Review of cyclosporine pharmacokinetic trials in healthy volunteers and kidney and liver transplant recipients: SangCyA versus neoral and sandimmune

Review of Cyclosporine Pharmacokinetic Trials in Healthy Volunteers and Kidney and Liver Transplant Recipients: . SangCyA Versus Neoral and Sandlmmune TimothyJ. Schroeder,M. Roy First, Rita R. AUoway, Shi-Hui Pan, A. Osama Gaber, Richard R. Lopez, RobertA. Fisher, William D. Irish, Daniel M. Canafax, and Philippe Pouletty SangCyA is a novel cyclosporine formulation that was compared with Neoral and Sandimmune (Novartis Pharmaceutical, E. Hanover, NJ) in various pilot and pivotal trials in healthy volunteers and in transplant patients to assess pharmacokinetic parameters, bioequivalence, and safety end points. Eleven studies compared SangCyA solution and Neoral (Novartis Pharmaceuticals, E. Hanover, NJ) or Sandimmune solutions using various designs. Study conditions in healthy volunteers included fasted and fed conditions, male and female gender, white and black race, TDx, Emit and HPLC assays, different Neoral manufacturing lots, and renal and hepatic transplant recipients. Multiple blood samples were obtained over 36 hours in healthy volunteers and 12 hours in transplant recipients and analyzed using different cyclosporine assays. Pharmacokinetic parameters were estimated using noncompartmental methods. SangCyA and Neoral were bioequivalent in healthy volunteer trials under fasted or fed conditions, in males and females, in whites and blacks, and using any of three assays (TDx, Emit, and HPLC). Bioequivalence and similar safety profiles of Sang-CyA and Neoral were also observed in renal and hepatic transplant recipients. Although Sandimmune and SangCyA were not bioequivalent in renal transplant, patients could be converted safely with a small dose decrease needed to maintain similar drug exposure. SangCyA and Neoral solutions are bioequivalent and interchangeable. Copyright © 1999 by W.B. Saunders Company Key words: Cyclosporine, Neoral, Sandimmune, SangCyA.

he development of a generic cyclosporine program was initiated by SangStat Medical Corporation (Menlo Park, CA) a number of years ago. The goal was to develop a formulation that was bioequivalent to Neoral (Novartis Pharmaceuticals, East Hanover, NJ) but used a new formulation technology that was proprietary and patentable. The Food and Drug Administration defines a generic drug as one with an identical active ingredient and strength and the same route of administration. 1 However, the excipi-

T

From the University of Cincinnati Medical Center, Cincinnati, OH," University of Tennessee,Memphis, TN; St Vincent Medical Center, Los Angeles, CA; SangStat Medical Carp, Menlo Park, CA,"and the Medical Collegeof Virginia,Richmond, VA, .Presentedin part at the XVI] Warld Congressof the Transplantation Society, Montreal, Canada,July 12-17,1998. Address reprint requests to Timothy J. Schroeder, MD, Transplant Division, Dept of Patholog~ and Laboratory Medicine, University of Cincinnati Medical Center,234 GoodmanSt, Cincinnati, 0H45267-0714. Copyright © 1999 by W.B. Saunders Company 0955-470X/99/1303-0002510.00/0

128

ents may be different from the reference product. Bioequivalence is shown in healthy volunteers in controlled trials using a randomized, crossover design. These studies are generally single-dose trials performed after an overnight fast in 18 to 24 healthy, nonsmoking adults. Bioequivalence is assessed using area under the blood concentration time curve (time 0 to the last quantifiable concentration calculated by trapezoidal integration [AUCo-~t], AUC extrapolated to infinity [AUCo--~]) and maximum blood concentration (Cmax). The log normalized ratio of the means must be between 80% to 125% for the generic product compared with the reference product. The cyclosporine development program initially assessed 273 different formulations. 2The most promising underwent in vitro and in vivo testing before trials of humans were initiated. Pilot trials of humans were conducted to optimize study conditions ~(ie, dose, assay, diet, and duration of pharmaeokinetic testing)) This was followed by two pivotal tri~ls

Transplantation Reviews, Vo113, No 3 (Ju~), 1999:pp 128-134

CyclosporinePharmacokineticTrials

performed according to Food and Drug Administration specifications (one under fasting conditions and one under fed conditions)) Further trials of healthy volunteers were conducted to study the effect of sex and race. 4 Finally, trials of transplant recipients were performed to assess pharmacokinetics, safety, and efficacy.5"9This report details the experience of more than 250 healthy volunteers and transplant recipients with SangCya (SangStat Medical Corp, Menlo Park, CA), previously designated as Sang-35.

Methods Study Procedures All studies were performed according to the Declaration of Helsinki and its amendments, following good clinical practice guidelines. All studies were approved by the respective ethics review boards, and all subjects gave written informed consent.

129

Transplant recipient studies. Patients were older than 18 years, with a body weight of 45 to 115 kg. Renal transplant recipients were more than 6 months posttransplantation, whereas hepatic transplant recipients were more than 12 months posttransplantation. Patients had stable renal and hepatic function, with no acute rejection in the previous 6 months. The cyclosporine dose was less than 8 mg/kg/d and unchanged over the previous 15 days. Female transplant recipients had a negative pregnancy test and practiced effective contraception. Patients who received multiorgan transplants, had a history of alcohol or drug abuse, were medically unstable, or were receiving concomitant medications known to affect cyclosporine pharmacokinetics were excluded. Details regarding patient characteristics (number of subjects, study population, sex, and race) and study conditions (diet, cyclosporine dose, pharmacokinetic duration, and assay) are listed in Tables 1 and 2.

Blood Samples and Cyclosporine Analysis

Inclusion Criteria

Healthy volunteer studies. Individuals had to be aged between 19 and 55 years, weigh 50 to 90 kg, and be within ± 15% of their ideal body weight, with no preexisting clinical conditions. Normal findings on physical examination and laboratory tests were required. Subjects had no history of alcohol or drug abuse and a negative urine screen. They could not participate in other clinical studies or donate blood within 30 days of the current study. Subjects could not have received medications known to induce or inhibit hepatic enzymes in the previous 30 days or over-the-counter medications in the 72 hours before the current study. Pregnant and nursing women were excluded, and only women using a medically acceptable form of birth control were enrolled.

In studies of healthy volunteers, blood samples were collected into tubes containing ethylenediaminetetraacetic acid before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, and 36 hours after cyclosporine administration, and in the studies of transplant recipients, before and 1, 1.5, 2, 3, 4, 6, 9, and 12 hours after cyclosporine administration, unless otherwise noted. Gyclosporine blood concentrations were measured using a validated monoclonal antibody-based fluorescence polarization immunoassay (TI~; Abbott Laboratories, Abbott Park, IL), a monoclonal antibody-based enzyme multiplied immunoassay (EMIT; Behring Diagnostics, San Jose, CA), or highperformance liquid chromatography by a central laboratory.

Table 1. Patient Characteristics Study No.

No. of Patients

1 2 3 4 5 6 7A 7B 8 9 10 11 Total

12 8 33 19 25 7 32 12 42 26 25 25 266

Population

Health rvolunteers Health ~volunteers Health rvolunteers Health' rvolunteers Health', volunteers Health pvolunteers Renal transplant recipients Renal transplant recipients Renal transplant recipients Hepatic transplant recipients Healthyvolunteers Healthy volunteers

Sex

Men Men Men Men Women Men Men/women Men/women Men/women Men/women Men/women Men/women

Race

White White White White White Black White/black White/black White/black White/black White White

130

Schroederet al

Table 2. Stud), Conditions Study No.

Diet

CSA Dose (rag)

Pharmacokinetic Duration (h)

Assay

1 2 3 4 5 6 7A 7B 8 9 10 11

Fasted/fed Fasted Fasted Fed Fasted Fasted Fasted Fasted Fasted Fasted Fasted Fed

300 500 500 500 300 500 293 - 114 283 -+ 105 308 - 91 280 + 78 500 500

24 24 36 36 36 36 12 12 12 12 36 36

TDx TDx/EMIT TDx/EMIT TDx TDx TDx TDx/HPLC TDx TDx TDx TDx TDx

Abbreviations:CSA,cyclosporine;TDx, monoclonalantibod)~basedfluorescencepolarizationimmunoassay;EMIT, enzyme-multiplied immunoassay;HPLC,high-performanceliquidchromatography.

Pharmacokinetic Analysis The following noncompartmental pharmacokinetic parameters were determined for each participant and treatment: Cm~, time to maximum concentration (Tma~),AUCo--.t, AUCo--~, apparent elimination rate constant determined by linear regression of the terminal linear portion of the Ln-concentration time curve, apparent terminal half-life, apparent totalbody clearance, and apparent extrapolated volume of distribution.

Statistical Analysis Data were tested for bioequivalence and presented as recommended by the Division of Bioequivalence Guidelines. A parametric general linear model was applied to analyze the pharmacokinetic parameters, using the SAS General Linear Model (GLM) procedure (version 6.08; SAS Institute, Cary, NC). Before analysis, values for Cma~,AUCo-t, and AUCo-~ were log transformed. Analysis of variance included the following: factors sequence, subject within sequence, period, and formulation. The two one-sided hypothesis tests were tested at the 5% level for Cm~.~, AUCo-~t, and AUCo-~ by constructing 90% confidence intervals (CIs) for the ratio of the geometric test and reference means. Calculations of the 90% CIs were performed using the least-square means and standard error estimates from the SAS GLM model. Bioequivalence with respect to a specific pharmacokinetic parameter was concluded if the 90% CI for the true mean ratio was within the range of 80% to 125%.

Results Stud), 1 was conducted in 12 male volunteers under fasted and fed conditions. No differences were seen in AUC, C .... or Tm~ comparing SangCya and Neoral under either fasted or fed conditions (Tables 3, 4, and 5). In study 2, in which a higher dose (500 rag) of SangCya and Neoral were compared in eight healthy men, both the TDx and EMIT assays were used. Similar pharmacokinetics were observed for both SangCya and Neoral irrespective of assay (Tables 3, 4, and 5). However, Cm~ and AUC values measured by TDx were greater than the Cmax and AUC values measured by EMIT, reflecting differences in assay specificity. Study 3 was performed in 36 healthy male volunteers who received a single 500-rag dose of SangCya and Neoral under fasted conditions in a randomized prospective crossover design. Both TDx and EMY]" testing were performed on samples collected from 0 to 36 hours after the dose. SangCya and Neoral had almost identical mean blood concentration time curves. There also were no differences in interindividual variability or in individual changes in AUC when treatment was switched from SangCya to Neoral or vice versa. The pharmacokinetic parameters Cmax (90% CI of the test/reference geometric mean ratio, 97 to 104), AUCo-t (90% CI, 97 to 103), and AUCo-~ (90% CI, 97 to 103) were well within the acceptable criteria for bioequivalence (80% to 125%; Tables 3, 4, and 5). The results obtained using the TDx assay were similar to results obtained with the EMIT assay (data not shown). Study 4 was performed as a three-way crossover design study of 21 male volunteers who received

131

CydosporinePharmacokineticTrials

Table 3. AUC for Various Studies

AUC (ng X h/mL)* Study No.

Sang-35

Neoralt

I Fasted Fed 2 TDx EMIT 3 4 5 6 7A 7B 8 9 10

8,180_ 1,331 8,145 - 1,670 13,929 _ 3,375 12,760 13,900 + 2,470 15,600 - 2,760 8,480 + 1,440 15,100 -+ 2,100 4,120 -+ 1,508 4,550 + 1,858 4,586 + 1,356~ 3,397 + 957 15,030 - 2,996 15,030 + 2,996 17,920 _ 3,659 17,920 - 3,659

7,622 ± 1,311 7,692 _ 1,903 14,118 ± 2,512 12,819 14,000 _+ 2,900 15,300 _+ 2,870 8,820 +- 1,880 17,000 Z 3,410 4,377 -+ 1,579 --3,572 - 1,448 16,130 _ 3,126 16,290 ± 3,141 18,554 _ 4,448 18,272 -+ 4,616

11

Sandimmune

3,468 +- 1,402 4,738 + 1,272

P

90% CI

.308 .485 1.000 .879 .998 .017 .305 .030 .358 .006 .036 .846 .001 .001 .301 .663

92-111 91-109 94-104 96-106 97-103 96-105 92-102 83-96 86-105 113-152 93-99 89-109 90-97 88-97J" 94-104t

Abbreviations:AUC, area under the blood concentrationv time curve; TDx, fluorescencepolarizationimmunoassay;EMIT, enzymemultipliedimmunoassay;CI, confidenceinterval. *Valuesexpressed as arithmetic mean ---SD. For patient studies, the AUC is from 0 to time t and not extrapolatedAUC. "~95%confidenceinterval. :[:Dosenormalized. SangCya and Neoral (500 mg) after a high-fat breakfast (fat, 33 g, ~41% fat; 720 Kcal) and SangCya under fasted conditions. SangCya and Neoral were bioequivalent when administered after a highfat meal. Again, the 90% CIs of the test/reference geometric m e a n ratio for C . . . . AUCo-t, and AUCo---~ were within the 80% to 125% bioequivalence acceptance limits (Tables 3-5). As a third

treatment in study 4 to assess the effect of food on SangCya, participants received Sang-Cya after a 10-hour fast. Similar pharmacokinetics were observed when comparing SangCya administered under fed and fasted conditions, showing that a high-fat meal had no effect on SangCya absorption. Study 5 was performed in 25 healthy female volunteers who received 300 mg of SangCya and

Table 4. Maximum Blood Concentration for Cyclosporine

Cm=(rig~re.L)* Study No.

Sang-35

Neoralt

1 Fasted Fed 2 TDx EMIT 3 4 5 6 7A 7B 8 9 10

1,414 ~ 178 1,503 + 217 2,121 1,453 1,690 - 252 1,670 - 332 1,250 + 275 1,720 ~ 476 890 ± 332 1,079 + 426 870 + 302~: 503 - 146 1,601 -+ 355 1,601 -~ 355 1,849 + 400 1,849 - 400

1,351 +- 132 1,373 _ 320 1,949 1,355 1,700 - 319 1,710 -+ 364 1,340 -+- 299 1,820 -+ 403 994 ± 391

I1

*Valuesexpressedas arithmetic mean +- SD. t95% confidenceinterval. SDose normalized.

Sandimmune

.360 .193

600 + 297 800 - 304 589 -+ 288 1,814 _+ 321 1,830 -+ 369 1,933 _+ 540 1,933 + 456

P

.929 .796 .088 .388 .204 .004 .040 .339 <.00 l <.001 .047 .143

90% CI 92-114 97-118 105-114 103-I 12 97-104 91-104 87-100 81- 108 84-102 134-249 102-118 81-106 84-92 83-92t 90-102# 90-1025-

132

Schroederet al

Table 5. Time to Maximum Blood Concentration for Cyclosporine Tm~ (h) Study No.

Sang-S5

1 Fasted Fed 2 TDx EMIT 3 4 5 6 7A 7B

1.5 -- 0.3 1.6 --- 0.6 1.3 --- 0.3 1.3 1.7 - 0.5 2.2 -+ 0.7 1.9 ± 1.3 2.2 + 1.7 1.4 -- 0.6 1.3 -+ 0.3 1.6 ± 0.8:~ 3.1+-1.2 2.4 ± 1.2 2.4 -+ 1.2 2.7 ± 1.2 2.7 ± 1.2

8

9 10 11

Neoral Sandimmune 1.6 --- 0.4 1.6 + 0.5 1.6 ± 0.6 2 1.8 ± 0.5 1.9-+ 1.2 1.8 ± 0.7 2.3 ± 0.7 1.3 -- 0.4 --2.9±1.6 2.0 +- 0.7 2.4 ± 0.8 2.1 ± 0.9 2.2 ± 0.9

2.4 ± 1.4 2.7 ± 0.9

P .535t .841t .382 .038 .295 .505 .764 1.0 .379 .018 <.001 .562 .905 .905 .005 .029

Note:Values expressedas arithmeticmean + SD. Abbreviations:T~.~,time to maximumbloodconcentration. tWileoxon'srank sum test. :~Dosenormalized.

Neoral in a prospective randomized two-way crossover study. Bioequivalence between the two formulations also was shown in this population (Tables 3-5). The AUC and Cm~ were less for both SangCya and Neoral compared with previous trials (studies 2-4). However, subjects received a higher cyclosporine dose in those studies (500 v 300 mg). Study 6 was conducted in seven black men who received 500 mg of SangCya and Neoral. Pharmacokinetic parameters also were similar in this group of subjects when comparing SangCya and Neoral (Tables 3-5). Study 7A was performed in 32 stable adult renal transplant recipients. This was an open-label, multidose, two-treatment, three-period, crossover study. The study consisted of three l-week administration periods. Subjects receiving Neoral were randomized to one of three sequences: Neoral/SangCya/Neoral, SangCya/Neoral/Neoral, or Neoral/Neoral/SangCya. Dosing with SangCya and Neoral resulted in almost identical cyclosporine pharmacokinetic profiles (Tables 3-5). Safety assessment showed no differences between SangCya and Neoral during the study period. Serum creatinine concentrations before the study initiation and at the end of the study were the same (1.4 + 0.4 mg/dL). The most commonly reported adverse event was headache, with an incidence of 22% after Neoral and 19% after SangCya. Study 7B used an identical study design to Study

7A, with the exception that the 12 stable renal transplant recipients were receiving Sandimmune (Novartis Pharmaceuticals, East Hanover, NJ) instead of Neoral. As expected, this crossover study showed lack of equivalence between SangCya and sandimmune. Significantly greater AUC and Cm~ and shorter Tmax values were observed with SangCya compared with Sandimmune (Tables 3-5). The mean serum creatinine concentrations remained unchanged during the study (1.1 + 0.3 v 1.1 + 0.2 mg/dL). The predominant cyclosporine-related adverse event was headache, with an incidence of 22% after Sandimmune and 19% after SangCya. Study 8 evaluated the safety of switching 42 stable adult renal transplant recipients from Sandimmune to SangCya, using a novel method to adjust cyclosporine doses based on attaining equivalent AUCs. O f the 42 patients entered, 21 patients showed bioequivalence by week 3 (earliest possible time point); an additional 11 patients, by week 4; and 7 more patients, by week 5. Conversion from Sandimmune to SangCya resulted in a significant increase in AUC, C .... and C,~, and an earlier Tmax(Tables 3-5). Dose adjustments based on attaining AUC equivalence resulted in an average 7% decrease in the SangCya dose. Serum creatinine levels and cyclosporine doses and trough levels have remained constant at 1 year after conversion to SangCya. Two episodes of acute rejection (days 144 and 153 after starting SangCya) occurred, and both were steroid responsive (one was related to noncompliance). This study showed that stable patients could be switched safely from Sandimmune to SangCya. Study 9 was a double-blind, randomized trial comparing SangCya and Neoral in 26 stable hepatic transplant recipients. Recipients were an average of 4.1 years posttransplantation. No significant differences were observed in AUC and Cm~.,when comparing patients treated with Neoral and SangCya (Tables 3-5). No serious adverse events occurred, and there were no clinically relevant changes in serum creatinine and bilirubin levels. Studies 10 and I1 were each conducted in 25 healthy adult male and female volunteers. Study design and conduct was similar to studies 3 and 4 with two exceptions; women were included in the study, and subjects received two different lots of Neoral (making it a three-way crossover study: SangCya, Neoral-1, Neoral-2). Again, SangCya and Neoral were found to be bioequivalent in healthy volunteers under both fasting and fed conditions.

CydosporinePharmacokineticTrials

Discussion The development of SangCya, a novel cyclosporine formulation, moved from in vitro studies of stability and compatibility to in vivo assessments of efficacy in a rat orthotopic heart transplant model. This was followed by pharmacokinetic studies in rodents to compare SangCya, Neorai, and Sandimmune. The 16 most promising formulations including SangGya were included in screening studies of healthy volunteers to assess pharmacokinetics. SangCya kinetics were most closely allied to those of Neoral in these screening trials. Before initiating pivotal regulatory trials, pilot studies were conducted to optimize trial conditions, including dose, assay, diet, and duration ofpharmacokinetic testing. The two doses used were 300 and 500 mg of both cyclosporine formulations. A 500-rag dose was chosen for the later pivotal trials because measurable cyclosporine blood levels were found at 12, 24, and 36 hours after this dose, allowing for optimal characterization of the terminal elimination portion of the pharmacokinetic curve. Pilot studies were performed under fasted and fed conditions based on regulatory requirements to show bioequivalence under both conditions for drugs in which a food effect may be expected (ie, cyclosporine).' Two different immunoassays (TDx and EMIT) were used in pilot studies. Although differences in pharmacokinetic parameters were observed when comparing the assays (ie, TDx results were greater for both formulations compared with EMIT results), no formulationderived differences were noted. After completion of these pilot trials, two pivotal regulatory trials were conducted in 33 and 19 healthy male volunteers, respectively. Virtually identical pharmacokinetic parameters were observed when comparing the two formulations,s Bioequivalence was shown under fasting and fed conditions using either TDx or EMIT (data not shown). Confirmatory studies were performed to assess formulation effect on sex and race. It has been suggested that these demographic factors affect the pharmacokinetics of cyclosporine.l°.ll Again, no formulation differences were noted. Whereas studies of healthy volunteers that Show bioequivalence fulfill regulatory requirements, additional pharmacokinetic, efficacy, and safety trials were conducted in transplant recipients. The first two studies (7A and 7B) were short-term studies of 32 and 12 stable renal transplant recipients receiving Neoral and Sandimmune, respectively. After a 1-week exposure, SangCya was found to be bioequivalent to Neoral with a similar safety profile. Also, SangCya

133

was found to have an increased AUC and Cmax and an earlier Tmax than Sandimmune, with a similar safety file. Study 8 was performed in 42 stable renal transplant recipients who have now been followed for more than a year. SangCya was found to be safe and efficacious with only two mild, steroid-responsive rejections reported in the follow-up. This 4.7% rejection incidence is similar to other large trials in which stable renal transplant recipients receiving Sandimmune were switched to Neoral.mS Pharmacokinetic studies performed as part of this trial confirmed that SangCya resulted in a greater AUC and Cmax and a shorter Tmax compared with Sandimmune. However, patients could be safely switched from one formulation to the other with a slight reduction in dose while maintaining similar trough blood levels. Stable hepatic transplant recipients were used in study 9. Reports have suggested that cyclosporine pharmacokinetics are the most variable in this group of patients. 1~,t5As such, this would appear to be the most challenging population to show bioequivalence between Neoral and SangCya. In a double-blind, prospective, randomized, crossover trial, similar pharmacokinetics, safety, and renal and hepatic function were observed when comparing SangCya and Neoral. Studies 10 and 11 were two additional studies conducted in healthy volunteers (both men and women). Two different lots of Neoral were used in three-way crossover designs. Again, SangCya and Neoral were found to be bioequivalent under both fasting and fed conditions. In conclusion, 12 studies performed in more than 250 healthy volunteers and stable renal and hepatic transplant recipients showed that SangCya was bioequivalent to Neoral irrespective of sex, race, dose, dietary conditions, or cyclosporine assay. Also, stable patients could be safely switched from either Sandimmune or Neoral to SangCya.

References 1. UnitedStates Foodand Drug Administration:Bioavallability and bioequivalence requirements. Federal Register 1997, 62:17997 2. SchroederTJ, LevyR, Pouletty,et ah A genericcyclosporine formulation development program. Transplant Proc 1997, 29:1235 3. SchroederTJ, Cho MJ, PollockGM, et al: Comparisonof two cyclosporineformulationsin healthy volunteers:Bioequivalence of the new Sang-35 formulationand Neoral.J Glin Pharm 1998,38:807 4. Johnston A, Keown PA, Holt DW: Simple bioequivalence criteria: Axe they relevant to criticaldose drugs?Experience gained fromcyclosporine.Ther DrugMonit 1997,19:375

134

Schroeder et al

5. First MR, Weiskittel P, Burton M, et al: Conversion of stable renal transplant recipients from Sandimmune to Sang-35, a novel cyclosporineformulation using a dose-normalized equivalence method. Transplant Proc 30:1697, 1998 6. Fisher RA, Pan SH, Lopez RR, et al: Pharmacokinetic and clinical evaluation of Sang-35 and Neoral in stable adult fiver transplant recipients. Transplant Proc 31:394-, 1999 7. AllowayRR, Canafax DM, Schroeder TJ, et ah Bioequivalence of Sang-35 and Neoral for cyclosporine metabolites in stable renal transplant patients. Clin Transplant (in press) 8. Gaston RS, First MR, AllowayRR, et al: Pharmacokinetic and clinical evaluation of Sang-35 vs. Neoral in stable renal transplant recipients. Transplant Proc 31:326, 1999 9. First MR, Alloway RR, Schroeder TJ: Development of Sang35: A cyclosporine formulation bioequivalent to Neoral. Clin Transplant 1998, 12:518 10. Harris RZ, Benet I_,Z,SchwartzJB: Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995, 50:222 11. Schroeder TJ, Hariharan S, First MR: Variations in bioavail-

ability of cyclosporine and relationship to clinical outcome in renal transplant subpopulations. Transplant Proc 1995, 27:837 12. Cole E, Keown P, Landsberg D, et al: Safety and tolerability of cyclosporineand cyclosporinemicroemulsion during 18 months of foUow-up in stable renal transplant recipients: A report of • the Canadian Neoral renal study group. Transplantation 1998, 65:505 13. Offerman G, Korn A: Safety and tolerability of cyclosporine microemulsion formulation (Sandimmune, Neoral) in stable renal transplant patients after 24 months of treatment. Transplant Proc 1996, 28:2204 14. Burckart GJ, Venkataramanan R, Ptachcinski RJ, et al: Cyclosporine pharmacokinetic profiles in liver, heart, and kidney transplant patients as determined by high-performance liquid chromatography. Transplant Proc 1986, 6:129 15. Mehta MU, Venkataramanan R, Burckart GJ, et ah Effect of bile on c),closporin absorption in liver transplant patients. BrJ Clin Pharmacol 1988, 25:579