same frequency as in the placebo group. CONCLUSIONS: A newly developed diclofenac patch is effective and safe for the treatment of blunt impact injuries.
Acute Disease↗
Artesunate and mefloquine given simultaneously for three days via a prepacked blister is equally effective and tolerated as a standard sequential treatment of uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study in Thailand.
The combination of artesunate and mefloquine is currently one of the most effective treatments against multidrug-resistant Plasmodium falciparum malaria. To improve patient compliance to such a combination, the two agents have been combined in a prepacked single blister. Patients were instructed to simultaneously co-administer the drugs once a day for three days. In the present randomized, double-blind, parallel group, comparative, single center study in Thailand, this concept was investigated in 204 adults and children with acute, uncomplicated P. falciparum malaria. Patients were randomized into two treatment groups and received once a day over a three-day period the following: Group A received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, approximately 8.5 mg/kg/day, simultaneously. Group B received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, sequentially (i.e., no mefloquine dose on the first day, 15 mg/kg on the second day, and 10 mg/kg on the third day). Both treatment groups showed no relevant differences in baseline demographic and clinical characteristics. Intent-to-treat analysis revealed a cure rate at day 28 (primary endpoint) of 100% in group A and 99% in group B (difference not significant). The secondary endpoints of mean time to fever clearance (group A = 34 hours, group B = 31 hours) and mean time to parasite clearance (group A = 44 hours group B = 48 hours) were similar between groups (both differences not significant). Tolerability was good in both treatment groups, with no difference in the overall incidence of adverse events. There was a low incidence of nausea/vomiting (4.9% in both groups) and central nervous system side effects (4.9% in group A versus 8.8% in group B). These were comparable between groups and generally of a mild nature. The three-day combination of artesunate and mefloquine (Artequin, Mepha, Ltd., Aesch, Switzerland) with the introduction of mefloquine on day 1 offers a practical dosing regimen that is highly effective and well tolerated in patients of different ages with uncomplicated P. falciparum malaria. It is likely that the prepacked blister approach translates clinically into a better patient compliance, thereby contributing to limit the development of drug resistance.
Adolescent↗
Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.
BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.
Adolescent↗
Memory testing in dementia: how much is enough?
Analyses of eight widely used memory measures (Word List Acquisition and Recall used in the Alzheimer's Disease Assessment Scale and the Consortium to Establish a Registry for Alzheimer's Disease neuropsychology battery, Wechsler Memory Scale-Revised [WMS-R] Logical Memory I and II, WMS-R Visual Reproduction I and II, the memory scores from the Neurobehavioral Cognitive Status Examination [NCSE], memory scores from the Mini-Mental State Examination [MMSE]), and the MMSE total score showed each to have moderate predictive power in differentiating between patients with mild dementia and healthy normal controls. When these instruments were combined in a logistic regression analysis, three of them had substantial predictive power. Together, the Word List Acquisition, WMS-R Logical Memory II, and WMS-R Visual Reproduction II were 97.26% accurate (100% sensitive and 94.59% specific) in distinguishing these two groups. The Word List Acquisition is a brief test that alone had high accuracy (92%). These memory tests are highly useful in the diagnosis of mild dementia.
Aged↗
Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.
BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.
Adolescent↗
Randomized trial of cyclosporine microemulsion (neoral) versus conventional cyclosporine in liver transplantation: MILTON study. Multicentre International Study in Liver Transplantation of Neoral.
BACKGROUND: The new microemulsion formulation of cyclosporine (Neoral) has been developed in an effort to improve the reliability of drug absorption. The objectives of this study were to assess the efficacy, safety, and tolerability of Neoral compared to the original formulation (Sandimmun) in liver transplant recipients. METHODS: In a double-blind, parallel group study conducted in 28 centers across Europe and the United States, patients receiving primary orthotopic liver allografts were randomized within 24 hr of transplantation, 198 to Neoral and 192 to Sandimmun. Patients with and without T-tube biliary drainage were included. Postoperatively, all patients also received intravenous (i.v.) cyclosporine, together with prednisolone and azathioprine. Antibody induction was excluded. Efficacy measures were rejections, graft failure, patient survival, and the efficacy of the study medication in achieving the desired cyclosporine blood levels. Safety was assessed by reported adverse events, blood pressure, serum creatinine, and other routine laboratory measurements. RESULTS: Kaplan-Meier analyses showed that the Neoral group performed better than the Sandimmun group, with the estimates for patients free of treated rejection and histologically confirmed rejection either showing or approaching statistical significance at the 5% level. By 52 weeks, 5.8% (95% confidence limits: -4.4-15.9%) fewer patients required treatment of acute rejection in the Neoral group. The proportion of patients experiencing at least one treated rejection episode by 2 weeks was 29.8% for Neoral and 43.2% for Sandimmun. For histologically confirmed rejection, these proportions were 32.8% and 44.3%, respectively. The proportion of patients experiencing at least one steroid-resistant rejection was 2.0% for Neoral and 6.3% for Sandimmun at week 2, and 3.0% and 9.9%, respectively, at week 3. All these differences were significant at P<0.05. By 52 weeks, graft failure was 6.3% on Neoral and 11.4% on Sandimmun, with respective patient survival figures of 85.4% and 85.8%. The median duration of the initial episode of i.v. cyclosporine was 4.0 days for Neoral, compared to 6.5 days for Sandimmun (P<0.001). Within the first 2 weeks, a larger percentage of patients in the Neoral group reached the lower target level of cyclosporine (P< or =0.01). The weight-adjusted daily doses of study medication were lower in the Neoral group (median dose: 4.86 vs. 5.42 mg/kg/day, P=0.001), but the blood levels of cyclosporine showed no difference. For those with a T-tube, more of the patients on Neoral remained free of treated rejection throughout the study period (P=0.042, Wilcoxon). By week 2, 44.9% of these patients in the Sandimmun group required treatment for rejection compared to 30.2% in the Neoral group (P=0.007). There was no significant difference between the groups for serum creatinine, blood pressure, other biochemical and hematological variables, or reported adverse events. CONCLUSIONS: In liver transplantation in the normal clinical setting, the pharmacokinetic advantages of Neoral translate into clinical superiority over Sandimmun without a negative impact on safety. Recent data indicate that it is not optimal to use i.v. cyclosporine initially in this type of study, but the benefit was seen despite this. In keeping with the previous pharmacokinetic studies, patients managed by T-tube biliary drainage, and hence with no or limited bile available in the gastrointestinal tract, did particularly well with Neoral.
Adult↗
Randomized, double-blind, one-year study of the safety and tolerability of cyclosporine microemulsion compared with conventional cyclosporine in renal transplant patients. International Sandimmun Neoral Study Group.
BACKGROUND: A microemulsion formulation of cyclosporine, Neoral, has been developed to overcome the problems associated with the poor and variable absorption of the traditional oil-based oral formulation, Sandimmune. The present study was conducted to compare the safety and tolerability of Neoral versus Sandimmune in maintenance renal transplant recipients over 1 year, and to assess the number of dose adjustments necessary to maintain trough cyclosporine concentrations within the desired therapeutic range. METHODS. Patients on Sandimmune were randomized to be converted to Neoral (n=373) or remain on Sandimmune (n=93) for 12 months. RESULTS: The proportion of patients needing dose increases to maintain cyclosporine trough levels within the desired range was significantly higher in the Sandimmune group during the first 3 months of the study, whereas the number of patients needing dose reductions was similar in both groups throughout the study period. There were no differences between the groups in terms of changes in blood pressure, serum creatinine levels, or other laboratory parameters. No significant differences in the incidence of adverse events known to be related to cyclosporine were observed between the treatment groups. More adverse events were causally related to Neoral than to Sandimmune by the investigators. However, overall, there were no clinically relevant differences between the treatment groups in the main safety and tolerability variables. CONCLUSIONS: The results of this study in maintenance renal transplant patients suggest that the improved pharmacokinetic characteristics of the microemulsion formulation of cyclosporine, Neoral, may facilitate the clinical management of cyclosporine immunosuppression, compared with the traditional formulation, Sandimmune. Furthermore, there is no evidence that the average improved bioavailability of Neoral has a negative impact on the main safety and tolerability variables, as no significant differences in graft function, the incidence of rejections, and most adverse events were seen.
Creatinine↗
Relative bioavailability of Neoral versus Sandimmune in the presence of a P450IIIA and P-glycoprotein inhibitor.
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
Improving the oral absorption of cyclosporine in malabsorbers: a review of the Neoral Compassionate Need Program.
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Administration, Oral↗
Cyclosporine microemulsion formulation (Neoral) in transplantation: pharmacokinetic/pharmacodynamic relationships.
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Administration, Oral↗
Comparative bioavailability of Neoral and Sandimmune in cardiac transplant recipients over 1 year.
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Administration, Oral↗
Cyclosporine monitoring in patients with renal transplants: two- or three-point methods that estimate area under the curve are superior to trough levels in predicting drug exposure.
The recent introduction of a cyclosporine microemulsion demonstrating less pharmacokinetic variability than the conventional formulation offers the potential for accurately and precisely predicting area under the curve (AUC) with a limited-sampling monitoring strategy. This was studied based on the pharmacokinetic profiles from 55 stable patients with renal transplants who were observed on two occasions at steady state on both formulations. Multiple linear regression analyses were performed on a training dataset from 27 patients, in which combinations of cyclosporine concentrations drawn from 0 to 4 hours postdose were regressed against the full AUC over the dosing interval. Predictor regression equations used concentration combinations ranging from one-point (concentrations at 0, 1, 2, 3, or 4 hours) through five-points (all five concentrations 0 to 4 hours). The predictive performance of these equations was then assessed in the training group with data from a subsequent profiling occasion and in the remaining 28 patients who constituted an independent test group. Prediction bias (mean prediction error) and prediction precision (absolute prediction error) were quantified and compared between formulations. Correlations between predicted and actual AUC were consistently stronger for the microemulsion, suggesting the possibility of more accurate and precise predictions of exposure than from the conventional formulation. For both formulations, the one-point predictors rendered the lowest prediction precision, and predictive performance improved considerably when multiple-point predictors were used. Significantly higher precision and lower variability were observed with the microemulsion for most predictors in the both training and test groups. For the microemulsion, two-point (C0 + C1 or C0 + C2) and three-point (C0 + C1 + C2) predictors yielded relatively unbiased and precise exposure predictions, inasmuch as mean absolute prediction error was less than 10% and 5%, respectively. Hence, a two- or three-point method may provide a clinically important improvement over the use of trough levels in monitoring cyclosporine therapy in patients with renal transplants.
Area Under Curve↗
Brain volume preserved in healthy elderly through the eleventh decade.
OBJECTIVE: To determine which brain regions lose volume with aging over time in healthy, nondemented elderly. BACKGROUND: Cross-sectional studies suggest widespread loss of brain volume with aging. These studies may be biased by significant numbers of preclinically demented elderly in the oldest comparison groups. Longitudinal studies may allow closer determination of the effect of aging unaffected by dementia. METHODS: Quantitative volumetric MRI was performed annually on 46 healthy subjects older than age 65 who had maintained cognitive health a mean of 5 years. Comparisons (analysis of variance) were made of rates of volume loss (slopes) divided into 11 young-old (mean age, 70 years), 15 middle-old (mean age, 81 years), and 20 oldest-old (mean age, 87 years) subjects. Regions of interest included CSF spaces, lobar regions, and limbic-subcortical regions. RESULTS: There were significant differences between groups in intracranial, total brain, left hemisphere, right hemisphere, temporal lobe, basilar-subcortical region, and hippocampus volumes, with oldest-old subjects showing the smallest volumes, followed by middle-old and young-old subjects. Oldest-old subjects had significantly greater subarachnoid volumes than the younger groups. There were no significant differences in rates of change of regions of interest across age groups. CONCLUSIONS: After age 65 there is minimal brain volume loss observed over time in healthy elderly. Brain volume differences seen cross-sectionally, at any age, likely reflect small, constant rates of volume loss with healthy aging. Healthy oldest-old subjects do not show greater rates of brain loss compared with younger elderly, suggesting that large changes seen in cross-sectional studies reflect the presence of preclinical dementia in older groups.
Aged↗
Optimizing the absorption of valspodar, a P-glycoprotein modulator, Part I: Selecting an oral formulation and exploring its clinical pharmacokinetics/dynamics.
Valspodar is a cyclosporine D analog used as a chemotherapy adjunct for modifying multidrug resistance. Two studies were sequentially performed to select an optimal oral formulation and to characterize selected aspects of its clinical pharmacokinetics/dynamics. An initial four-way crossover study with 20 volunteers compared the pharmacokinetics of single fasting administrations of 200 mg by intravenous infusion and 600 mg orally as a conventional oral solution, a microemulsion oral solution, and a microemulsion soft gelatin capsule. The two microemulsion dosage forms demonstrated significantly faster and less variable rates of absorption compared with the conventional oral solution. The microemulsion dosage forms were bioequivalent with absolute bioavailability nearly double that of the conventional oral solution. Based on these results, the microemulsion capsule was further investigated in a four-way randomized crossover study with 24 volunteers who received single fasting administrations of 200, 400, and 600 mg and a 400-mg administration after a fat-rich meal. Dose proportionality in area under the curve (AUC) was demonstrated over this dose range. Administration after a fat-rich meal caused a slight time lag until absorption began, a delay in time to reach the peak concentration, and a moderate increase of 24% in AUC. Serial determinations of total bilirubin were explored as a potential pharmacodynamic marker for P-glycoprotein inhibition. A similar magnitude of reversible hyperbilirubinemia was seen at all dose levels suggesting that P-glycoprotein inhibition in the biliary canaliculi was maximal even at the lowest dose tested. The microemulsion formulation (oral solution or soft gelatin capsule) represents an improved and less variable oral delivery form providing dose-proportional drug exposure over a clinically relevant dose range.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Optimizing the absorption of valspodar, a P-glycoprotein modulator, Part II: Quantifying its pharmacokinetic variability and refining the bioavailability estimate.
A randomized, sequential, bioreplication study was performed with 24 healthy volunteers to assess the pharmacokinetic variability of oral and intravenous administrations of valspodar, a multidrug resistance modulator for use as a chemotherapy adjunct. Subjects received 200 mg as a 2-hour intravenous infusion and 400 mg orally as microemulsion soft gelatin capsules each given on two separate occasions. Following replicate intravenous administrations, reproducibility in peak concentration and area-under-the-curve was demonstrated by interoccasion equivalence testing. Low to moderate inter- and intra-subject pharmacokinetic variability were observed with coefficients of variation ranged from 9% to 19%. Absolute bioavailability from the microemulsion formulation was 60%. Replicate oral administrations demonstrated uniform and repeatable absorption with interoccasion equivalence in peak concentration, time to reach the peak concentration, and area-under-the-curve. Coefficients of inter- and intra-subject variation for these parameters ranged from 10% to 20% indicating low to moderate pharmacokinetic variability. When variabilities were compared between the two routes of administration, the absence of differences indicated that the rate and extent of drug absorption from the microemulsion formulation was as uniform and repeatable as by intravenous infusion.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Cyclosporine and nonsteroidal antiinflammatory drugs: exploring potential drug interactions and their implications for the treatment of rheumatoid arthritis.
A series of clinical pharmacology studies was performed to screen for possible pharmacokinetic/dynamic contributions to drug interactions reported in rheumatoid arthritis patients receiving cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs). No clinically relevant pharmacokinetic changes in any of the drugs were noted when single-dose cyclosporine was coadministered during a steady-state regimen of aspirin, indomethacin, or piroxicam in healthy volunteers. Only with diclofenac was an interaction observed whereby the diclofenac area under the concentration-time curve was doubled in the presence of cyclosporine. Based on the outcomes of the screening studies, steady-state coadministration of both diclofenac and cyclosporine was assessed in rheumatoid arthritis patients, confirming the drug interaction of diclofenac with cyclosporine. Although the drug interaction was accompanied by a significant rise in serum creatinine, there was no apparent concentration-effect relationship, inasmuch as the increase in diclofenac exposure was not related to the magnitude of increase in serum creatinine. Based on the results of these five drug-drug interaction studies and the known biotransformation pathways of nonsteroidal antiinflammatory drugs, it is speculated that the pharmacokinetic interaction, which is unique to diclofenac, is caused by inhibition by cyclosporine of diclofenac's first-pass metabolism. Caution and appropriate clinical monitoring are recommended whenever cyclosporine and NSAIDs are coadministered; however, diclofenac in particular should be administered near the lower end of its therapeutic range when it is initially combined with cyclosporine in the treatment of rheumatoid arthritis.
Anti-Inflammatory Agents, Non-Steroidal↗
Evidence for earlier stabilization of cyclosporine pharmacokinetics in de novo renal transplant patients receiving a microemulsion formulation.
Sequential cyclosporine pharmacokinetic assessments were performed at four centres within the context of a double-blind, multicenter clinical trial comparing the safety and tolerability of the conventional formulation with cyclosporine for microemulsion in de novo renal transplant patients. The initial average daily oral dose was 9.3 mg/kg given in two divided doses every 12 hr with subsequent dose reductions individually titrated to maintain trough concentrations within the target therapeutic range. Pharmacokinetic profiles were assessed at week 2, once between weeks 4-6, and at week 12 in 12 patients on the conventional formulation and 9 patients on the microemulsion. Over the study duration, cyclosporine daily doses were comparable in both study arms and were reduced in parallel from 9.2 to 6.9 to 4.7 mg/kg/day at the three successive pharmacokinetic visits. Dose-normalized peak and area-under-the-curve (AUC) increased between the week 2 and week 4-6 assessments for both formulations. Thereafter, these parameters continued to increase for the conventional formulation but exhibited a high degree of within-in patient stability for the microemulsion between week 4-6 and week 12. Between-formulation comparisons indicated that the rate and extent of cyclosporine absorption from the microemulsion were significantly higher over the study duration. Specifically, at week 2, 4-6 and 12, dose-normalized AUC was 49%, 63%, and 32% higher for the microemulsion. Intrasubject coefficients of variability for pharmacokinetic parameters of the conventional formulation ranged from 26.3% to 68.2%. Corresponding values for the microemulsion were reduced by approximately half, ranging from 13.1% to 38.7%. The correlation between predose trough concentration and AUC was stronger for the microemulsion (r(2)0.819 vs. 0.635) over the full range of systemic exposures attained throughout the study. These results provide initial evidence that, as doses are reduced with time posttransplant, the cyclosporine dose-exposure relationship from the microemulsion may stabilize earlier than that from the conventional formulation, allowing increased pharmacokinetic control over cyclosporine use in this critical posttransplant period.
Administration, Oral↗